UNIVERSITY  OF  CALIFORNIA 

MEDICAL  CENTER  LIBRARY 

SAN  FRANCISCO 


PHYSIOLOGY  AND  BIOCHEMISTRY 
IN  MODERN  MEDICINE 


BY 


J.  J.  E.  MACLEOD,  M.B. 

PROFESSOR  OF  PHYSIOLOGY  IN   THE  UNIVERSITY   OF  TORONTO,   TORONTO,   CANADA;    FORMERLY 

PROFESSOR    OF    PHYSIOLOGY    IN    THE    WESTERN    RESERVE    UNIVERSITY, 

CLEVELAND,   OHIO 


ASSISTED  BY 
ROY  G.  PEARCE,  A.  C.  REDFIELD,  AND  N.  B.  TAYLOR 

AND  BY  OTHERS 


FOURTH  EDITION 


WITH  243  ILLUSTRATIONS,  INCLUDING 
9  PLATES  IN  COLORS 


ST.  LOUIS 

C.  V.  MOSBY  COMPANY 
1922 


COPYRIGHT,  1918,  1919,  1920,  1922,  BY  C.  V.  MOSBY  COMPANY 
(All   Rights  Strictly  Reserved) 


(Printed   in   U.    S.   A.) 


Press 

C.  V.  Mosby  ( 
St.  Louis,  i 


TO 
.M.  W.  M. 


PREFACE  TO  FOURTH  EDITION 

The  opportunity  has  been  taken  in  this  edition  to  revise  each  chapter 
so  as  to  incorporate  as  much  as  possible  of  what  has  been  added  to  physi- 
ological knowledge  during  the  past  two  years.  Certain  chapters  have 
been  rewritten,  such  as  those  on  the  output  of  the  heart,  the  conditions 
causing  alterations  in  the  acid  base  equilibrium  of  the  blood,  the  normal 
electrocardiogram  and  the  movements  and  emptying  of  the  stomach. 
Considerable  alterations  have  also  been  made  in  portions  of  other  chap- 
ters so  as  to  permit  of  the  incorporation  of  the  recent  work  on  intra- 
cardiac  pressure,  the,  capillary  circulation,  the  mechanism  of  adaptation 
to  mountain  sickness,  pancreatic  diabetes,  etc.  Several  of  the  figures 
appearing  in  earlier  editions  have  been  replaced  by  others  of  greater 
usefulness.  These  alterations  have  been  made  without  changing  the 
paging  of  the  book. 

The  author  has  again  to  thank  Dr.  N.  B.  Taylor  for  valuable  assist- 
ance in  rewriting  two  of  the  chapters  and  in  reading  the  proof. 

J.  J.  R.  MACLEOD. 

Toronto,  Canada, 
1922. 


PREFACE  TO  THIRD  EDITION 

Many  changes  have  been  made  in  the  present  (third)  edition  of  the 
book.  The  section  on  the  nervous  system  has  been  entirely  recast  and  re- 
written by  my  colleague,  A.  C.  Redfield,  who,  besides  bringing  this  part 
of  the  subject  up  to  date,  has  incorporated  with  it  an  account  of  the 
fundamental  principles  of  neuromuscular  physiology.  Although  no  ap- 
plication of  this  subject  may  at  present  be  apparent  in  the  investigation 
of  disease  it  is  certain  that  such  exists;  but  it  can  be  made  only  after  the 
clinical  researcher  has  become  familiar  with  the  brilliant  work  which 
has  been  done  in  the  field  in  recent  years  by  Keith  Lucas,  Adrian,  and 
others.  It  is  the  function  of  a  volume  of  this  nature  to  describe  not 
merely  what  already  has  been  achieved  in  the  clinical  applications  of 
physiology,  but  also  to  anticipate  where  this  application  is  likely  soon 
to  be  made  and  to  prepare  the  way  by  describing  the  physiological  prin- 
ciples that  may  be  involved. 

Another  section  in  which  complete  changes  have  been  called  for,  is 
that  relating  to  the  chemistry  of  respiration.  This  has  been  rewritten 


VI  PREFACE 

and  rearranged  so  as  to  incorporate  the  recent  work  on  the  effects  of 
deficiency  oi;  oxygen  on  the  respiratory  center,  as  well  as  the  interesting 
and  important  clinical  applications  of  the  subject.  Several  new  chapters 
have  been  added  dealing  with  such  practical  problems  as  the  measure- 
ment of  the  functional  capacity  of  the  heart,  the  principles  of  ventilation 
and  the  therapeutic  value  of  oxygen,  and  the  chapters  on  vitamines,  on 
the  capillary  circulation,  on  surgical  shock,  and  on  the  interpretation  of 
polysphygmograms  have  been  rewritten. 

In  practically  every  other  section  of  the  book  many  additions  have 
been  made,  particularly  in  that  which  deals  with  the  endocrine  organs, 
and  several  new  figures  and  tables  have  been  added.  To  make  room  for 
these  changes  some  of  the  more  technical  details,  appearing  in  the  pre- 
vious editions,  have  been  put  in  small  print  and  some  of  the  figures 
removed.  This  has  been  done  in  order  to  keep  the  volume  as  near  to  its 
original  bulk  as  possible. 

I  wish  to  take  this  opportunity  to  thank  my  colleagues  here  and  else- 
where for  many  valuable  suggestions  and  for  their  encouraging  com- 
ments on  the  book.  I  am  also  greatly  indebted  to  Dr.  N.  B.  Taylor  for 
his  assistance  in  the  preparation  of  this  edition  and  for  reading  the  proofs. 

J.  J.  E.  MACLEOD. 

Toronto,  Canada, 
1920. 


PREFACE  TO  FIRST  EDITION 

The  necessity  of  allotting  the  various  subjects  of  the  medical  curric- 
ulum to  different  periods,  so  that  the  more  strictly  scientific  subjects 
are  completed  in  the  earlier  years,  has  the  great  disadvantage  that  the 
student,  being  no  longer  in  touch  with  laboratory  work,  fails  to  employ 
the  scientific  knowledge  with  full  advantage  in  the  solution  of  his  clin- 
ical problems.  He  is  apt  to  regard  the  first  two  or  three  years  in  the 
laboratory  departments  as  inconsequential  in  comparison  with  the  sup- 
posedly more  practical  instruction  offered  during  the  subsequent  clinical 
years.  He  is  taught  by  his  laboratory  instructors  to  observe  accurately, 
and  to  correlate  the  observed  facts,  so  that  he  may  be  enabled  to  draw 
conclusions  as  to  the  manner  of  working  of  the  various  functions  of  the 
animal  body  in  health,  and  before  proceeding  to  his  clinical  studies,  he 
is  required  to  show  a  proficiency  in  scientific  knowledge,  because  it  is 
recognized  that  this  must  serve  as  the  basis  upon  which  his  knowledge 
of  disease  is  to  be  built.  When  the  clinic  is  reached,  however,  the  meth- 
ods of  the  scientist  are  not  infrequently  cast  aside  and  an  understanding 


PREFACE  Vll 

of  disease  is  sought  for  largely  by  the  empirical  method ;  namely,  by  the 
endeavor  to  see  and  examine  innumerable  patients,  to  diagnose  the  case 
according  to  the  grouping  of  the  signs  and  symptoms,  and  to  treat  it  by 
the  prescribed  methods  of  experience.  So  much  has  to  be  learned  and  so 
much  has  to  be  seen  during  the  clinical  years,  that  the  student  gives  little 
thought  to  the  nature  of  the  functional  disturbance  which  is  responsible 
for  the  symptoms;  he  fails  to  realize  that  after  all,  there  is  no  essen- 
tial difference  between  the  condition  brought  about  in  his  patient  by 
some  pathological  lesion,  and  that  which  may  be  produced  in  the  labora- 
tory by  experimental  procedures,  by  drugs  or  by  toxins.  It  must  of 
course  be  recognized  that  just  as  the  science  of  medicine  originated  by 
the  grouping  of  symptoms  into  more  or  less  characteristic  diseases  for 
which  the  most  favorable  method  of  treatment  had  to  be  discovered  by 
experience,  so  must  a  certain  part  of  the  medical  training  be  more  or 
less  empirical  but  it  should  at  the  same  time  be  realized  that  such  a 
method  is  only  a  means  to  an  end,  and  that  the  real  understanding  of 
disease  can  be  acquired  only  when  every  abnormal  condition  is  inter- 
preted as  a  primary  or  secondary  consequence  of  some  perverted  bodily 
function,  and  when  the  training  in  observation  and  the  inductive  method 
is  carried  from  the  laboratory  into  the  clinic. 

It  is  a  constant  experience  of  clinical  instructors  who  would  employ 
scientific  methods  of  instruction,  that  they  find  the  students  not  only 
indifferent  to  an  analysis  of  their  cases  from  the  functional  standpoint, 
but  also  that  they  are  too  inadequately  prepared  in  fundamental  phys- 
iological knowledge,  to  make  the  analysis  possible.  The  student  may 
have  a  superficial  acquaintance  with  the  main  facts  of  physiological  science 
but  have  failed  to  acquire  the  enquiring  habit  of  mind  which  will  en- 
able him,  through  reflection,  comparison,  and  personal  research,  to  ap- 
ply the  knowledge  in  practical  medicine  and  surgery. 

For  this  lack  of  correlation  between  the  laboratory  and  clinical  stud- 
ies, the  clinical  instructors  are  not  alone  responsible.  The  laboratory 
courses  are  frequently  given  without  any  attempt  being  made  to  show 
the  student  the  bearing  of  the  subject  in  the  interpretation  of  disease, 
or  to  train  him  so  that  in  his  later  years  he  may  be  able  to  adapt  the 
methods  of  investigation  which  he  learned  in  the  laboratory,  to  the  study 
of  morbid  conditions.  It  is  self-evident  that  (without  any  knowledge 
of  disease)  the  extent  to  which  the  student  in  the  earlier  years  of  the 
course  could  be  expected  to  appreciate  the  clinical  significance  of  what 
he  learns  in  the  laboratory  is  limited,  but  this  should  not  deter  the  in- 
structor from  indicating  whenever  he  can,  the  general  application  of 
scientific  knowledge  in  the  interpretation  of  diseased  conditions.  But 


Vlll  PREFACE 

the  chief  remedy  of  the  evil  undoubtedly  lies  partly  in  the  continuance 
of  certain  of  the  laboratory  courses  into  the  clinical  years,  and  partly 
in  the  study  of  medical  literature  in  which  the  application  of  physiology 
and  biochemistry  in  the  practice  of  medicine  is  emphasized. 

Notwithstanding  the  sufficient  number  of  excellent  textbooks  in  phys- 
iology available  to  the  medical  student,  there  is  none  in  which  partic- 
ular emphasis  is  laid  upon  the  application  of  the  subject  in  the  routine 
practice  of  medicine.  In  the  present  volume  the  attempt  is  made  to 
meet  such  a  want,  by  reviewing  those  portions  of  physiology  and  bio- 
chemistry which  experience  has  shown  to  be  of  especial  value  to  the 
clinical  investigator.  The  work  is  not  intended  to  be  a  substitute, 
either  for  the  regular  textbooks  in  physiology,  or  for  those  in  functional 
pathology.  It  is  supplementary  to  such  volumes.  It  does  not  start  like 
the  modern  test  in  functional  pathology,  with  a  consideration  of  the 
diseased  condition,  and  then  proceed  to  analyze  the  possible  causes  and 
consequences  of  this  disturbances  of  function  which  this  exhibits;  but 
it  deals  with  the  present-day  knowledge  of  human  physiology  in  so  far 
as  this  can  be  used  in  a  general  way  to  advance  the  understanding  of 
disease.  In  a  sense  it  is  therefore  an  advanced  text  in  physiology  for 
those  about  to  enter  upon  their  clinical  instruction,  and  at  the  same 
time,  a  review  for  those  of  a  maturer  clinical  experience  who  may- desire 
to  seek  the  physiological  interpretation  of  diseased  conditions. 

In  attempting  to  fulfil  these  requirements,  it  has  been  deemed  essen- 
tial to  go  back  to  the  fundamentals  of  the  subject,  and  to  explain  as 
simply  as  possible  the  physical  and  physicochemical  principles  upon 
which  so  large  a  part  of  physiological  knowledge  depends.  Physiology 
may  be  considered  as  an  application  of  the  known  laws  and  facts  of 
physics  and  chemistry  to  explain  the  functions  of  living  matter,  and  it  is 
only  after  the  extent  to  which  this  application  can  be  made  has  been 
appreciated,  that  the  knowledge  may  be  used  to  serve  as  the  foundation 
upon  which  a  superstructure  of  clinical  knowledge  can  be  built. 

In  order  that  the  volume  might  be  maintained  of  reasonable  size,  it 
has  been  necessary  to  select  certain  parts  of  the  subject  for  particular 
emphasis,  the  basis  of  selection  being  the  degree  to  which  our  knowledge 
clearly  shows  the  value  of  the  application  of  physiological  methods  both 
of  observation  and  of  thought  in  the  study  of  diseased  conditions.  This 
has  not  been  done  to  the  extent  of  omitting  the  apparently  less  essential 
parts,  for  these  have  been  treated  in  sufficient  detail  to  link  the  others 
together  so  as  to  preserve  a  logical  continuity,  and  show  the  bearing  of 
one  field  of  knowledge  on  another.  There  are  however  certain  parts 
of  the  science,  particularly  the  physiology  of  nerve  and  muscle,  of  the 
special  senses,  and  of  reproduction,  for  which  application  in  the  general 
fields  of  medicine  and  surgery  is  limited,  and  these  parts  have  been 


PREFACE  IX 

omitted  entirely.  It  has  been  judged  that  this  perhaps  somewhat  arbi- 
trary selection  is  justified  on  the  ground  that  the  ordinary  text  in 
physiology  covers  these  subjects  sufficiently,  except  for  the  specialist, 
for  whom  on  the  other  hand,  no  adequate  review  would  have  been  pos- 
sible within  the  limits  of  such  a  volume  as  this.  With  reference  to  bio- 
chemistry, no  attempt  is  made  to  review  the  properties  or  describe  the 
characteristic  tests  of  the  various  chemical  ingredients  of  the  body  tis- 
sues and  fluids.  This  is  already  sufficiently  done  in  the  textbooks  on 
biochemistry,  and  in  the  numerous  manuals  on  clinical  methods.  Bio- 
chemical knowledge  is  treated  rather  from  the  physiologist's  stand- 
point, as  an  integral  part  of  his  subject,  particular  attention,  neverthe- 
less, being  paid  to  the  far-reaching  applications  of  this  latest  depart- 
ment of  medical  science,  in  the  elucidation  of  many  obscure  problems 
of  clinical  medicine,  such  as  those  of  diabetes,  nephritis,  acidosis,  goiter 
and  myxedema.  To  make  the  volume  of  value  to  those  who  may  not 
have  had  time  or  opportunity  to  familiarize  themselves  with  the  techni- 
cal methods  of  the  physiologist  and  biochemist  as  used  in  the  modern 
clinic,  a  certain  amount  of  space  is  devoted  to  a  brief  description  of  the 
methods  that  appear  at  present  to  be  receiving  most  attention,  and  to 
be  of  greatest  value. 

Finally,  it  should  be  mentioned  that  the  principles  of  serum  diagnosis 
and  therapy  are  omitted,  since  these  belong  to  a  highly  specialized  science 
requiring  an  intensive  training  of  its  own. 

In  the  hope  that  the  volume  may  be  instrumental  in  arousing  sufficient 
interest  to  stimulate  a  more  intensive  study  of  the  various  subjects 
which  it  introduces,  a  brief  bibliography  is  given  at  the  end  of  each 
section.  The  references  selected  are  to  papers  that  are  more  partic- 
ularly known  to  the  author;  they  are  not  necessarily  the  most  impor- 
tant publications  on  the  subject,  but  are  often  chosen  because  of  the 
useful  reviews  of  previous  work  contained  in  them,  rather  than  because 
of  their  own  originality.  Some  of  the  papers,  however,  are  referred  to 
as  authority  for  statements  of  fact  which  may  arouse  in  the  reader  a 
desire  to  ponder  for  himself  the  evidence  upon  which  these  are  based. 
The  references  are  usually  divided  into  two  groups,  "monographs"  and 
"original  papers,"  and  it  is  only  occasionally  that  specific  reference  is 
made  to  the  former  in  the  context.  The  original  papers,  on  the  other 
hand,  are  referred  to  by  numbers.  "With  the  general  field  of  the  subject 
so  well  covered  by  such  excellent  textbooks  as  Bayliss'  "Principles  of 
General  Physiology,"  Stewart's,  Howell's,  Starling's,  and  Halliburton 's 
"Human  Physiologies,"  and  Leonard  Hill's  "Recent  and  Further  Ad- 
vances in  Physiology,"  the  author  has  felt  free  to  pick  and  choose  from 
the  monographs  and  original  papers,  topics  that  are  ordinarily  passed 
over  cursorily  in  the  textbook,  and  when  this  has  been  done,  the  refer- 


X  PREFACE 

ences  are  somewhat  more  extensive.  Such  is  the  case  for  example  in 
the  chapters  relating  to  the  chemistry  of  respiration,  to  the  metabolism 
of  carbohydrates  and  fats,  to  the  problems  of  dietetics  and  growth,  to  the 
physicochemical  basis  of  neutrality  regulation  in  the  animal  body,  and  to 
the  action  of  enzymes. 

Acknowledgment  is  gratefully  made  for  the  assistance  and  advice 
in  the  preparation  of  the  book,  particularly  to  Doctor  R.  G.  Pearce,  for 
the  contribution  of  several  chapters,  to  which  his  name  is  attached,  and 
for  which  he  is  entirely  responsible;  and  to  Doctor  E.  P.  Carter,  whose 
criticisms,  after  patient  perusal  of  the  unfinished  manuscript,  were  of 
inestimable  value  in  its  final  revision.  Acknowledgment  is  also  made 
to  Doctor  R.  W.  Scott  and  Professor  F.  E.  Lloyd,  for  valuable  criticism 
and  advice,  and  to  the  former  for  a  chapter  on  the  "  Clinical  Applica- 
tion of  Electrocardiographs. "  To  Miss  Achsa  Parker,  M.A.,  the  author 
owes  a  great  debt  of  gratitude  for  the  thorough  and  painstaking  way  in 
which  she  prepared  the  manuscript  for  the  press,  and  for  her  never- 
tiring  endeavors  to  have  the  spelling  and  punctuation  in  conformity 
with  Webster's  Dictionary.  For  assistance  in  the  preparation  of  the 
index  thanks  are  due  to  Miss  Marion  Armour  and  Mrs.  MacFarlane, 
and  for  permission  to  use  certain  of  the  figures  and  illustrations,  to  the 
various  authors  and  publishers  who  granted  it.  For  the  excellent  man- 
agement and  careful  execution  of  the  presswork,  the  author  wishes  to 
thank  the  publishers,  whose  courteous  and  friendly  dealings  have  always 
made  the  work  easier. 

J.  J.  R.  MACLEOD. 

University  of  Toronto, 
Toronto,  Canada. 


CONTENTS 


PART  I 

THE  PHYSICOCHEMICAL  BASIS  OF  PHYSIOLOGICAL 

PROCESSES 

CHAPTER  I                                                           PAGE 
GENERAL    CONSIDERATIONS 1 

The  Laws  of  Solution,  3;  Gas  Laws,  3;  Osmotic  Pressure,  4;  Biological  Meth- 
ods for  Measuring  Osmotic  Pressure,  6;  Hemolysis,  7;  Plasmolysis,  8. 

CHAPTEE  II 
OSMOTIC  PRESSURE   (CONT'D.) 10 

Measurement  by  Depression  of  Freezing  Point,  10;  The  Eole  of  Osmosis,  Dif- 
fusion, and  Allied  Processes  in  Physiological  Mechanisms,  11,  Physical  Fac- 
tors Involved  in  Absorption,  Excretion  and  Lymph  Formation,  13. 

CHAPTEE  III 

ELECTRICAL  CONDUCTIVITY,  DISSOCIATION,  AND  IONIZATION .    .     16 

Determination  of  Conductivity,  17;  Biological  Applications,  19. 

CHAPTEE  IV 

THE  PRINCIPLES  INVOLVED  IN  THE  DETERMINATION  OF  THE  HYDROGEN-ION  CONCEN- 
TRATION     22 

Titrable  Acidity  and  Alkalinity,  22 ;  Actual  Degree  of  Acidity  or  Alkalinity, 
23;  Mass  Action,  23;  Application  to  the  Measurement  of  H-ion  Concentration, 
26;  Application  in  Determining  the  Eeal  Strength  of  Acids  or  Alkalies,  28. 

CHAPTEE  V 

THE  PRINCIPLES  INVOLVED  IN  THE  MEASUREMENT  OF  HYDROGEN-ION  CONCENTRA- 
TION (CONT'D) 29 

The  Electrical  Method,  29 ;  The  Indicator  Method,  32. 

[    CHAPTEE  VI 

KEGULATION  OF  NEUTRALITY  IN  THE  ANIMAL  BODY  AND  ACIDOSIS 36 

Buffer  Substances,  36;   Theory  of  Acidosis,  38;   Measurement  of  the  Eeserve 
Alkalinity,  41;    Titration   Methods,   41;    CO2-Combining   Power,   42;    Indirect 
Methods.  46;   Eelationship  Between  CO2-content  of  Blood  and  Hydrogen-ion 
Concentration,  49. 

CHAPTEE  VII 
COLLOIDS       51 

Characteristic  Properties,  51;  Characteristics  of  True  Colloidal  Solutions,  52; 
Tyndall  Phenomenon,  52;  Eelative  Indiffusibility,  52;  Electrical  Properties, 
56;  Brownian  Movement,  58;  Osmotic  Pressure,  58. 


xii  CONTENTS 

CHAPTER  VIII  PAGE 

COLLOIDS    (CONT'D)       61 

Suspensoids  and  Emulsoids,  61;  Gelatiuization,  62;  Imbibition,  63;  Action  of 
Electrolytes  on  Colloids,  63;  Proteins  as  Colloids,  64;  Surface  Tension,  65; 
Adsorption,  66;  Reactions  which  Depend  on  Adsorption,  67;  Conditions  that 
Influence  or  are  Influenced  by  Adsorption,  68;  Biological  Processes  Depend- 
ing on  Adsorption,  70. 

CHAPTER  IX 

FERMENTS,  OB  ENZYMES 71 

The  Nature  of  Enzyme  Action,  72;  Properties  of  Enzymes,  73;  Reversibility 
of  Enzyme  Action,  77;  Specificity  of  Enzyme  Action,  79;  Peculiarities  of 
Enzymes,  80;  Types  of  Enzyme,  81;  Enzyme  Preparations,  82;  Conditions  for 
Enzymic  Activity,  82. 


PART  II 
THE  BLOOD  AND  THE  LYMPH 

CHAPTER  X 

BLOOD:     ITS  GENERAL  PROPERTIES    (BY  R.   G.  PEARCE) 85 

Quantity  of  Blood  in  the  Body,  85;  Water  Content,  87;  Proteins,  88;  Fer- 
ments and  Antiferments,  90. 

CHAPTER  XI 

THE  BLOOD  CELLS    (BY  R.   G.  PEARCE) 92 

Red  Blood  Corpuscles,  or  Erythrocytes,  92 ;  Origin,  93 ;  Rates  of  Regeneration, 
94;  Hemolysis,  96;  Leucocytes,  97;  Blood  Platelets,  98. 

CHAPTER  XII 

BLOOD   CLOTTING       99 

Visible  Changes  in  the  Blood  During  Clotting,  99;  Methods  of  Retarding 
Clotting  of  Drawn  Blood,  100;  Nature  of  the  Clotting  Process,  102;  Influence 
of  Calcium  Salts,  104;  Influence  of  Tissues,  105. 

CHAPTER  XIII 

BLOOD  CLOTTING  (CONT'D) 107 

Theories  of  Blood  Clotting,  107 ;  Intravascular  Clotting,  108 ;  Measurement  of 
the  Clotting  Time,  109;  Blood  Clotting  in  Various  Physiological  Conditions, 
111;  Blood  Clotting  in  Disease,  111;  Hemorrhagic  Diseases,  113;  Thrombus 
Formation,  113. 

CHAPTER  XIV 

LYMPH  FORMATION  AND  CIRCULATION — CEREBROSPINAL  FLUID 115 

General  Considerations,  115;  Experimental  Investigations,  118;  Edema,  120; 
Cerebrcspinal  Fluid,  121. 


CONTENTS  XI 11 


PART  III 
CIRCULATION  OF  THE  BLOOD 

CHAPTER  XV  «  PAGE 

BLOOD  PRESSURE 124 

The  Mean  Arterial  Blood  Pressure,  125;  Mercury  Manometer  Tracings,  125; 
Spring  Manometer  Tracings,  128;  Clinical  Measurements,  129. 

CHAPTEE  XVI 

THE  FACTORS  CONCERNED  IN  MAINTAINING  THE  BLOOD  PRESSURE 135 

Pumping  Action  of  the  Heart,  135;  Peripheral  Resistance,  135;  Amount  of 
Blood  in  the  Body,  138;  Effects  of  Hemorrhage  and  Transfusion,  140;  Vis- 
cosity of  the  Blood,  141;  Elasticity  of  Vessel  Walls,  143. 

CHAPTER  XVII 
THE  ACTION  OP  THE  HEART 145 

The  Pumping  Action  of  the  Heart,  145;  Intracardiac  Pressure  Curves,  146; 
Comparison  of  the  Curves,  148. 

CHAPTER  XVIII 

THE  PUMPING  ACTION  OF  THE  HEART  (CONT'D) 151 

Contour  of  the  Intracardiac  Curves,  151;  Ventricular  Curve,  151;  Auricular 
Curve,  153;  The  Mechanism  of  Opening  and  Closing  of  the  Valves,  154;  The 
Heart  Sounds,  156;  Causes  of  Sounds.  157;  Record  of  Heart  Sounds  (Elec- 
trophonograms),  158. 

CHAPTER  XIX 

THE   NUTRITION    OF    THE    HEART 161 

Blood  Supply,  161;  Perfusion  of  the  Heart  Outside  the  Body,  161;  Heart- 
Lung  Preparation,  163;  Resuscitation  of  the  Heart  in  Situ,  165;  Relationship 
of  the  Chemical  Composition  of  the  perfusion  Fluid  in  Cold-blooded  and 
Warm-blooded  Hearts,  166. 

CHAPTER  XX 

PHYSIOLOGY   OF   THE    HEARTBEAT 170 

Origin  and  Propagation  of  the  Beat,  170;  Physiological  Characteristics  of 
Cardiac  Muscle,  170;  Myogenic  Hypothesis,  171;  Neurogenie  Hypothesis, 
172;  The  Pacemaker  of  the  Heart  and  Heart-block,  174;  Physiological  Char- 
acteristics of  Cardiac  Muscle,  176. 

CHAPTER  XXI 

PHYSIOLOGY  OF  THE  HEARTBEAT  (CONT'D) 182 

Origin  and  Propagation  of  the  Beat  in  the  Mammalian  Heart,  182;  Conduct- 
ing Tissue  in  Mammalian  Heart,  182;  Site  of  Origin  of  Beat,  187. 

CHAPTER  XXII 

PHYSIOLOGY   OF   THE   HEARTBEAT    (CONT'D) 191 

Mode  of  Propagation  in  the  Auricles  and  from  the  Auricles  to  the  Ventricles, 
191;  Spread  of  Beat  in  the  Ventricle,  193;  Fibrillation  of  the  Ventricles  and 
Auricles,  195. 


XIV  CONTENTS 

CHAPTER  XXIII  PAGE 

THE  BLOODFLOW  IN  THE  ARTERIES 198 

The  Pulses,  198;  General  Characteristics,  198;  Eate  of  Transmission  of  Pulse 
Waves,  198;  Contour  of  the  Pulse  Curves,  200;  Velocity  Pulse,  200;  Palpable 
Pulse^202;  Analysis  of  the  Curve,  202;  The  Dicrotic  Wave,  203;  Causes  of 
Disappearnce  of  the  Pulse  in  the  Veins,  205. 

CHAPTER  XXIV 

RATE  OF  MOVEMENT  OF  THE  B-LOOD  IN  THE  BLOOD  VESSELS 206 

Velocity  of  Flow  in  a  Vessel,  206;  Mass  Movement  of  the  Blood  in  a  Vas- 
cular Area,  208;  The  Visceral  Bloodflow  in  Man,  212;  Circulation,  212;  Work 
of  the  Heart,  213;  Circulation  Time,  214;  Movement  of  Blood  in  the  Veins, 
214. 

CHAPTER  XXV 

THE  OUTPUT  OF  THE  HEART  IN  RELATION  TO  THE  VENOUS  INFLOW,  CHANGE  OF 

RATE,  'ETC 216 

Output  of  the  Heart  per  Beat,  216;  Effect  of  Alteration  in  Rate  of  Heart 
Beat  on  Output  of  Blood,  218;  Dilatation  and  Tonus,  219;  Dynamics  of  Cir- 
culation, 219;  Reserve  Power  of  the  Heart,  220;  Testing  Cardiac  Efficiency, 
220. 

CHAPTER  XXVI 

THE  CONTROL  OF  THE  CIRCULATION 221 

Nerve  Control,  222;  Vagus  Control  in  the  Cold-blooded  and  the  Mammalian 
Heart,  222;  Tonic  Vagus  Action,  226;  Afferent  Vagus  Impulses,  227;  Mech- 
anism of  Action  of  Vagus  on  the  Heart,  229;  Termination  of  the  Vagus  Fi- 
bers in  the  Heart,  230 ;  Sympathetic  Control,,  232. 

CHAPTER  XXVII 

THE  CONTROL  OF  THE  CIRCULATION  (OONT'D) 234 

Nerve  Control  of  the  Peripheral  Resistance,  234;  Detection  of  Constriction 
or  Dilatation,  234;  Detection  of  Vasomotor  Fibers  in  Nerves,  236;  Origin  of 
Vasomotor  Nerve  Fibers,  237;  Vasomotor  Nerve  Centers,  240;  Independent 
Tonicity  of  Blood  Vessels,  241. 

CHAPTER  XXVIII 

THE  CONTROL  OF  THE  CIRCULATION   (CONT'D) 242 

Control  of  the  Vasomotor  Center,  242;  Hormone  Control,  242;  Nerve  Control, 
243;  Pressor  and  Depressor  Impulses,  243;  Reciprocal  Innervation  of  Vas- 
cular Areas,  247;  Influence  of  Gravity  on  the  Circulation,  248;  Capillary 
Circulation,  251. 

CHAPTER  XXIX 

PECULIARITIES  OF  BLOOD  SUPPLY  IN  CERTAIN  VISCERA 254 

Circulation  in  the  Brain,  254;  Anatomical  Peculiarities,  254;  Physical  Condi- 
tions of  the  Intracranial  Circulation,  256;  Physiological  Conditions  of  the  In- 
tracranial  Circulation,  258;  Vasomotcr  Nerves,  262;  Intracranial  Pressure, 
263;  Circulation  through  the  Lungs,  264;  Circulation  Through  the  Liver, 
265;  The  Coronary  Circulation,  267. 

CHAPTER  XXX 

CLINICAL  APPLICATIONS  OF  CERTAIN  PHYSIOLOGICAL  METHODS 270 

Electrocardiograms,  270;  Interpretation  of  Electrocardiograms  by  the  Triangle 
Method,  271;  The  Ventricular  Complex,  274. 


CONTENTS  XV 

CHAPTER  XXXI  PAGE 

CLINICAL  APPLICATIONS  OF  CERTAIN  PHYSIOLOGICAL  METHODS  (CONT'D)  .  .  .  278 
Electrocardiograms  in  the  More  Usual  Forms  of  Cardiac  Irregularities,  278; 
Sinus  Arrhythmia,  278;  Sinus  Bradycardia,  278;  The  Extrasystoles,  278; 
Paroxysmal  Tachycardia,  281;  Auricular  Fibrillation,  281;  Auricular  Flutter, 
281;  Heart-Block,  282;  Ventricular  Hypertrophies  and  Defects  of  the  Divi- 
sions of  the  A-V  Bundle,  284. 

CHAPTER  XXXII 

CLINICAL  APPLICATIONS  OF  CERTAIN  PHYSIOLOGICAL  METHODS    (CONT'D)     .     .     .     285 
Polysphygmograms,  285;  Venous  Pulse  Tracings,  285;  Abnormal  Pulses,  291. 

CHAPTER  XXXIII 

CLINICAL  APPLICATIONS  OF  CERTAIN  PHYSIOLOGICAL  METHODS    (CONT'D)     .     .     .    296 
Measurement  of  the  Mass  Movement  of  the  Blood,  296;   The  Normal  Flow, 
297;   Clinical  Conditions  Which  Affect  the  Bloodflow,  298. 

CHAPTER  XXXIV 

SHOCK 301 

Varieties  of  Shock,  301;'  Experimental  Investigations  of  Shock,  304;  Hista- 
mine  Shock,  307;  Traumatic  Toxemia  Factor  in  Shock,  309;  Cause  of  Second- 
ary Symptoms,  310;  Treatment  and  Prognosis,  311. 


PART  IV 
RESPIRATION 

CHAPTER  XXXV 
RESPIRATION 316 

Mechanics  of  Respiration,  316;  Pressure  of  the  Air  in  the  Lungs,  316;  Respir- 
atory Tracings,  320;  The  Intrapleural  Pressure,  321;  Influence  on  Blood 
Pressure,  323. 

CHAPTER  XXXVI 

THE  MECHANICS  OF  RESPIRATION   (CONT'D)    (BY  R.  G.  PEARCE) 327 

Variations  in  Dead  Space,  Residual  Air  and  Mid  and  Vital  Capacities  in 
Various  Physiological  and  Pathological  Conditions,  327. 

CHAPTER  XXXVII 

THE  MECHA.NICS  OF  RESPIRATION  (CONT'D) 332 

Mechanism  of  the  Changes  in  Capacity  of  the  Thorax  and  Lungs,  332;  The 
Movements  of  the  Ribs,  332;  The  Action  of  the  Musculature  of  the  Ribs,  336; 
The  Action  of  the  Diaphragm,  337;  The  Effects  of  the  Respiratory  Movements 
on  the  Lungs,  342. 

CHAPTER  XXXVIII 

THE  CONTROL  OF  THE  RESPIRATION 344 

The  Respiratory  Centers,  344;  Reflex  Control  of  the  Respiratory  Center,  348. 


XVI  CONTENTS 

CHAPTER  XXXIX  PAGE 

THE  CONTROL  OF  KESPIRATION  (CONT'D) 352 

Hormone  Control  of  the  Eespiratory  Center,  352;  Tension  of  CO2  and  O2  in 
Arterial  Bloorl,  354;  Tension  of  CO2  and  O2  in  Alveolar  Air,  356;  Tension 
of  CO2  and  O2  in  Venous  Blood,  359 ;  Fallacies  in  Estimation  of  the  Alveolar 
Gases,  361. 

CHAPTER  XL 

THE  CONTROL  OF  RESPIRATION  (CONT'D) 363 

Variations  in  the  Alveolar  CO2  and  the  Acid  Base  Balance  in  Health  and 
Disease,  363. 

CHAPTER  XLI 

THE   CONTROL    OF   RESPIRATION    (CONT'D) 366 

The  Nature  of  the  Respiratory  Hormone,  366;  Relationship  between  CO.,  of 
Inspired  Air  and  Pulmonary  Ventilation,  367 ;  Possibility  that  CO2  Specifically 
Stimulates  the  Center,  368;  Relationship  between  Alveolar  CO2  and  Respira- 
tory Activity,  371. 

CHAPTER  XLII 

THE    CONTROL   OF    RESPIRATION    (CONT'D) 373 

Alveolar  CO,  Tension  in  Conditions  of  Anoxemia,  373;  Constancy  of  the  Al- 
veolar CO2  Tension  under  Normal  Conditions,  373;  The  Nature  of  Changes 
Produced  in  the  Body  in  Anoxemia,  378. 

CHAPTER  XLIII 

THE    CONTROL   OF   RESPIRATION    (CONT'D) 382 

Apnea,  382;  Periodic  Breathing,  385;  Types  of  Periodic  Breathing,  385; 
Causes  of  Periodic  Breathing,  386. 

CHAPTER  XLIV 

RESPIRATION  BEYOND  THE  LUNGS 391 

Transportation  of  Gases  by  tlje  Blood,  392;  Transportation  of  Oxygen,  392; 
Dissociation  Curve  of  CO2,  396;  Difference  between  Curves  of  Blood  and 
Hemoglobin  Solutions,  396;  Rate  of  Dissociation,  399;  Dissociation  Constant, 
401. 

CHAPTER  XLV 

RESPIRATION   BEYOND   THE   LUNGS    (CONT'D) 403 

Means  by  Which  the  Blood  Carries  the  Gases,  403;  Oxygen  Requirement  of 
the  Tissues,  408;  Mechanism  by  which  the  Demands  of  the  Tissues  for  Oxy- 
gen are  met,  412. 

CHAPTER  XLVI 

THE  PHYSIOLOGY  OF  BREATHING  IN  RAREFIED  AND  COMPRESSED  AIR 415 

Mountain  Sickness,  415;  Compressed  Air  Sickness  (Caisson  Disease),  420; 
Application  of  Foregoing  Laws  in  Practice,  424. 

CHAPTER  XLVII 
ADAPTATIONS  OF  THE  CIRCULATORY  AND  RESPIRATORY  SYSTEMS  DURING  MUSCULAR 

EXERCISE 427 

Circulatory  Changes  Accompanying  Muscular  Exercise,  427;  Mechanical  Fac- 
tors, 428;  Nervous  Factor,  430;  Hormone  Factor,  431. 


CONTENTS  XV11 

CHAPTEE  XLVIII  PAGE 

ADAPTATIONS  OF  THE  CIRCULATORY  AND  RESPIRATORY  MECHANISMS  DURING  MUS- 
CULAR EXERCISE  (CONT'D) 435 

The  Effect  of  Muscular  Exercise  on  the  Composition  of  the  Alveolar  Air,  435 ; 
Second-Wind,  438;  Influence  of  Oxygen,  439;  After  Effects,  440;  Effort  Syn- 
drome, 441. 

CHAPTER  XLIX 

OXYGEN  UNSATURATION  OF  THE  BLOOD  CYANOSIS.     THE  THERAPEUTIC  VALUE  OF 

OXYGEN 443 

Oxygen  Unsaturation  of  the  Blood,  443;  Therapeutic  Value  of  Oxygen,  445. 


PART  V 
DIGESTION 

CHAPTER  L 

GENERAL  PHYSIOLOGY  OF  THE  DIGESTIVE  GLANDS 453 

Microscopic  Changes  During  Activity,  453;  Mechanism  of  Secretion,  455; 
Other  Changes  During  Activity,  456;  Control  of  Glandular  Activity,  457; 
Nervous  Control,  458. 

CHAPTER  LI 

PHYSIOLOGY  OF  THE  DIGESTIVE   GLANDS    (CONT'D) 460 

Hormone  Control,  460;  Nervous  Control  of  Pancreas,  462. 

CHAPTER  LII 

PHYSIOLOGY  OF  THE  DIGESTIVE  GLANDS    (CONT'D) 465 

Normal  Conditions  of  Secretion,  465 ;  Normal  Secretion  of  Saliva,  466 ;  Se- 
cretion of  Gastric  Juice,  467;  The  Intestinal  Secretions,  476. 

CHAPTER  LIII 
THE  MECHANISMS  OF  DIGESTION 478 

Mastication,  478;  Deglutition  or  Swallowing,  479;  The  Cardiac  Sphincter, 
482;  Vomiting,  483. 

CHAPTER  LIV 

THE  MECHANISMS  OF  DIGESTION  (CONT'D) 485 

Movements  of  the  Stomach,  485;  Character  of  the  Movements,  485;  Effect  of 
the  Stomach  Movement  on  the  Food,  488;  Emptying  of  the  Stomach,  491; 
Control  of  the  Pyloric  Sphincter,  491 ;  Influence  of  Pathological  Conditions  on 
the  Emptying,  494;  Gastroenterostomy,  494. 

CHAPTER  LV 

THE  MECHANISMS  OF  DIGESTION  (CONT'D) 497 

Movements  of  the  Intestines,  497;  Movements  of  the  Small  Intestine,  497; 
Movements  of  the  Large  Intestine,  503;  Effect  of  Clinical  Conditions  on  the 
Movements,  504. 


XV111  CONTENTS 

CHAPTER  LVI  PAGE 

HUNGER,  APPETITE  AND  THIRST 506 

Hunger,  506;  Bemote  Effects  of  Hunger  Contractions,  509;  Hunger  During 
Starvation,  510;  Control  of  Hunger  Mechanism,  5-11;  Thirst,  514;  Sensation 
of  Thirst,  514. 

CHAPTER  LVII 
BIOCHEMICAL  PROCESSES  OP  DIGESTION 515 

Digestion  in  the  Stomach,  515;  .Functions  of  Hydrochloric  Acid,  516;  Amount 
of  Acid,  516;  Source  of  Acid,  517;  Action  of  Pepsin,  519;  Clotting  of  Milk 
in  the  Stomach,  521. 

CHAPTER  LVIII 

BIOCHEMICAL   PROCESSES   OF   DIGESTION    (CONT'D) 523 

Digestion  in  the  Intestines,  523;  Pancreatic  Digestion,  523;  The  Bile,  526; 
Chemistry  of  Bile,  528. 

CHAPTER  LIX 

BACTERIAL  DIGESTION  IN  THE  INTESTINE 533 

Bacterial  Digestion  of  Protein,  535;  Botulism,  537. 


PART  VI 
THE  EXCRETION  OF  URINE 

CHAPTER  LX 

THE  EXCRETION  OF  URINE  (By  R.  G.  P'EARCE) 541 

Structure  of  Kidney,  541;  Mechanism  of  the  Excretion  of  Urine,  544; 
Theories  of  Renal  Function,  545;  Diuretics,  552;  Albuminuria,  552;  Influence 
of  the  Nervous  System  on  the  Excretion  of  Urine,  553. 

CHAPTER  LXI 

THE  AMOUNT  AND  COMPOSITION  OF  THE  URINE  IN  HEALTH  AND  DISEASE  (By  R.  G. 

PEARCE) 555 

Amount,  556;  Specific  Gravity,  556;  Depression  of  Freezing  Point,  557; 
Reaction,  558;  Solid  Constituents,  560;  Quantitative  Changes  in  the  Blood  and 
Urine  in  Disease,  567. 


PART  VII 
METABOLISM 

CHAPTER  LXII 
METABOLISM 570 

Energy  Balance,  571;  Methods  for  Measuring  Energy,  572;  Normal  Values, 
573;  Standard  for  Comparison,  575;  Influence  of  Age  and  Sex,  577;  Influence 
of  Diseases,  578;  Material  Balance  of  the  Body,  579;  Methods  for  Measur- 
ing Outputs,  579. 


CONTENTS  XIX 

CHAPTER  LXIII  PAGE 

THE    CARBON    BALANCE 582 

Respiratory  Quotient,  582;  Influence  of  Diet,  582;  Influence  of  Metabolism, 
584;  Magnitude  of  the  Respiratory  Exchange,  585;  Influence  of  Body  Tem- 
perature, 586. 

CHAPTER  LXIV 
A   CLINICAL  METHOD  FOR  DETERMINING  THE   RESPIRATORY   EXCHANGE   IN   MAN 

(BY  R.  G.  PEARCE) 589 

The  Mouthpiece,  589;  The  Valves,  590;  Tissot  Spirometers,  591;  Douglas 
Bag,  592;  Haldane  Gas  Apparatus,  593;  Calculations,  596. 

CHAPTER  LXV 
STARVATION       600 

Excretion  of  Nitrogen,  600;  Energy  Output,  602;  Nitrogenous  Metabolites, 
602;  Excretion  of  P'urines,  603;  Excretion  of  Sulphur,  603;  Normal  Metab- 
olism, 604;  Nitrogenous  Equilibrium,  605;  Protein  Sparers,  605. 

CHAPTER  LXVI 

NUTRITION  AND   GROWTH       608 

The  Food  Factor  of  Growth,  608;  Relationship  of  Proteins  to  Growth  and 
Maintenance  of  Life,  609. 

CHAPTER  LXVII 

NUTRITION  AND  GROWTH  (CONT'D) 617 

Relationship  of  Carbohydrates  and  Fats  to  Growth,  617;  Accessory  Food  Fac- 
tors, or  Vitamines,  618. 

CHAPTER     LXVIII 

DIETETICS 625 

Calorie  Requirement,  625;  The  Protein  Requirement,  627;  Accessory  Food 
Factors,  630;  Digestibility  and  Palatability,  630. 

CHAPTER  LXIX 
THE  METABOLISM   OF  PROTEIN       632 

Introductory,  632;  Chemistry  of  Protein  and  of  the  Amino  Acids,  633. 

CHAPTER  LXX 

THE  METABOLISM  OF  PROTEIN  (CONT'D) 641 

Amino  Acids  in  the  Blood  and  Tissues,  641 ;  Fate  of  the  Amino  Acids,  645. 

CHAPTER  LXXI 

THE  METABOLISM  OF  PROTEIN  (CONT'D) 647 

End  Products  of  Protein  Metabolism,  647 ;  Urea  and  Ammonia,  649 ;  Urea 
Ratio,  650 ;  Influence  of  Liver  on  Ammonia-Urea  Ratio,  651 ;  Perfusion  of  Or- 
gans, 652;  Clinical  Observations,  654. 

CHAPTER  LXXII 
THE  METABOLISM  OF  PROTEIN  (CONT'D) 656 

Creatine  and  Creatinine,  656;  Essential  Chemical  Facts,  656;  Metabolism, 
657 ;  Influence  of  Food,  Age,  and  Sex,  657 ;  Origin  of  Creatine  and  Creatinine, 
659. 


XX  CONTENTS 

CHAPTER  LXXIII  PAGE 

THE  METABOLISM  OF  PROTEIN  (CONT'D) 662 

Undetermined  Nitrogen  and  Detoxication  Compounds,  662;  Ethereal  Sul- 
phates and  Glycuronates,  665. 

CHAPTER  LXXIV 

URIC  ACID  AND  THE  PURINE  BODIES 667 

Chemical  Nature  of  the  Purines,  667;  Chemical  Nature  of  the  Substances  Con- 
taining Purine  and  Pyrimidine  Bases,  669;  History  of  Nucleic  Acid  in  the 
Animal  Body,  671 ;  Balance  Between  Intake  and  Output  of  Purine  Substances 
under  Various  Physiological  and  Pathological  Conditions,  674. 

CHAPTER  LXXV 

URIC  ACID  AND  THE  PURINE  BODIES  (CONT'D) 676 

Source  of  Endogenous  Purines,  676;  Influence  of  Various  Physiological  Con- 
ditions, of  Drugs,  and  of  Disease  on  the  Endogenous  Uric-acid  Excretion, 
680;  Uric  Acid  of  Blood,  681. 

CHAPTER  LXXVI 

THE  METABOLISM  OF  THE  CARBOHYDRATES 685 

Capacity  of  the  Body  to  Assimilate  Carbohydrates,  685;  Assimilation  Limits, 
685;  Tolerance  of  the  Body  for  Glucose,  688;  Digestion  and  Absorption,  689; 
Sugar  Level  in  the  Blood,  690;  Value  of  Blood  Examination  in  Diagnosis  of 
Diabetes,  691;  Relationship  Between  Sugar  Concentration  of  the  Blood  and 
the  Occurrence  of  Glycosuria,  692. 

CHAPTER  LXXVII 

THE  METABOLISM  OF  THE  CARBOHYDRATES  (CONT'D) 694 

Fate  of  Absorbed  Glucose.  Gluconeogenesis,  694;  Storage  of  Sugar,  694; 
Sources  of  Glycogen,  694;  Gluconeogenesis  in  Normal  Animals,  699. 

CHAPTER  LXXVIII 

THE  METABOLISM  OF  THE  CARBOHYDRATES    (CONT'D) 701 

Fate  of  Glycogen,  701;  Regulation  of  the  Blood  Sugar  Level,  703;  Nerve  Con- 
trol and  Nervous  Experimental  Diabetes,  704;  Nervous  Diabetes  in  Man,  706; 
Hormone  Control  and  Permanent  Diabetes,  707;  Utilization  of  Glucose  in  Tis- 
sues, 708;  Diabetes  and  the  Ductless  Glands,  710;  Relationship  of  Pancreas 
to  Sugar  Metabolism,  710;  Pathogenesis  of  Pancreatic  Diabetes,  712;  Dia- 
betic Acidosis  or  Ketosis,  715;  Starvation  Treatment,  716. 

CHAPTER     LXXIX 

FAT    METABOLISM 718 

Chemistry  of  Fatty  Substances,  718;  Digestion  of  Fats,  721;  Absorption  of 
Fats,  722. 

CHAPTER  LXXX 
FAT    METABOLISM    (CONT'D) 726 

Fat  of  Blood,  726;  Methods  of  Determination,  726;  Variations  in  Blood  Fat, 
727;  Depot  Fat,  730;  Fat  in  the  Liver,  731. 


CONTENTS  XXI 

CHAPTER  LXXXI  PAGE 

FAT   METABOLISM    (CONT'D) 736 

Production  of  Fatty  Acid  out  of  Carbohydrate,  736;  Method  by  which  the 
Fatty  Acid  is  Broken  Down,  737. 

CHAPTER  LXXXII 

CONTROL  OF  BODY  TEMPERATURE  AND  FEVER 742 

Variations  in  Body  Temperature,  742 ;  Factors  in  Maintaining  the  Body  Tem- 
perature, 743;  Control  of  Temperature,  747;  Fever,  748;  Mechanism  of  Fever, 
748;  Changes  in  the  Body  During  Fever,  750;  Essential  Cause  of  Fever, 
752 ;  Heat-regulating  Center,  752 ;  Significance  of  Fever  in  the  Organism,  753. 

CHAPTER  LXXXIII 

THE  PHYSIOLOGICAL  PRINCIPLES  OF  VENTILATION 754 

Relationship  Between  Chemical  Composition  of  the  Air  and  the  Well-being 
of  the  Body,  754;  Relationship  Between  the  Physical  Conditions  of  the  Air 
and  the  Well-being  of  the  Body,  757 ;  Relationship  between  the  Conditions  of 
Ventilation  and  Susceptibility  to  Infections,  759;  Methods  for  Determining 
the  Healthfulness  of  Air,  763. 


PART  VIII 
THE  ENDOCRINE  ORGANS,  OR  DUCTLESS  GLANDS 

CHAPTER  LXXXIV 

GENERAL   CONSIDERATIONS,    THE   ADRENAL    GLANDS 766 

Methods  of  Investigation,  767;  Adrenal  Gland,  768;  Cortex,  768;  Medulla, 
770;  Adrenalectomy,  771;  Adrenal  Disease  in  Man,  772;  Suprarenal  Extracts, 
773;  Physiological  Action,  774. 

CHAPTER  LXXXV 

THE  ADRENAL   GLANDS,    (CONT'D) 779 

Variations  in  Physiological  Activity,  779;  Assaying  the  Epinephrine  Content 
of  the  Gland,  779;  Epinephrine  Content  of  the  Blood,  780;  Autoinjection 
Method,  784;  Association  of  the  Adrenal  with  Other  Endocrine  Organs,  788. 

CHAPTER  LXXXVI 

THE    THYROID   AND   PARATHYROID    GLANDS 791 

Structural  Relationships,  791;  Thyroid  Gland,  792;  Condition  of  Gland,  792; 
Experimental  Thyroidectomy,  794;  Disease  of  the  Thyroid,  795;  Relationship 
with  Other  Endocrine  Organs,  800;  Parathyroids,  800;  Experimental  Para- 
thyroidectomy,  800;  Injury  or  Disease  of  the  Parathyroids  in  Man,  801. 

CHAPTER  LXXXVII 
THE  PITUITARY  BODY 806 

Structural  Relationships,  806;  Functions,  807;  Clinical  Manifestations  of 
Deranged  Pituitary  Function,  816;  Relationship  with  Other  Endocrine  Or- 
gans, 818. 


XX11  CONTENTS 

CHAPTER  LXXXVIII 

PAGE 

THE  PINEAL  GLAND,  THE  GONADS,  AND  THE  THYMUS 820 

Pineal  Gland,  820;  Gonads  or  the  Generative  Organs,  821;  Generative  Glands 
of  the  Male,  821;  Generative  Organs  of  the  Female,  822;  Thymus,  824. 


PART  IX 

THE  CENTRAL  NERVOUS  SYSTEM  AND  THE  CONTROL  OF 
MUSCULAR  ACTIVITY 

(Rewritten  by  A.  C.  Redfield) 

CHAPTER  LXXXIX 

THE  EVOLUTION  OF  THE  NEUROMUSCULAR  MECHANISM 827 

Primitive  Neuromuscular  Mechanisms,  827;  The  Nerve  Net,  830;  The  Cen- 
tral Nervous  System,  830. 

CHAPTER  XC 

THE  CONDUCTION  OF  THE  NERVOUS  IMPULSE 836 

Conduction  in  the  Nerve  Fiber,  837;  The  All  or  None  Law,  837;  Refractory 
Period,  839;  Conduction  between  Neurons,  841;  Resistance  Due  to  Synapse, 
842;  Summation,  842;  Inhibition,  843;  Canalization,  844;  Myoneural  Junc- 
tion, 845. 

CHAPTER  XCI 

THE  NUTRITION  OF  NERVOUS  TISSUE 846 

Function  of  the  Nerve  Cell  Body,  846;  Degeneration  and  Regeneration  of 
Nerve  Fibers,  846;  Metabolism  of  the  Nerve  Fiber,  850;  Metabolism  of  the 
Central  Nervous  System,  851. 

CHAPTER  XCII 
THE    RECEPTORS 854 

The  Evolution  of  Specialized  Receptors,  854;  Quality  of  Sensation  and  Its 
Local  Sign,  855;  Referred  Pain,  858;  Cutaneous  and  Deep  Sensibility,  859; 
Touch,  860;  Heat  and  Cold,  861;  Pain,  862;  Distribution  of  Sensitivity  in 
the  Body,  863. 

CHAPTER  XCIII 

THE  AFFERENT  PATHS  OF  SENSORY  IMPULSES 866 

Segmental  Distribution  of  Afferent  Nerves,  866;  Ascending  Pathways  in  the 
Spinal  Cord,  868;  Afferent  Paths  in  the  Brain  Stem,  871;  Afferent  Impulses 
Which  Fail  to  Produce  Sensation,  872. 

CHAPTER  XCIV 

THE   SENSORY  CENTERS   OF  THE  BRAIN 876 

The  Sensory  Center  of  the  Optic  Thalamus,  876;  The  Sensory  Centers  of  the 
Cerebral  Cortex,  878;  The  Visual  Areas,  880;  Sensory  Hallucinations,  883. 


CONTENTS  xxiii 

CHAPTEE  XCV 

PAGE 

THE  MOTOR  AREAS  OF  THE  CEREBRUM  AND  THE  EFFERENT  PATHWAY  TO  SKELETAL 

MUSCLE       884 

The  Motor  Area  of  the  Cerebral  Cortex,  885;  The  Visuo-Motor  Areas,  886; 
The  Efferent  Pathway  in  the  Brain  and  Cord,  888;  Distribution  of  Efferent 
Nerves,  890;  Spinal  Reflexes,  891. 

CHAPTER  XCVI 

THE  AUTONOMIC  NERVOUS  SYSTEM,  OR  THE  EFFERENT  P'ATHWAY  TO  SMOOTH  MUS- 
CLES  AND    GLANDS       893 

The  Organization  of  Efferent  Nerves  to  the  Viscera,  893;  The  Double  Inner- 
vation  of  the  Visceral  Organs,  896;  The  Function  of  the  Autonomic  Nervous 
System,  897;  The  Axon  Reflex,  898;  Function  of  the  Bulbo-sacral  Divisions, 
899 ;  The  Mechanism  for  Emptying  the  Bladder,  900 ;  Function  of  the  Thorac- 
ico-Lumbar  Division,  901 ;  Effects  of  Impulses  from  the  Viscera  Upon  Central 
Nervous  Activity,  902. 

CHAPTER  XCVII 

MUSCULAR  CONTRACTION 904 

The  Tonic  Contraction  of  Skeletal  Muscle,  905;  Tetanic  Contraction  of 
Skeletal  Muscle,  906;  The  All  or  None  Law,  908;  Chemistry  of  Tetanic  Con- 
traction, 910;  Smooth  Muscle,  912. 

CHAPTER  XCVIII 
POSTURAL   COORDINATION       914 

Reflex  Adjustment  of  Tone,  914;  The  Posture  of  the  Body  as  a  Whole,  917; 
Compensatory  Movements  of  the  Eyes,  918;  Clinical  Tests  of  Labyrinthine 
Mechanism,  920;  The  Tendon  Jerks,  921. 

CHAPTER  XCIX 

THE  CENTRAL  CONTROL  OF  POSTURAL  REACTIONS;  THE  CEREBELLUM 924 

The  Influence  of  the  Brain  on  the  Local  Tonic  Reflex,  924;  Function  of  the 
Cerebellum,  926;  Localization  of  Function  in  the  Cerebellum,  929;  'Compensa- 
tion for  Cerebellar  Injuries,  931. 

CHAPTER  0 

THE  INTEGRATION  OF  ACTION  WITHIN  THE  REFLEX  ARC 933 

The  Receptors,  933;  Summation,  934;  Refractory  Period,  934;  Reciprocal 
Inhibition,  937;  Action  of  Strychnine  and  Tetanus  Toxin  on  Reciprocal  In- 
hibition, 941;  The  Reflex  Figure,  941;  Rules  for  the  Spread  of  Spinal  Re- 
flexes, 944. 

CHAPTER  CI 

THE  INTEGRATION  OF  SIMULTANEOUS  AND  SUCCESSIVE  REFLEXES 945 

Principle  of  the  Final  Common  Path,  945;  Integration  of  Allied  Reflexes, 
946;  Integration  of  Antagonistic  Reflexes,  947. 

CHAPTER  CII 

THE  INTEGRATIVE  ACTION  OF  THE  CEREBRUM 951 

Relation  of  the  Cerebrum  to  the  Distance  Receptors,  952;  Conditioned  Re- 
flexes, 954. 


XXIV  CONTENTS 

CHAPTER  CIII 

PAGE 

THE  HIGHER  FUNCTIONS  OF  THE  CEREBRUM  IN  MAN  ;  APHASIA 958 

Psychopathological  Applications,  960. 

CHAPTER  CIV 

SUMMARY  OF  THE  ORGANIZATION  OF  THE  MAMMALIAN  NERVOUS  SYSTEM;  SPINAL 

SHOCK 963 

Spinal  Shock  and  the  Recovery  of  Reflexes  in  Animals,  965 ;    Spinal  Shock 
and  the  Recovery  of  Reflexes  in  Man,  967;   The  Cause  of  Spinal  Shock,  969. 


ILLUSTRATIONS 

FIG.  PAGE 

1.  Diagram  of  osmometer 5 

2.  Hematocrite 7 

3.  Plasmolysis  in  cells  from  Tradesoantia  discolor 9 

4.  Apparatus  for  measurement  of  the  depression  of  freezing  point  of  solution     .  11 

5.  Diagram  of  conductivity  cells 18 

6.  Wheatstone  Bridge  for  the  measurement  of  electric  resistance 18 

7.  Diagram  to  show  type  of  electrodes  used  in  studying  electromotive  force     .     .  30 

8.  Diagram  of  apparatus  for  the  measurement  of  the  H-ion  concentration     .     .  31 

9.  Chart  of  tints  as  used  in   colorimetric  measurement  of  H-ion   concentration 

(Color  Plate)       34 

10.  Diagram  of  apparatus  for  saturating  blood  and  plasma  with  expired  air     .     .  43 

11.  Van  Slyke's  apparatus  for  measuring  the  CCycombining  power  of  blood  in 

blood   plasma ' 44 

12.  TJltramicroscope  (slit  type)  for  the  examination  of  colloidal  solutions     ...  53 

13.  To  show  diffusion  into  gelatin  of  a  crystalloid  stain,  and  the  nondiffusion  of  a 

colloid    stain        54 

14.  Diagram  from  W.  Ostwald  showing  the  relative  size  of  various  particles  and 

colloidal  dispersoids  compared  with  a  red  blood  corpuscle  and  an  anthrax 

bacillus        55 

15.  Capillary  analysis  of  colloids       57 

16.  Diagram  to  show  structure  of  gels 62 

17.  Diagram  to  illustrate  surface  tension       65 

18.  Traube's   stalagmometer 66 

19.  Diagram    of   the   graphic    coagulometer 110 

20.  Coagulometer 110 

21.  Mercury  manometer  and  signal  magnet,  arranged  for  recording  the  mean  ar- 

terial blood  pressure  in  a  laboratory  experiment 126 

22.  The  arterial  blood  pressure  recorded  with  a  mercury  manometer   (lower  trac- 

ing)  along  with  a  tracing  of  the  respiratory  movement  of  the  thorax     .  127 

23.  Hiirthle's  spring  manometer 128 

24.  Normal  curve  of  arterial  blood  pressure  obtained  with  spring  manometer     .     .  128 

25.  Diagram  based  on  experiments  on  dogs  to  show  the  systolic,   diastolic  and 

mean  blood  pressures  at  different  parts  of  the  circulatory  system     .     .     .  129 

26.  Apparatus  for  measuring  the  arterial  blood  pressure  in  man 131 

27.  Effect  of  cutting  the  vagus  nerve  on  the  arterial  blood  pressure 136 

28.  Effect  of  stimulating  the  peripheral  end  of  the  right  vagus  on  the  arterial 

blood  pressure 136 

29.  Effect  of  stimulation  of  the  left  splanchnic  nerve  on  the  arterial  blood  pressure  137 

30.  Composite  curves  to  show  effects  of  hemorrhage  and  transfusion  of  various 

solutions  on  blood  pressure 140 

31.  Diagram  of  experiment  to   show  that  the  diastolic  pressure   depends   on  the 

elasticity   of   the   vessel   wall 144 

32.  Diagram   of   Wiggers'   optical   manometer ,147 

XXV 


XXVI  ILLUSTRATIONS 

FIG.  PAGE 

33.  Optical  records  of  intraventricular   pressure 148 

34.  Superimposed  pressure  curves  after  being  graduated 150 

35.  Diagram    to    illustrate    optical    method    for    recording    pressure    curves    from 

auricles        152 

36.  Diagram  to  show  the  positions  of  the  cardiac  valves 156 

37.  Electrophonograms   along    with    intraventricular    pressure    curves    from    three 

different    experiments 159 

38.  Arrangement  of  apparatus  for  heart-lung  preparation 164 

39.  Volume  curve  of  ventricles  of   cat    (lower   curve)    in  a  heart-lung  perfusion 

preparation 169 

40.  Heart  and  cardiac  nerves  of  Limulus  polyphemus 173 

41.  Heart-block  produced  by  applying  clamp 175 

42.  Tracing   of  contraction   of  ventricle,   showing  the   effect   of   the   local   appli- 

cation of  heat  to  the  auricle 175 

43.  Frog  heart  showing  the  position  of  the  first  and  second  ligatures  of  Stannius  176 

44.  Effects  of  stimuli  of  increasing  strength  on  skeletal  and  cardiac  muscle  to 

illustrate  the  "all  or  nothing"  principle  in  the  latter     .......  177 

45.  The  effects  of  successive  stimuli  on  skeletal  and  cardiac  muscle  to  show  the 

prominence  of  the  staircase  phenomenon,  or  treppe,  in  the  latter     .     .     .  178 

46.  The  effects  of  successive  stimuli  and  of  tetanizing  stimuli  on  skeletal  muscle 

and  cardiac   muscle 179 

47.  Myograms  of  frog's  ventricle,  showing  effect  of  excitation  by  break  induc- 

tion shocks  at  various  moments  of  the  cardiac  cycle 180 

48.  Heart  of  tortoise  as  suspended 183 

49.  Dissection  of  heart  to  show  auriculoventricular  bundle 184 

50.  Photograph  of  model  of  the  auriculoventricular  bundle  and  its  ramifications, 

constructed  from   dissections   of  the  heart 184 

51.  Diagram  of  an  auricle  showing  the  arrangement   of  the  muscle  bands;    the 

concentration  point;    and  the   outline  of  the  node 186 

52.  Diagram  to  show  the  general  ramifications   of  the  conducting  tissue  in  the 

heart    of   the   mammal 186 

53.  Diagram  to  illustrate  the  development  and  spread  of  the  wave  of  negativity 

in  a  strip  of  muscle  (curarized  sartorius)  when  stimulated  at  the  end     .  188 

54.  Simultaneous  electrocardiograms  to   show  the   cause  for   extrinsic   deflections  190 

55.  Diagram  of  experiment  by  Lewis  showing  the  times  at  which  the  excitation 

wave  appeared  on  the  front  of  the  heart 194 

56.  Diagram  of  Chauveau's  dromograph 200 

57.  Diagram  to  show  principle  of  Pitot's  tubes  for  measuring  velocity  pulse     .     .  201 

58.  Cybulski's  photohematotachometer 201 

59.  Dudgeon's   sphygmograph 201 

60.  Pulse  tracing    (sphygmogram)    taken  by  sphygmograph 202 

61.  Forms  of  apparatus  for  measurement  of  blood  velocities 207 

62.  Plethysmograph  for  recording  volume  changes  in  the  hand  and  forearm     .     .  210 

63.  Effect  of  venous  supply  on  volume  of  heart 217 

64.  Simultaneous  tracings  from  auricle  and  ventricle  of  turtle's  heart     ....  223 

65.  Effect  of  vagus  stimulation  on 'heart  of  turtle 223 

66.  Tracing   to    show    that    vagus    stimulation    may    diminish    transmission    from 

auricles  to  ventricles                                                            224 


ILLUSTRATIONS  XXV11 

FIG.  PAGE 

67.  Tracing   to    show   that   vagus   stimulation   may    facilitate    transmission    from 

auricles    to    ventricles 225 

68.  Diagram  to  show  the  innervation  of  the  heart  in  the  frog  or  turtle.     (Color 

Plate.) 228 

69.  Frog  heart  tracing  showing  the  action  of  nicotine 231 

70.  Schematic   representation   of   the   innervation   of   the   heart   of   the   mammal. 

(Color  Plate.) 232 

71.  Tracings  showing  the  effects  on  the  heartbeat   of  the  frog  resulting  from 

stimulation  of  the  sympathetic  nerves  prior  to  their  union  with  the  vagus 

nerve 233 

72.  Boy's   kidney   oncometer     .      .      . 235 

73.  Fall  of  blood  pressure  from  excitation  of  the  depressor  nerve     ......  244 

74.  The  effect  of  strong  stimulation   (heat)    of  the  skin  of  the  foot  on  the  ar- 

terial blood  pressure  and  respiratory  movements 245 

75.  Diagram  showing  the  probable  arrangements  of  the  vasomotor  reflexes     .     .  246 

76.  Aortic  blood  pressure,  showing  the  effect  of  posture 249 

77.  Tracing  to  show  the  effect  of  gravity  on  the  arterial  blood  pressure     .     .     .  250 

78.  The  effect  of  gravity  on  the  aortic  pressure  after  division  of  the  spinal  cord 

in   the   upper   dorsal   region 250 

79.  Capillaries  from  abdominal  wall  of  guinea  pigs  after  injection  of  india  ink     .  252 

80.  Tracing  showing  simultaneous  records   of  the   arterial  blood   pressure,   the 

venous  pressure,   the   intracranial   pressure,   the   pressure   in   the   venous 

sinuses 260 

81.  Electrocardiographic   apparatus    as   made   by   the   Cambridge    Scientific    Ma- 

terials  Co 271 

82.  Normal  electrocardiogram 273 

83.  Electrocardiogram   (dog)   taken  simultaneously  with  curves  from  auricle  and 

ventricle 274 

84.  Diagrams  to  show  spread  of  electrical  current  in  heart  and  the  use  of  Ein- 

thoven's  triangle 276 

85.  Sinus   bradycardia 279 

86.  Auricular  extrasystole 279 

87.  Ventricular  extrasystoles  arising  in  the  right  ventricle 279 

88.  Ventricular  extrasystole  arising  in  the  left  ventricle 279 

89.  Paroxysmal   tachycardia 280 

90.  Auricular   fibrillation      . 280 

91.  Auricular  flutter 282 

92.  Delayed  conduction 282 

93.  Partial  dissociation 283 

94A.  Electrocardiogram  showing  a  lesion  of  the  branch  of  the  conducting  bundle  284 
94B.  Illustrating  the  effect  upon  the  electrocardiogram  of  a  defect  of  the  left  di- 
vision of  the    bundle 284 

95.  Tracings  of  the  jugular  pulse,  apex  beat,  carotid  and  radial  pulses     ....  286 

96.  Polysphygmograph 288 

97.  Normal  jugular  tracing 288 

97.  Superimposed  pressure  curves  from   aorta,   ventricle   and   auricle,   along   with 

electrocardiogram  and  phonocardiogram 289 

98.  Polysphygmograms  including  jugular,  apex  and  rndial  tracings 290 

99.  Delayed  conduction 291 

100.  Dropped  beats      .     t     ,                                                      292 


XXV111  ILLUSTRATIONS 

FIG.  PAGE 

101.  Premature  beats    (extrasy  stoles)    ventricular  in  origin 292 

102.  Paroxysmal  tachycardia 293 

103.  Auricular    flutter 294 

104.  Auricular  flutter 294 

105.  Auricular  fibrillation 295 

106.  Showing  the  appearance  of  the  blood  vessels  in  the  ears  of  a  rabbit  in  a 

state  of  deep  shock.     (Color  Plate.)       304 

107.  Diagram  showing  amounts  of  air  contained  by  the  lungs  in  various  phases 

of   ordinary   and    of   forced   respiration 318 

108.  Diagram  of  structure  of  air  sacs,  atria,  alveolar  ducts,  etc 318 

109.  Pneumograph 321 

110.  Effect  of  abdominal  and  chest  breathing  on  the  pulse  and  blood  pressure 

of   man 325 

111.  First  dorsal  vertebra,  sixth  dorsal  vertebra  and  rib.     Axis  of  rotation  shown 

in  each  case 333 

112.  Lower  half  of  the  thorax  from  the  6th  dorsal  to  the  4th  vertebra,  seen  from 

the  front 335 

113.  Intercostal  muscles  of  5th  and  6th  spaces 336 

114.  Hamberger's  schema  to  demonstrate  the  functional  antagonism  of  internal 

and  external  intercostals 336 

115.  Schema  to  demonstrate  that  the  function  of  the  internal  intercartilaginous 

intercostals  is  identical  with  that  of  the  external  interosseous  intercostals     337 

116.  Diagram  to  show  the  effect  of  high  and  low  positions  of  the  diaphragm  on 

the  costal  angle 339 

117.  Diagram  to  show  the  effect  of  clinical  displacements  of  the  diaphragm  on 

the  costal  angle 340 

118.  Diagram  to  show  cuts  required  for  isolation  of  the  phrenic  center     ....     345 

119.  Diagram  to  show  certain  positions  in  the  medulla  and  upper  cervical  cord, 

where  sections  may  be  made  without  seriously  disturbing  the  respirations     346 

120.  Diagram  to  show  where  cuts  are  made  to  isolate  the  chief  respiratory  center 

from  afferent  impulses 347 

121.  Diagram  showing  principle  for  measurement  of  the  tension  of  CO2  in  blood  355 

122.  The  gas  analysis  pipette  for  the  microtonometer  shown  in  Fig.  123     .     .     .  356 

123.  Microtonometer,  to  be  inserted  into  a  blood  vessel 356 

124.  Apparatus  for  collection  of  a  sample  of  alveolar  air  by  Haldane's  method     .  357 

125.  Fridericia's  apparatus  for  measuring  the  CO2  in  alveolar  air 358 

126.  Curves  to  show  the  relationship  between  the  O2  and  CO2  tensions  in  alveolar 

air  and  arterial  blood 358 

127.  Same  as  Fig.  126,  except  that  in  this  case  the  tension  of  CO2  in  the  alveolar 

air  was  experimentally  altered 359 

128.  Curves  showing  relationship  between  total  CO2  in  solution  and  PH  at  varying 

CO2  pressure' 364 

129.  Curve  showing  the  respiratory  response  to  CO2  in  the  decerebrate  cat     .     .     368 

130.  The  behavior  of  the  respiratory  volume,  the  blood  pressure  and  the  pulse 

during  progressive  anoxemia 376 

131.  Curves  showing  variations  in  alveolar  gas  tensions  after  forced  breathing  for 

two  minutes 383 

132.  Various  types  of  periodic  breathing 385 


ILLUSTRATIONS  XXIX 

FIG.  PAGE 

133.  Quantitative  record  of  breathing  air  through  a  tube  260  cm.  long  and  2  cm. 

in  diameter 383 

134.  Barcroft's  tonometer  for  determining  the  curve  of  absorption  of  oxygen  by 

hemoglobin  or  blood 394 

135.  Barcroft's  differential  blood  gas  manometer 394 

136.  Barcroft  blood  gas  manometer 395 

137.  Typical  dissociation  curve.     (Color  Plate.)       396 

138.  Average  dissociation  curves 397 

139.  Degree  of  variation  in  dissociation  curve  of  man 398 

140.  Dissociation  curves  of  human  blood 399 

141.  Curves  showing  relative  rates  of  oxidation  and  reduction  of  blood  as  in- 

fluenced by  temperature  and  tension  of  CO2 400 

142.  Curve  of  CO2  tension  in  blood 405 

142.  CO2  tension  at  various  altitudes 417 

143.  Cells  of  parotid  gland  showing  zymogen  granules 454 

144.  Parotid  gland  of  rabbit  in  varying  states  of  activity  examined  in  fresh  state  454 

145.  Diagrammatic  representation  of  the  innervation  of  the  salivary  glands  in  the 

dog.     (Color  Plate.) 458 

146.  Pancreatic  acini  stained  with  hematoxylin 462 

147.  Three  preparations  of  pancreatic  acini  stained  by  eosin  orange  toluidin  blue  463 

148.  Diagram   of  stomach  showing  miniature  stomach  separated  from   the  main 

stomach  by  a  double  layer  of  mucous  membrane 468 

149.  Typical  curve  of  secretion   of  gastric  juice   collected  in  5-minute  intervals 

on  mastication  of  palatable  food  for  20  minutes 471 

150.  Cubic  centimeters  of  gastric  juice  secreted  after  diets  of  moat,  bread,  and  milk  475 

151.  Digestive  power  of  the  juice,  as  measured  by  the  length  of  the  protein  column 

digested  in  Mett's  tubes,  with  diets  of  flesh,  bread,  and  milk     ....  475 

152.  Loop  of  intestine  after  tying  off  the  portions,  cutting  the  nerves  running  to 

the  middle  portion  and  returning  the  loop  to  the  abdomen  for  some  time  477 

153.  The  changes  which  take  place  in  the  position  of  the  root  of  the  tongue,  the 

soft  palate,  the  epiglottis  and  the  larynx  during  the  second  stage  of  swal- 
lowing       480 

154.  Schematic  outline  of  the  stomach 486 

155.  Outlines  of  the  shadows  cast  by  the  stomach  at  intervals  of  an  hour  each 

after  feeding  a  cat  with  food  impregnated  with  bismuth  subnitrate     .     .  487 

156.  Skiagrams  of  human  stomach  at  intervals  after  food,  illustrating  a  gastric 

cycle 488 

157.  Section  of  the  frozen  stomach  (rat)  some  time  after  feeding  with  food  given 

in  three  differently  colored  portions 489 

158.  Tracings  showing  the  relationship  between  contractions  of  the  antrum  (lower 

tracing)   and  the  pyloric  sphincter    (upper  tracing) 492 

159.  Diagram  of  the  relationships  of  the  contractions  of  antrum,  sphincter,  and 

t    duodenum,  and  the  passage  of  chyme  from  antrum  to  duodenum     .     .     .  493 

160.  Apparatus  for  recording  contractions  of  the  intestine 498 

161.  Diagrammatic  representation  of  the  process  of  segmentation  in  the  intestine  499 

162.  Intestinal  contractions  after  excision  of  the  abdominal  ganglia  and  section  of 

both  vagi t 500 


XXX  ILLUSTRATIONS 

FIG.  PAGE 

163.  The  effect  of  excitation  of  both  splanchnic  nerves  on  the  intestinal  contrac- 

tions         .     .  502 

164.  The  effect  of  stimulation  of  light  vagus  nerve  on  the  intestinal  contractions  502 

165.  Diagram  of  time  it  takes  for  a  capsule  containing  bismuth  to  reach  the  various 

parts  of  the  large  intestine 504 

166.  Diagram  of  method  for  recording  stomach  movements 507 

167.  Tracing  of  the  tonus  rhythm  of  the  stomach  three  hours  after  a  meal     .     .  508 

168.  Tracings  from  the  stomach  during  the  culmination  of  a  period  of  vigorous 

gastric  hunger  contractions           508 

169.  Showing  augmentation  of  the  knee-jerk  during  the  marked  hunger  contrac- 

tions       509 

170.  Diagram  of  the  uriniferous  tubules,  the  arteries,  and  the  veins  of  the  kidney  542 

171.  Cross  section  of  convoluted  tubules  from  kidney  of  rat 543 

172.  Diagram  of  blood  supply  of  Malpighian  corpuscle  and  of  convoluted  tubules 

in  amphibian  kidney 549 

173.  Nerve  supply  of  the  kidney 553 

174.  Respiration  calorimeter  of  the  Russell  Sage  Institute  of  Pathology,  Bellevue 

Hospital,  New  York 572 

175.  Chart  of  determining  surface  area  of  man  in  square  meters  from  weight  in 

kilograms  and  height  in  centimeters  according  to  formula 576 

176.  Diagram   of  Atwater-Benedict   respiration   calorimeter 580 

177.  Nose  clip,  face  mask,  and  mouth  piece 590 

178.  Diagram  of  respiratory  valves 590 

179.  The  Tissot  spirometer 591 

180.  The  Douglas  bag  method  for  determining  the  respiratory  exchange     .     .     .  592 

181.  Haldane  gas  apparatus  and  Pearce   sampling  tube 593 

182.  Curve  constructed  from  data  obtained  from  a  man   who  fasted  for  thirty- 

one  days     . 601 

183.  Curves  of  growth  of  rats  on  basal  rations  plus  the  various  proteins  indicated  610 

184.  Curves  of  growth  of  rats  on  basal  rations  plus  the  proteins  indicated     .     .     .  611 

185.  Photographs  of  rats  of  same  brood  on  various  diets 613 

186.  Curves  of  growth  of  rats  as  influenced  by  the  accessory  food  factors     .     .     .  620 

187.  Vividiffusion  apparatus  of  J.  J.  Abel 642 

188.  Curves  showing  the  amount  of  amino  nitrogen  taken  up  by  different  tissues 

after  the  cutaneous  injection  of  amino  acids 643 

189.  Curves  showing  the  concentrations  of  amino-acid  nitrogen  in  the  blood  dur- 

ing fasting  and  protein  digestion 644 

190.  Curves  showing  the  percentage  of  glucose  in  blood  after  a  constant  injection 

of  an  18  per  cent  solution  into  a  inesenteric  vein 691 

191.  Child  aged  4^  years  suffering  from  hypernephroma 769 

192.  Arrangement   of  apparatus  for   recording  contractions   of   a  uterine  strip,   intes- 

tinal strip,  or  ring,  etc     .- 781 

193.  Tracing  showing  the  effect  of  epinephrine  on  the  intestinal  contractions  and 

on  the  arterial  blood  pressure       782 

194.  Arrangement  of  apparatus  for  perfusion  of  the  vessels  of  a  brainless  frog     .  783 

195.  Microphotographs  of  thyroid  gland  of  a  dog 793 

196.  Cretin,  nineteen  years   old 796 

197.  Case  of  myxedma  before  and  after  treatment 797 

198.  Drawing  from  a  photograph  of  mesial  sagittal  section  through  the  pituitary 

gland  of  a  human  fetus     .     .    „ 807 


ILLUSTRATIONS  XXXI 

FIG.  PAGE 

199.  Tracing    showing   the    action    of    pituitrin    011    the   uterine    contractions    and 

blood  pressure  in  a  dog 812 

200.  Tracing  showing  the  constructing  action  of  pituitrin  on  the  bronchioles  and 

its  effect  on  blood  pressure  in  a  spinal  dog     .     .     .     . 813 

201.  Showing  the  appearance  before  and  after  the  onset  of  acromegalic  symptoms  815 

202.  Hand  of  a  person  affected  with  acromegaly 817 

203.  The  evolution  of  the  nervous  system 829 

204.  Normal  cell  from  the  anterior  horn,  stained  to  show  Nissl's  granules     .     .     .  831 

205.  Arborization  of  collaterals  from  the  posterior  root  fibers  around  the  cells  of 

the  posterior  horn 832 

20(3.  Part  of  a  ventral  cornual  cell  from  the  calf's  spinal  cord  stained  to  show 

neurofibrils 833 

207.  Schema   of   simple   reflex   arc 833 

208.  Diagram  of  nervous  system  of  segmented  invertebrate 834 

209.  Diagram  illustrating  the  effect  of  areas  of  narcosis  on  the  strength  of  the 

nerve   impulse 839 

210.  The  recovery  of  excitability  in  the  nerve  fiber  after  the  passage  of  a  nerve 

impulse •     .     .     .  840 

211.  Degeneration  and  regeneration  of  a  sectioned  nerve  fiber 847 

212.  Evolution   of   the    sense   organs       855 

213.  Cold  spots  and  heat  spots  of  an  area  of  skin  of  the  right  hand 860 

214.  Diagram  showing  the  segmented  arrangement  of  the  sensory  nerves     .     .     .  867 

215.  Diagram  of  the  afferent  paths  followed  by  sensory  impulses  within  the  spinal 

cord  and  brain 869 

216.  Afferent  paths  connecting  the  retina  with  the   visual  area   of  the  cerebral 

cortex 881 

217.  Outer  aspect  of  the  brain  of  the  chimpanzee  showing  the  position  of  the  motor 

centers •    .     .  885 

218.  Diagram  to  illustrate  the  different  arrangements  of  the  internuncial  neurons 

of  the  voluntary  and  autonomic  nervous  systems       894 

219.  Diagram  of  the  autonomic  nervous  system.      (Color  Plate.) 894 

220.  Diagram  showing  the  main  parts  of  the  autonomic  nervous  system.      (Color 

Plate.) 896 

221.  Schematic  representation  of  the  autonomic  nervous  system.      (Color  Plate.)  898 

222.  Diagram  of  an  axon  reflex  in  a  sensory  nerve  fiber  of  the  skin 899 

223.  Electromyogram  of  the  voluntary  contraction  of  the  flexor  muscles     .     .     .  907 

224.  The  contraction  of  a  single  fiber  of  the  sartorius  muscle  of  the  frog    .     .     .  907 

225.  The  all  or  none  nature  of  the  contraction  of  a  single  fiber  of  skeletal  muscle  909 

226.  Eeciprocal  inhibition 916 

227.  Records  of  the  contraction  of  the  isolated  extensor  muscle  of  the  knee  of 

the  cat 917 

228.  Compensatory  movements  of  the  eyes  and  fins  of  the  dogfish 919 

229.  The  semicircular  canals  of  the  ear 919 

230.  A  tracing  of  the  knee-jerks  of  a  normal  man  and  of  a  man  with  a  cerebellar 

injury 922 

231.  Schema  of  the  parts  of  the  mammalian  cerebellum 929 

232.  Diagrams  to  represent  a  ventral  view  of  the  left  half  and  a  dorsal  view  of 

the  right  half  of  the  cerebellum 930 


XXX11  ILLUSTRATIONS 

FIG.         .  PAGE 
233  and  234.  The  inferolateral  and  the  posterior  aspect  of  the  human  cerebellum 

indicating   certain  cerebellar   localizations  according   to   Barany     .     .     .  931 

235.  Footprints  after  destruction  of  the  cerebellum  in  a  dog 932 

236.  Tracing  from  the  hind  limb  of  a  spinal  dog  during  the  scratching  movements  935 

237.  Diagram  showing  the  reflex  arcs  involved  in  the  scratch  reflex 936 

238.  The  region  of  body  of  dog  from  which  the  scratch  reflex  can  be  elicited     .     .  936 

239.  Record  from  myograph  connected  with  the  extensor  muscle  of  the  knee     .     .  939 

240.  Sherrington's   diagram   illustrating   the   mechanism    of    reciprocal   inhibition  940 

241.  Reflex  figures 942 

242.  Successive  induction  illustrated  by  the  crossed-extension  reflex 949 

243.  Postures  assumed  by  the  robber  fly  when  the  eyes  are  unequally  illuminated  953 


PHYSIOLOGY   AND    BIOCHEMISTRY 
IN  MODERN  MEDICINE 


PART  I 

THE],  PHYSICOCHEMICAL    BASIS    OF  PHYSIOLOGICAL 

PROCESSES 


CHAPTER  I 
GENERAL  CONSIDERATIONS 

The  work  of  the  physiologist  consists,  in  large  part,  in  ascertaining  to 
what  extent  the  known  laws  of  physics  and  chemistry  find  application 
in  explaining  the  phenomena  of  life.  He  gathers  from  the  vast  store- 
house of  physical  and  chemical  knowledge  whatever  is  of  value  in  the 
interpretation  of  the  various  mechanisms  that  work  together  to  com- 
pose the  living  machine,  and  having  added  to  this  knowledge  he  passes 
it  on  for  use  by  those  who  are  concerned  in  the  study  and  treatment  of 
disease. 

Many  of  the  most  important  steps  in  the  advance  of  physiological 
knowledge  in  recent  years  have  depended  upon  the  discovery  of  some 
hitherto  unknown  physical  or  chemical  law,  or  upon  the  elaboration  of 
some  accurate  method  for  the  measurement  of  the  phenomena  upon 
which  these  or  previously  known  laws  depend.  The  discoveries  of 
van't  Hoff,  Arrhenius,  and  Ostwald  of  the  so-called  laws  of  solution 
were  soon  followed  by  important  observations  on  their  relationship  to 
the  movement  of  fluids  and  dissolved  substances  through  cell  mem- 
branes; the  discoveries  of  Hardy,  Willard  Gibbs,  etc.,  of  the  behavior  of 
colloids  and  of  the  phenomena  of  surface  tension  found  application  in 
explaining  many  hitherto  inexplicable  peculiarities  in  the  activities  of 
ferments;  the  discovery  by  Nernst,  etc.,  of  methods  for  the  measurement 
of  the  electro-motive  force  of  dissolved  substances  was  applied  to  de- 
termine the  actual  reaction  or  hydrogen-ion  concentration  of  animal 

1 


2  PHYSICOCHEMICAL   BASIS   OF   PHYSIOLOGICAL   PROCESSES 

fluids,  and  to  explain  the  generation  of  the  electric  currents  which  ac- 
company muscular,  nervous,  and  glandular  activity. 

It  would  be  out  of  place  here  to  devote  much  space  to  a  detailed  ac- 
count of  such  matters.  They  belong  more  properly  in  the  domain  of 
general  than  in  that  of  human  physiology.  General  physiology  is  con- 
cerned with  the  study  of  the  essential  nature  of  the  vital  processes; 
whereas  human  physiology  is  merely  a  branch  of  the  subject  in  which 
special  attention  is  devoted  to  the  application  of  the  truths  of  general 
physiology  to  the  working  of  the  human  machine.  For  the  physician 
and  surgeon  a  knowledge  of  human  physiology  is  as  essential  as  is  a 
knowledge  of  the  construction  of  a  piece  of  machinery  for  the  engineer 
who  attempts  its  repair,  but  obviously  to  acquire  this  knowledge  the 
fundamental  principles  of  general  physiology  must  first  of  all  be  under- 
stood. For  these  reasons  the  introductory  chapters  are  devoted  to  a 
brief  review  of  the  most  important  of  the  physicochemical  principles 
upon  which  the  working  of  the  cell  depends. 

From  the  viewpoint  of  the  physical  chemist  the  cell  consists  of  an 
envelope  of  more  or  less  permeable  material  inclosing  a  solution  of 
various  crystalloids  and  colloids,  which  are  in  a  state  of  equi- 
librium with  one  another.  This  equilibrium  is  readily  altered  by 
various  influences  that  may  act  on  the  cell,  and  the  resulting 
changes  manifest  themselves  outwardly  by  alterations  in  the  shape 
and  volume  of  the  cell — growth  and  motion;  by  the  extrusion  of 
some  of  its  contents — secretion;  or  by  the  propagation  to  other  parts  of 
the  cell,  or  its  processes,  of  the  state  of  disturbed  equilibrium — nervous 
impulse.  Besides  the  activities  that  are  dependent  upon  physicochem- 
ical changes,  purely  chemical  processes  go  on  in  the  cell.  Many  of 
these  consist  in  the  breakdown  and  oxidation  of  complex  unstable  organic 
molecules,  a  process  identical  with  that  occurring  in  combustion  outside 
the  cell.  Others  involve  the  building  up,  stage  by  stage,  of  complex 
substances  out  of  the  elements  or  out  of  simpler  molecules.  Chemical 
transformations  occur  in  the  cell  which,  in  the  chemical  laboratory,  re- 
quire the  most  powerful  reagents  and  physicochemical  forces,  either  the 
strongest  of  acids,  alkalies,  oxidizing  agents,  etc.,  or  extreme  degrees 
of  heat,  electrical  energy,  etc.  But  this  is  not  all,  for  in  the  cell  these 
chemical  transformations  are  capable  of  being  guided  to  a  very  remark- 
able degree  of  nicety  so  as  to  produce  intermediate  products  that  are 
used  for  some  special  purpose  either  by  the  cell  that  produced  them  or, 
after  transportation  by  the  blood,  etc.,  by  cells  in  other  parts  of  the 
organism. 
It  is  customary  to  speak  of  the  cell  as  a  chemical  laboratory,  but  it 


LAWS  OF  SOLUTION  O 

is  more  than  this;  it  is  a  laboratory  furnished  not  only  with  the  equip- 
ment of  the  chemist  but  directed  in  the  harmonious  operation  of  its 
many  activities  by  a  guiding  hand  which  far  surpasses  anything  else  known 
to  man.  Chemical  transformations  that  require  for  their  accomplishment 
the  greatest  skill  proceed  without  apparent  difficulty  in  the  cell.  To 
what  are  these  changes  due?  What  is  the  nature  of  the  chemical  rea- 
gents and  forces,  and  what  is  the  directive  influence  that  guides  them 
in  their  varied  activities?  To  these,  which  are  among  the  great  ques- 
tions of  general  physiology,  the  reply  may  be  given  that  the  reagents 
are  the  ferments  or  enzymes,  and  that  the  directive  influence  operates 
through  the  susceptibility  of  enzymic  activities  to  changes  in  the  envi- 
ronment in  which  the  enzymes  are  acting.  In  many  cases  these  changes 
can  be  explained  on  a  physicochemical  basis  as  dependent  upon  the 
known  laws  of  mass  action  or  surface  tension;  in  other  cases  they  de- 
pend on  purely  chemical  changes  in  the  cell  contents,  such  as  changes 
in  reaction  or  the  accumulation  of  chemical  substances  that  act  like 
poisons  on  the  enzyme.  But  there  are  still  others  that  appear  to  depend 
on  influences  which  as  yet  are  quite  unknown  to  the  physical  chemist, 
such  as  the  changes  in  cell  activity  that  can  be  brought  about  by  the 
nerve  impulse. 

These  preliminary  remarks  will  serve  to  indicate  the  problems  with 
which  we  must  first  occupy  our  attention.  They  concern  the  physico- 
chemical  nature  of  saline  solutions  and  of  colloids,  and  the  general  na- 
ture of  enzyme  action.  The  knowledge  which  we  acquire  will  be  found 
to  be  of  value,  not  only  because  it  will  help  us  to  understand  the  nature 
of  the  workings  of  the  normal  healthy  cell,  but  because,  here  and  there, 
it  will  indicate  possible  causes  for  derangement  in  cellular  function  and 
suggest  rational  means  by  which  we  may  attempt  to  rectify  the  fault. 


THE  PHYSICOCHEMICAL  LAWS  OF  SOLUTION 

The  Gas  Laws 

Three  fundamental  principles  of  general  chemistry  serve  as  the  basis 
for  an  understanding  of  the  nature  of  solutions.  The  first  is  that  if 
we  take  a  quantity  of  any  gas  equal  to  its  molecular  weight  in  grams 
(called  a  gram-molecule  or  for  sake  of  brevity  a  mol),  it  will  occupy  ex- 
actly 22.4  liters  at  a  temperature  of  0°  C.  and  a  pressure  of  760  mm.  Hg. ; 
the  second  is  that,  as  we  compress  a  gas,  its  pressure  will  increase  in  exactly 
the  same  proportion  as  the  volume  diminishes  (the  volume  of  a  gas  is  in- 
versely proportional  to  its  pressure)  ;  the  third  is  that  all  gases  expand  by 


4  PHYSICOCHSMICAL   BASIS   OF   PHYSIOLOGICAL   PROCESSES 

1/273  part  of  their  volume  at  0°  C.  for  every  degree  C.  that  their  tempera- 
ture is  raised.* 

The  pressure  of  a  gas  is  measured  by  connecting  a  pressure  gauge  or 
manometer  with  the  vessel  which  contains  the  gas.  Now,  it  is  plain 
that  if  the  22.4  liters,  which  is  the  volume  occupied  by  a  gram-molecular 
quantity,  were  compressed  so  as  to  occupy  a  volume  of  1  liter,  its  pressure 
would  be  22.4  times  that  of  1  atmosphere,  or  22.4  x  760  mm.  Hg — the 
temperature  remaining  constant.  Under  these  conditions  we  must  im- 
agine that  the  molecules  of  gas  are  crowded  together  by  the  compression, 
and  if  we  further  conceive  of  these  molecules  as  being  in  constant  mo- 
tion, then  we  can  understand  why  the  pressure  should  increase  just  in 
proportion  as  we  confine  the  space  in  which  they  can  move. 

One  other  property  of  gases  must  be  borne  in  mind — namely,  their 
tendency  to  diffuse  from  places  where  the  pressure  is  high  to  places 
where  it  is  low  until  the  pressure  is  the  same  throughout. 

OSMOTIC  PRESSURE 

These  fundamental  facts  regarding  the  behavior  of  gases  suggested 
to  van't  Hoff  the  hypothesis  that  molecules  of  dissolved  substances  must 
behave  in  a  similar  manner  to  those  of  gases.  To  put  this  hypothesis  to 
the  test,  it  is  necessary  that  we  have  some  method  for  measuring  the 
pressure  of  dissolved  molecules.  We  can  not,  as  in  the  case  of  a  gas, 
use  an  ordinary  manometer,  for  this  would  measure  only  the  pressure 
of  the  solvent  on  the  walls  of  its  container  and  would  tell  us  nothing  of 
the  pressure  of  the  dissolved  molecules.  We  must  use  some  filter  or 
membrane  that  will  allow  the  molecules  of  the  solvent  but  not  those  of 
the  dissolved  substance  to  pass  through  it.  It  is  evident  that  if  such  a 
filter  is  placed,  for  example,  between  a  solution  of  sugar  in  water  and 
water  alone,  the  molecules  of  the  latter  will  diffuse  into  the  solution 
until  this  has  become  so  diluted  that  the  pressure  of  the  dissolved  mol- 
ecules is  equal  on  both  sides  of  the  membrane.  Such  a  membrane  is 
called  semipermeable ;  the  diffusion  of  molecules  through  it  is  called 
osmosis,  and  the  pressure  which  is  generated,  the  osmotic  pressure.  If 
we  prevent  the  water  molecules  from  actually  diffusing  by  opposing 
a  pressure  which  is  equal  to  that  with  which  they  tend  to  diffuse  through 
the  membrane,  we  can  tell  the  magnitude  of  the  osmotic  pressure  (Fig.  1). 

In  applying  these  facts  to  test  the  hypothesis  that  molecules  in  solution 


*This  implies  that  at  -273°  C.  the  gas  would  occupy  no  volume.  Before  this  temperature  is 
reached,  however,  the  liquefaction  of  the  gas  sets  in.  The  temperature  -273°  C.  is  known  as  absolute 
zero.  An  observed  temperature  pins  273°  is  called  the  absolute  temperature.  Another  way  of  stat- 
ing the  above  law  is  therefore  that  the  volume  is  directly  proportional  to  the  absolute  temperature. 
At  273°  C.  the  volume  of  a  gas  at  0°  C.  would  be  doubled,  or  if  expansion  were  prevented  the 
pressure  would  be  doubled. 


LAWS  OF  SOLUTION 


obey  the  same  laws  as  those  in  gaseous  form,  we  must  employ  a  semi- 
permeable  membrane  which  is  rigid  enough  to  withstand  the  pressure 
and  which  forms  part  of  the  walls  of  a  closed  vessel  connected  with  a 
manometer.  If  we  place  in  such  an  osmometer  a  solution  containing  the 
molecular  weight  in  grams  of  some  substance  dissolved  in  one  liter  of 
solvent,  a  so-called  gram-molecular  solution,  it  is  obvious  that,  if  the 
gas  laws  are  to  apply,  the  osmotic  pressure  should  equal  that  of  22.4 
liters  of  a  gas  compressed  to  the  volume  of  one  liter;  in  other  words, 
it  should  equal  22.4  x  760  =  17,024  mm.  Hg.  Although  there  are  very 
considerable  technical  difficulties  in  making  a  semipermeable  membrane 
that  is  strong  enough  to  withstand  such  a  pressure,  yet  this  has  been  accom- 


w 


Fig.  1. — Diagram  of  osmometer.  The  cylindrical  vessel  (0),  with  a  bottom  of  unglazed 
clay,  the  pores  of  which  are  filled  with  a  precipitate  of  copper  ferrocyanide  to  form  a  semi- 
permeable  membrane,  is  suspended  in  an  outer  vessel,  and  is  closed  above  by  a  tightly  fitting 
stopper  pierced  by  a  tube  leading  to  a  manometer  (M).  O  contains  a  strong  solution  of  cane 
sugar,  and  W  contains  water.  The  water  molecules  tend  to  pass  through  the  semipermeable 
membrane  into  the  cane  sugar  solution,  and  since  the  cane  sugar  molecules  can  not  pass  in 
the  opposite  direction,  the  pressure  in  O  rises  and  is  recorded  in  M.  This  equals  the  osmotic 
pressure. 

plished,  and  the  fundamental  principle  has  therefore  been  firmly  estab- 
lished that  substances  in  solution  obey  the  same  laws  as  gases. 

Further  proof  that  the  gas  laws  apply  to  solutions  has  been  secured  by 
showing  that  the  osmotic  pressure  (of  a  dilute  solution)  is  directly  pro- 
portional to  the  concentration  of  the  dissolved  substance  (the  solute) 
and  to  the  absolute  temperature.  It  also  obeys  the  law  of  partial  pres- 
sures, which  states  that  the  total  pressure  exerted  by  a  mixture  (of  gases 
or  dissolved  molecules)  is  the  sum  of  the  pressures  which  each  constit- 
uent of  the  mixture  would  exert  were  it  alone  present  in  the  space 
occupied  by  the  mixture. 


6  PHYSICOCHEMICAL   BASIS   OF   PHYSIOLOGICAL   PROCESSES 

Since  the  osmotic  pressure  is  analogous  to  the  pressure  of  a  gas  and 
is  therefore  proportional  to  the  molecular  concentration  (i.  e.,  number 
of  molecules  in  unit  space),  it  follows  that  a  semipermeable  membrane 
can  be  used  to  determine  the  relative  concentration  of  two  solutions  of 
the  same  substance.  When  a  watery  solution  of  some  substance  is 
placed  in  an  osmometer  that  is  surrounded  by  a  similar  but  more  dilute 
solution,  water  molecules  will  diffuse  into  the  osmometer  until  the  pres- 
sure is  equal  on  the  two  sides  of  the  semipermeable  membrane;  that  is, 
the  water  will  pass  from  the  solution  having  a  lower  osmotic  pressure 
into  the  solution  having  the  higher  pressure.  When  two  solutions  have 
the  same  osmotic  pressure,  they  are  said  to  be  isotonic;  when  that  of  one 
is  greater  than  that  of  the  other,  it  is  hypertonic;  and  when  less,  hypotonic. 

Biological  Methods  for  Measuring  Osmotic  Pressure 

A  practical  biological  application  of  these  principles  can  very  readily 
be  made  if,  instead  of  a  rigid  semipermeable  membrane  such  as  that 
figured  in  the  diagram,  we  employ  one  that  is  extensible  and  takes  the 
form  of  a  closed  sac ;  then  as  diffusion  of  water  occurs  the  sac  will  either 
distend  when  it  contains  a  stronger  solution  than  that  outside,  or  shrivel 
or  crenate  when  the  reverse  conditions  obtain.  Many  animal  and  veg- 
etable protoplasmic  membranes  are  semipermeable,  including  the  en- 
velope of  red  blood  corpuscles.  Thus,  if  we  examine  blood  corpuscles 
under  the  microscope  and  add  to  them  a  saline  solution  of  higher  os- 
motic pressure  than  blood  serum,  they  will  visibly  diminish  in  size  and 
become  irregular  in  shape;  whereas  if  the  solution  is  of  lower  osmotic 
pressure,  they  will  distend.  If  no  change  occurs,  the  osmotic  pressure  of 
the  cell  contents  must  equal  that  of  the  saline  solution  in  which  the  cells 
are  immersed,  from  which  it  is  clear  that  we  can  readily  determine  the 
magnitude  of  the  osmotic  pressure  if  we  know  the  strength  of  the 
saline  solution. 

Instead  of  measuring  the  individual  cells  under  the  microscope,  we  can 
measure  the  space  they  occupy  in  the  fluid  in  which  they  are  suspended. 
For  this  purpose  a  portion  of  the  suspension  is  placed  in  a  graduated 
tube  of  narrow  bore,  which  is  rotated  in  a  horizontal  position  by  a  cen- 
trifuge after  being  closed  at  one  end.  The  graduation  at  which  the 
upper  edge  of  the  column  of  cells  stands  after  centrifuging  is  a  measure 
of  the  relative  amounts  of  cells  and  of  fluid  in  the  suspension.  Having 
found  this  value  for  cells  suspended  in  an  isotonic  solution,  as  for  exam- 
ple, blood  corpuscles  in  blood  serum,  we  may  then  proceed  to  ascertain  it 
for  the  same  cells  suspended  in  an  unknown  solution;  if  we  find  that  the 
cells  now  occupy  a  greater  volume,  the  saline  solution  must  have  an  os- 


LAWS  OF  SOLUTION  7 

motic  pressure  that  is  lower  than  that  of  serum  in  approximate  proportion 
to  the  readings  on  the  tube  in  the  two  cases,  and  vice  versa. 

The  above  apparatus,  called  a  hematocrite  (Fig.  2)  has  been  very  ex- 
tensively used  in  the  collection  of  data  concerning  the  relative  osmotic 
pressures  of  different  physiological  fluids. 

Hemolysis 

Another  way  for  determining  the  relative  osmotic  pressure  of  dif- 
ferent solutions  consists  in  placing  equal  amounts  (a  few  drops)  of 
blood  in  a  series  of  test  tubes  containing  solutions  of  different  strengths, 
and  after  allowing  the  tubes  to  stand  for  some  time,  noting  in  which  of 
them  laking  of  the  blood  corpuscles  occurs.  In  solutions  which  are 
isotonic  or  hypertonic  with  the  contents  of  the  corpuscles,  the  latter 
will  settle  to  the  bottom  of  the  tube  and  the  supernatant  fluid  will  be 
untinted  with  hemoglobin,  but  in  solutions  which  are  distinctly  hypotonic, 
the  sediment  will  be  less  distinct  and  the  supernatant  fluid  red. 


Fig.  2.— Hematocrite.  The  graduated  glass  tubes  are  filled  with  the  two  specimens  of 
blood,  or  corpuscular  suspension,  and  then  rotated  rapidly  by  a  centrifuge.  The  relative  heights 
at  which  the  corpuscular  sediment  stands  in  the  two  tubes  is  proportional  to  the  osmotic 
pressures  of  the  fluid  in  which  the  corpuscles  are  suspended. 

By  noting  (1)  the  lowest  concentration  (percentage  composition)  of 
the  solutions  in  which  the  corpuscles  sink  to  the  bottom  and  leave  the 
supernatant  fluid  colorless,  and  (2)  the  highest  concentration  in  which 
the  corpuscles  when  they  settle  leave  the  supernatant  fluid  tinted  red,  we 
can  determine  the  limiting  concentrations  for  solutions  of  different  .sub- 
stances. Thus,  with  bullock's  blood  the  following  results  were  obtained 
(Hamburger) : 


SUBSTANCE 


PERCENTAGE  STRENGTH  OF  SOLUTION  IN  WHICH 
I  II 

SUPERNATANT  FLUID       SUPERNATANT  FLUID 
WAS  COLORLESS  WAS  RED 


KN03 

1.04 

0.96 

NaCl 

0.60 

0.56 

K2S04 

1.16 

1.06 

C^H^O,,  (Cane  sugar) 

6.29 

5.63 

CH3COOH   (Pot.  acetate) 

1.07 

1.00 

MgSO4.7H2O 

3.52 

3.26 

CaCL, 

0.85 

0.79 

8  PHYSICOCHEMICAL   BASIS   OF   PHYSIOLOGICAL   PROCESSES 

The  mean  of  these  limiting  concentrations  is  the  critical  concentration 
and  indicates  the  strength  of  each  solution  that  can  be  added  to  blood 
without  causing  any  damage  to  the  corpuscles.  This  critical  concen- 
tration is  not,  as  might  at  first  sight  be  imagined,  the  same  as  that 
which  is  isotonic  with  the  contents  of  the  corpuscles,  but  distinctly 
below  it.  The  reason  for  this  becomes  apparent  if  we  observe  the  be- 
havior of  corpuscles  suspended  in  an  isotonic  solution  which  is  then 
gradually  diluted.  As  dilution  proceeds,  the  corpuscles  distend,  until  at 
last  their  envelopes  burst  and  the  hemoglobin  is  discharged.  The  lim- 
iting concentrations  of  a  given  salt  vary  for  different  corpuscles;  thus, 
the  concentration  of  sodium  chloride  solution  that  just  causes  laking  of 
frog's  blood  corpuscles  is  0.21  per  cent,  that  of  human  blood  0.47  per  cent, 
and  that  of  horse  blood  0.68  per  cent.  It  is  the  strength  of  the  corpuscular 
envelope  rather  than  variations  in  the  osmotic  pressure  of  the  contents 
that  is  responsible  for  these  differences. 

The  above  described  method  of  hemolysis,  as  it  is  called,  can  not  be 
used  for  comparisons  of  osmotic  pressure  in  cases  in  which  the  solution 
contains  substances  which  alter  the  permeability  of  the  corpuscular 
envelop;  for  example,  it  can  not  be  used  when  urea,  or  ammonium 
salts,  or  certain  toxic  bodies  are  present.  We  may  therefore  ascertain 
whether  a  given  substance  has  a  damaging  influence  on  the  corpuscular 
envelope  by  finding  whether  hemolysis  occurs  when  we  suspend  the  cor- 
puscles in  a  solution  that  is  known  by  physical  methods  to  be  isotonic  with 
the  corpuscular  contents.  We  can  further  determine  the  approximate 
degree  of  this  toxic  influence  by  estimating  by  color  comparisons 
(colorimetry)  the  amount  of  hemoglobin  that  has  diffused  out  of  the 
corpuscles. 

Plasmolysis 

An  analogous  method  for  determining  osmotic  pressure  is  that  of 
plasmolysis,  in  which  the  behavior  of  certain  plant  cells  is  observed 
microscopically  while  they  are  in  contact  with  solutions  of  different 
strengths.  When  the  surrounding  solution  is  isotonic  with  the  cell 
contents,  the  latter  fill  the  cell  and  extend  up  to  the  more  or  less  rigid 
cell  wall  '(A  in  Fig.  3);  but  when  the  solution  is  hypertonic,  the  cell 
contents  become  detached  from  the  cell  wall  at  one  or  more  places — 
plasmolysis  (B  and  C).  The  semipermeable  membrane  in  this  case  is 
therefore  not  the  cell  wall  but  the  layer  of  protoplasm  on  the  surface 
of  the  cell  contents.  The  method  can  be  used  only  for  detecting  solu- 
tions that  are  hypertonic,  for  with  those  that  are  hypotonic  the  cells 
merely  become  turgid  and  exert  more  pressure  on  the  more  or  less 
rigid  cell  wall.  Many  of  the  conclusions  that  have  been  drawn  from 


LAWS  OF  SOLUTION 

results  obtained  by  the  plasmolytic  method  have  recently  been  called  in 
question,  because  no  regard  has  been  taken  of  the  power  of  the  colloids 
of  the  cell  to  absorb  (imbibe)  water  (see  page  63). 

The  methods  of  hemolysis  and  plasmolysis  have  been  used  for  the  inves- 
tigation of  many  problems  in  medicine  besides  those  pertaining  strictly  to 
osmotic  pressure.  In  the  case  of  certain  toxic  fluids,  such  as  snake  venom, 
tetanus  toxin,  etc.,  determination  of  the  hemolytic  power  has  proved  of 
value  in  roughly  assaying  the  damaging  influence  on  other  cells  than 
blood  corpuscles.  Studies  in  hemolysis  have  also  been  especially  valuable 
in  working  out  the  mechanism  by  which  cellular  toxins  in  general  develop 
their  action,  and  the  conditions  under  which  this  action  may  be  counter - 


Fig.  3. — To  show  plasmolysis  in  cells  from  Tradescantia  discolor.  A.  normal  cell;  B, 
plasmolysis  in  0.22  M.  cane  sugar;  C,  pronounced  plasmolysis  in  1.0  M.  KNO3;  h,  the  cell 
wall;  p,  the  protoplasm.  (After  De  Vries.) 

acted,  as  by  the  development  of  antibodies.  Furthermore,  any  solution 
that  is  to  be  injected  into  the  animal  body,  either  intravenously  or  subcu- 
taneously,  should  first  of  all  be  tested  by  the  above  methods  in  order  to 
find  out  whether  it  is  isotonic  with  the  body  fluids.  If  a  hypertonic  so- 
lution is  injected,  it  will  result  in  the  abstraction  of  water  from  the  tissue 
cells,  whereas  a  hypotonic  solution  will  cause  the  water  content  of  these  to 
increase.  Advantage  has  recently  been  taken  of  this  water-abstracting 
effect  of  hypertonic  solutions  in  the  treatment  of  wounds.  By  constantly 
bathing  them  with  strong  saline  solutions,  an  outflow  of  water  is  set  up 
from  the  tissue  cells  that  border  on  the  wound,  and  this  tends  to  bring  to 
the  focus  of  infection  the  defensive  substances  that  are  present  in  animal 
fluids. 


CHAPTER  II 
OSMOTIC  PRESSURE  (Cont'd) 

MEASUREMENT  BY  DEPRESSION  OF  FREEZING  POINT 

The  limitations  in  the  use  of  the  plasmolytic  and  hemolytic  methods 
in  the  precise  measurement  of  the  osmotic  pressure  of  the  body  fluids 
have  rendered  it  necessary  to  find  some  physical  method  that  will  be 
generally  applicable.  Because  of  technical  difficulties,  it  is  impracticable 
to  measure  the  pressure  directly  by  employing  an  osmometer,  so  that 
some  indirect  method,  depending  on  a  readily  measurable  physical  prop- 
erty which  varies  in  proportion  to  the  osmotic  pressure  of  the  dissolved 
substances,  must  be  used.  Fortunately,  one  such  exists  in  the  property 
which  dissolved  substances  have  in  lowering  the  temperature  at  which 
the  pure  solvent  solidifies;  the  freezing  point  of  pure  water,  for  example, 
is  lowered  when  substances  are  dissolved  in  it,  and  the  extent  of  this 
lowering,  with  certain  reservations  which  will  be  explained  later  (page 
16),  is  proportional  to  the  molecular  concentration  of  the  solution  and 
independent  of  the  chemical  nature  of  the  substance  dissolved.  This 
lowering  of  temperature  is  designated  by  the  Greek  letter  A,  and  to 
measure  it  a  thermometer  is  used  which  is  not  only  extremely  sensitive 
but  in  which  the  level  of  the  mercury  column  can  be  adjusted  so  that  it 
stands  at  a  convenient  level  on  the  scale  corresponding  to  the  freezing 
point  of  whatever  solvent  was  used  in  making  the  solution  under  investi- 
gation (Beckman's  thermometer)  (Fig.  4).  Having  ascertained  the  exact 
position  on  the  scale  of  this  thermometer  at  which  the  pure  solvent  freezes, 
the  observation  is  repeated  with  the  solution,  the  osmotic  pressure  of  which 
is  to  be  determined. 

A  gram-molecular  solution  in  water  (having  therefore  an  osmotic  pres- 
sure of  17.024  mm.  Hg)  has  a  freezing  point  that  is  1.86°  C.  lower  than 
that  of  pure  water.  This  is  known  as  the  " freezing  point  constant," 
and  it  varies  for  different  solvents,  being  3.9  for  acetic  acid  and  4.9 
for  benzene.  If  an  unknown  watery  solution  is  found  to  have  a  freez- 
ing point  that  is  A°  C.  lower  than  that  of  wa'ter,  its  osmotic  pressure 

,  Ax  17.024 

will  equal  — r-^ mm.  Hg. 

l.oo 

The  depression  of  the  freezing  points  produced  by  the  various  body 

10 


OSMOTIC   PRESSURE 


11 


fluids  has  been  compared,  the  objects  in  view  being  to  see  whether 
osmotic  pressure  is  a  property  which  changes  under  different  physiological 
and  pathological  conditions,  and  to  find  out  by  comparison  of  the  osmotic 
pressures  of  the  fluids  in  contact  with  a  membrane,  whether  physical 
forces  alone  can  be  held  responsible  for  the  transference  of  substances 
through  it  from  one  fluid  to  the  other. 


THE  ROLE  OF  OSMOSIS,  DIFFUSION,  AND  ALLIED  PROCESSES 
IN  PHYSIOLOGICAL  MECHANISMS 

The  Transference  of  Substances  Through  Cell  Membranes.— An  ac- 

investigations    in    which    the    foregoing    meth- 


count    of    some    of    the 


Fig.  4. — Apparatus  for  measurement  of  the  depression  of  freezing  point  of  solutions.  The 
solution  is  placed  in  the  large  test  tube  with  the  side  arm,  and  in  it  is  suspended  the  bulb 
of  a  Beckmann  thermometer  with  a  platinum  loop  to  serve  for  stirring.  The  upper  end^of 
the  mercury  column  of  the  thermometer  is  shown  magnified  at  the  upper  left  corner.  ihe 
amount  of  mercury  in  the  thermometer  tube  can  be  regulated  by  tapping  the  upper  end  with 
the  thermometer  in  various  positions.  The  test  lube  is  protected  by  an  outer  tube,  which  is 
then  placed  in  a  vessel  containing  a  freezing  mixture. 

ods  have  been  used  will  illustrate  their  value  in  revealing  the  mech- 
anism involved  in  the  transference  of  water  and  dissolved  substances 
through  cell  membranes,  as  occurs  in  absorption  of  food  in  the 
intestine,  in  the  formation  of  lymph  and  urine,  and  so  forth.  In  em- 
ploying physical  methods  in  the  elucidation  of  such  problems,  it  is 
always  most  necessary  to  proceed  with  great  care,  since  the  physical 


12  PHYSICOCHEJMICAL   BASIS   OF   PHYSIOLOGICAL   PROCESSES 

chemist  works  with  pure  solutions,  while  the  physiologist  has  to  use 
fluids  that  are  always  complicated  and  frequently  very  variable  in  com- 
position. We  must  simplify  the  problem  as  far  as  possible  by  having 
clearly  before  us  the  exact  nature  of  the  biological  problem  which  a  com- 
parison of  physicochemical  values,  such  as  osmotic  pressure,  may  ena- 
ble us  to  elucidate,  and  we  must  consider  the  other  physical  forces 
which  may  assist  or  modify  the  particular  one  we  are  investigating. 

In  the  physical  experiments  described  above,  the  semipermeable  mem- 
brane may  be  conceived  of  as  composed  of  pores  of  such  a  size  that 
they  permit  only  the  smallest  of  molecules — those  of  water — to  pass 
through  them.  Semipermeable  membranes  with  larger  pores  may,  how- 
ever, exist — that  is,  membranes  which  permit  water  molecules  and  mole- 
cules of  simple  chemical  substances  to  pass,  but  hold  back  those  com- 
posed of  large  complex  molecules.  Such  a  semipermeable  membrane 
would  allow  the  saline  constituents  but  not  the  proteins  of  blood  serum 
to  pass.  It  is,  however,  no  longer  semipermeable  towards  all  of  the  dis- 
solved substances,  and  the  process  of  diffusion  through  it  is  more  gener- 
ally designated  as  one  of  dialysis  than  of  osmosis. 

Since  the  passage  of  dissolved  molecules  through  membranes  de- 
pends upon  the  principle  of  diffusion,  its  rate  will  be  proportional  to 
the  osmotic  pressures  of  the  solutions  on  the  two  surfaces  of  the  mem- 
brane and  to  the  size  of  the  molecules,  small  molecules  diffusing  more 
quickly  than  large  ones.  Suppose  a  membrane  permeable  to  sodium 
chloride  and  water  is  placed  between  two  fluids  containing  sodium 
chloride  in  solution,  but  in  greater  concentration  in  one  of  them  than 
in  the  other:  although  the  sodium  chloride  will  diffuse  from  the  stronger 
to  the  weaker  solution,  the  water  will  tend  to  diffuse  still  more  quickly  (be- 
cause its  molecules  are  smaller)  in  the  opposite  direction,  until  the  number 
of  sodium-chloride  molecules  in  a  given  volume  of  solution  is  equal  on 
both  sides  of  the  membrane.  For  a  time,  therefore,  the  volume  of  the 
stronger  solution  will  increase.  The  differences  which  exist  in  the  dif- 
fusibility  of  dissolved  molecules  are  analogous  to  those  which  have 
long  been  known  to  exist  in  the  diffusibility  of  gases,  but  the  relation 
between  rate  of  diffusibility  and  molecular  weight  is  not  so  simple  as 
the  ratio  between  these  two  quantities  in  gases.  These  relationships, 
however,  indicate  several  further  possibilities  in  the  explanation  of  the 
mechanism  of  exchange  of  substances  through  membranes,  and  must  not 
be  overlooked,  as  they  often  are,  in  the  interpretation  of  physiological 
phenomena.  An  excellent  review  of  the  possible  conditions  is  given 
by  Starling  in  his  " Human  Physiology."4  For  example,  let  us  suppose 
the  substances  dissolved  in  the  fluid  on  the  two  sides  of  a  semipermeable 
membrane,  such  as  the  peritoneum,  to  be  different  in  diffusibility,  as  cane 


OSMOTIC   PRESSURE  13 

sugar,  which  does  not  readily  diffuse,  and  sodium  chloride,  which  diffuses 
quickly;  the  osmotic  flow  will  take  place  from  the  sodium-chloride  solu- 
tion to  that  of  cane  sugar  even  though  the  sodium-chloride  solution  is 
stronger  than  the  sugar. 

Furthermore,  the  simple  laws  of  osmosis  may  be  upset  by  an  attrac- 
tive influence  of  the  membrane  toward  certain  substances  [due  to  their 
becoming  dissolved  or  adsorbed  in  it  (see  page  66)]  but  not  toward 
others.  Many  membranes  of  this  nature  are  known  to  the  chemist 
(e.  g.,  rubber  membranes  in  contact  with  gases,  pyridine  solutions,  etc.), 
and  it  is  probable  that  such  a  property  of  selective  solubility  may  play 
a  not  unimportant  role  in  the  transference  of  substances  across  animal 
membranes  (Kahlenberg5). 

These  few  conditions  which  may  modify  the  direction  of  the  osmotic 
flow,  are  indicated  here  to  show  how  involved  such  problems  are,  and 
how  careful  we  must  be  not  to  assume  that,  because  a  substance  is  trans- 
ferred through  a  living  membrane  contrary  to  the  simpler  laws  of  os- 
mosis and  diffusion,  it  must  involve  the  expenditure  of  forces  different 
from  those  operating  in  dead  membranes. 

Another  force  comes  into  operation  in  causing  transference  of  sub- 
stances through  membranes — namely,  that  of  filtration.  This  is  a  purely 
mechanical  process,  in  which  molecules  are  forced  through  the  pores  of  a 
filter  (i.  e.,  membrane)  by  differences  in  pressure  on  its  two  sides. 

We  are  now  in  a  position  to  consider  in  how  far  the  above  physical 
forces  explain  certain  physiological  problems. 

The  Physical  Factors  Involved  in  Absorption,  Excretion  and  Lymph 
Formation. — 1.  Is  the  absorption,  into  the  Hood  and  lymph  circulating 
in  the  intestinal  walls,  of  substances  in  solution  in  the  intestinal  contents, 
entirely  dependent  upon  the  processes  of  filtration,  diffusion  and  osmosis  f 
The  absorption  of  wreak  solutions  of  highly  diffusible  substances  is  probably 
very  largely  a  matter  of  osmosis  and  diffusion,  and  water  passes  quickly 
into  the  blood  because  of  osmotic  attraction,  but  that  other  forces  ordi- 
narily come  into  play  is  very  clearly  established  by  the  following  ob- 
servations. If  a  piece  of  intestine  is  isolated  from  the  rest  by  placing 
two  ligatures  on  it,  and  the  isolated  loop  filled  either  with  a  solution  con- 
taining the  same  saline  constituents  in  similar  proportions  as  in  blood 
serum,  or  better  still,  with  some  of  the  same  animal's  blood  serum,  it 
will  be  found  after  some  time  that  all  of  the  solution  becomes  absorbed 
into  the  blood;  the  contents  of  the  loop  are  therefore  absorbed  into  the 
blood,  even  though  the  osmotic  pressures  of  the  dissolved  substances  are 
the  same  on  both  sides  of  the  membrane  (Weymouth  Eeid6). 

The  intestinal  membrane  seems  to  possess  towards  readily  diffusible 


14  PHYSICOCHEMICAL   BASIS   OF   PHYSIOLOGICAL   PROCESSES 

substances  a  permeability  which  varies,  not  at  all  with  the  physical 
diffusibility  of  the  substance,  but  with  its  value  from  a  physiological 
standpoint.  Thus,  sodium  sulphate  and  sodium  chloride  diffuse  through 
ordinary  membranes  with  about  equal  facility,  and  yet  if  a  solution  con- 
taining these  two  salts  is  placed  in  the  intestine,  the  chloride  will  be 
absorbed  into  the  blood  much  more  quickly  than  the  sulphate.  Sodium 
sulphate  in  watery  solution  diffuses  through  a  membrane  fifteen  times 
more  quickly  than  cane  sugar,  but  from  the  intestinal  lumen,  cane 
sugar  is  absorbed  ten  times  more  quickly  than  sodium  sulphate.  If. 
however,  the  vitality  of  the  epithelium  is  destroyed,  as  by  first  of  all 
bathing  it  with  a  solution  of  sodium  fluoride,  then  the  sulphate  and 
chloride  will  be  absorbed  at  an  equal  rate. 

Although  diffusion  and  osmosis  can  not  therefore  play  any  significant 
role  in  the  normal  process  of  absorption  from  the  intestine,  we  must 
not  entirely  discount  them;  under  certain  circumstances,  these  physical 
forces  may  assert  their  influence  as,  for  example,  when  concentrated 
saline  solutions  are  present.  Such  solutions  will  attract  water  from  the 
blood,  and,  other  things  being  equal,  more  will  be  attracted  the  less 
permeable  the  epithelium  happens  to  be  towards  the  saline  employed. 
Sulphates  and  phosphates  will  attract  more  water  than  chlorides  or 
acetates.  This  property  of  the  saline  solutions  to  attract  water  coun- 
teracts the  natural  tendency  for  the  water  to  be  absorbed,  and  the 
large  volume  of  fluid  stimulates  peristalsis. 

2.  Do  the  physical  processes  of  filtration,  diffusion  and  osmosis  suf- 
fice to  account  for  the  production  of  urine  by  the  kidneys?  Under  normal 
conditions  the  molecular  concentration  of  the  urine,  as  determined  by 
the  depression  of  freezing  point,  is  considerably  greater  than  that  of 
the  blood.  This  indicates  that  excretion  must  have  occurred  contrary 
to  the  laws  of  diffusion  and  osmosis;  in  other  words,  that  the  renal  cells 
must  have  compelled  dissolved  molecules  to  be  transferred  from  the 
blood  to  the  urine,  although  the  difference  in  concentration  would  cause 
them  to  pass  in  the  opposite  direction.  This  force,  sometimes  called  for 
want  of  a  better  name  " vital  activity,"  must  depend  on  the  operation  of 
processes  that  are  quite  distinct  from  those  of  diffusion,  etc.;  but  that 
they  are  necessarily  of  a  nonphysical  nature  (e.  g.,  vital)  is  less  probable 
than  that  they  depend  on  some  physical  process  the  nature  of  which  our 
present  knowledge  does  not  permit  us  to  understand. 

By  comparing  the  osmotic  pressures  of  urine  and  blood,  attempts 
have  been  made  to  measure  the  work  done  by  the  kidney  in  the  produc- 
tion of  urine.  Thus,  it  has  been  found  that  A  for  normal  urine  (human) 
is  about  1.8,  and  for  blood  about  0.6,  from  which  it  may  be  calculated 
that  in  the  production  of  1  kilogram  of  urine  150  kilogrammeters  of 


OSMOTIC   PRESSURE  15 

work  are  expended.*  But  that  such  comparisons  of  the  osmotic  pres- 
sure of  blood  and  urine  are  fallacious  as  an  indication  of  the  work  of 
the  kidney  is  evidenced,  not  alone  by  the  results  of  the  above  calcula- 
tions, but  also  by  the  fact  that  under  certain  circumstances  (as  after 
copious  diuresis)  the  osmotic  pressure  of  the  urine  may  be  considerably 
lower  than  that  of  the  blood. 

For  some  time  after  the  application  of  osmotic  pressure  measurements 
to  the  study  of  biological  problems,  it  was  thought  that  determination 
of  A  in  urine  might  be  of  clinical  value  as  a  criterion  of  renal  efficiency, 
especially  in  one  kidney  as  compared  with  the  other.  For  this  purpose 
A  was  determined  in  samples  of  urine  removed  from  each  ureter  by 
catheterization.  The  tests  of  renal  efficiency  based  on  the  rate  of  excre- 
tion and  on  the  specific  gravity  of  the  urine,  following  ingestion  of  a  fixed 
amount  of  water,  have  been  found  of  much  greater  value. 

3.  Is  the  formation  of  lymph  purely  a  physical  process?  The  osmotic 
pressure  of  normal  lymph  is  nearly  always  somewhat  below  that  of 
blood  serum,  although  occasionally  it  has  been  found  to  be  a  trifle 
higher.  Physical  processes,  such  as  filtration,  might  therefore  suffice 
to  account  for  its  formation  under  most  conditions.  But  when  we  con- 
sider the  excessive  production  of  lymph  that  occurs  as  a  result  of  cel- 
lular activity  or  following  the  injection  of  certain  substances,  called 
"lymphagogues,"  it  is  not  so  easy  to  explain  the  production  in  such 
terms,  although  some  interesting  attempts  have  been  made  to  do  so  by 
those  that  are  wedded  to  the  mechanistic  view.  For  example,  the  very 
marked  increase  in  lymph  flow  which  occurs  as  a  result  of  muscular 
exercise  or  glandular  activity  has  been  attributed  to  the  fact  that  dur- 
ing such  processes  large  molecules  become  broken  down  into  small  ones 
in  the  cell  protoplasm,  so  that  the  osmotic  pressure  is  raised  and  water 
is  attracted  into  the  the  cell  until  the  latter  becomes  distended  and  a 
process  of  filtration  into  the  neighboring  lymph  spaces  occurs  (see 
page  119). 

There  are  several  other  physiological  processes  of  secretion  and  excre- 
tion which  might  be  considered  in  the  present  relationship,  but  the  above 
instances  will  suffice  to  illustrate  the  general  principle  upon  which  all  of 
them  have  to  be  considered. 

*Osmotic  pressure  corresponding  to  A  =  -0.6°  C.  ermals  5,662  mm.  Hg  (75  m.  of  H2O),  and 
that  corresponding  to  A  —  "1-8°  C.  equals  16,986  mm.  Hg  (225  m.  HoO).  The  difference  is  there- 
fore equal  to  a  column  of  water  150  m.  high.  According  to  these  calculations  it  would  appear  that 
the  kidney  in  producing  the  average  daily  output  of  1500  c.c.  urine  performs  225  kilogrammeters  of 
work  in  comparison  with  the  14,000  kilogrammeters  which  the  heart  is  computed  to  perform  in  the 
same  time  (page  213). 


CHAPTER  III 

ELECTRICAL  CONDUCTIVITY,  DISSOCIATION,  AND 
IONIZATION 

The  osmotic  pressure  is  not  infrequently  found  to  be  considerably 
greater  than  that  expected  from  the  strength  of  the  solution.  Although 
A  of  a  gram-molecular  watery  solution  of  cane  sugar  (342  gm.  to  the  liter) 
is  1.86  (see  page  10),  that  of  sodium  chloride  (58.5  gm.  to  the  liter)  is 
considerably  greater.  If  the  hypothesis  regarding  the  relationship  of 
molecular  concentration  to  osmotic  pressure  is  to  hold  good,  it  becomes 
necessary  to  explain  this  apparent  inconsistency;  one  must  account  for 
a  greater  number  of  dissolved  units  than  is  represented  by  the  actual 
number  of  dissolved  molecules  (i.e.,  weight  of  dissolved  substances). 

It  was  observed  that  the  power  to  conduct  the  electric  current — electrical 
conductivity — in  the  case  of  solutions  (e.  g.,  of  sugar)  which  have  an 
osmotic  pressure  that  corresponds  to  the  weight  of  dissolved  substances 
is  practically  nil,  whereas  the  conductivity  of  those  solutions  which  give 
higher  osmotic  pressure  is  quite  pronounced.  Arrhenius  made  the  hy- 
pothesis that  the  conductivity  depends  on  the  splitting  of  molecules  into 
two  or  more  portions  or  ions,  each  of  which  carries  either  a  positive  or  a 
negative  electric  charge,  and  that  it  is  only  when  such  dissociation  occurs 
that  the  electric  current  can  be  conducted  through  the  solution,  the  ions 
serving  as  it  were  as  floats  carrying  the  electric  current.  When  sodium 
chloride  is  dissolved  in  water,  it  splits  into  Na  carrying  a  positive  charge 
and  Cl  carrying  a  negative  charge,  or  Na+Cl~,  as  it  is  written;  on  the 
other  hand,  when  sugar  is  dissolved,  the  molecules  remain  unbroken  and 
no  electric  charges  are  set  free. 

Substances  which  thus  dissociate  are  called  electrolytes,  and  those  which 
do  not,  nonelectrolytes.  When  the  electric  current  is  passed  through  a 
solution  of  electrolytes,  the  ions  which  carry  a  positive  charge  move  to 
the  electrode  or  pole  by  which  the  current  leaves  the  solution — that  is,  in 
the  same  directions  as  the  current;  and  since  this  electrode  is  called  the 
cathode,  these  are  called  cations.  Hydrogen  and  the  metals  belong  to 
this  group.  The  ions  carrying  a  negative  charge  go  in  the  opposite  direc 
tion,  against  the  current — that  is,  towards  the  electrode  by  which  the  cur- 
rent enters,  or  the  anode;  they  are  therefore  called  anions.  They  include 
oxygen,  the  halogensrand  the  acid  groups,  such  as  S04,  C03,  etc. 

It  must  be  understood  that  this  dissociation  into  ions  is  already  present 

16 


ELECTRICAL  CONDUCTIVITY,  DISSOCIATION,   IONIZATION  17 

in  the  solution  before  any  electric  current  passes  through  it,  the  ions 
being  however  uniformly  distributed  throughout — that  is,  arranged  so 
that  the  negative  charges  of  the  anions  precisely  neutralize  the  positive 
charges  of  the  cations.  The  electric  current  causes  the  electrodes  to  be- 
come charged,  the  one  positively,  the  other  negatively,  so  that  an  attrac- 
tive force  is  exerted  on  the  ions  of  opposite  sign.  This  causes  the  nega- 
tively charged  ions  to  migrate  towards  the  positive  electrode,  and  the 
positively  charged,  towards  the  negative  electrode.  It  is  this  migration 
of  the  ions  that  endows  the  solution  with  conducting  qualities. 

In  water,  or  in  a  solution  of  a  nonelectrolyte,  molecules  of  H20  or  non- 
electrolyte  exist  thus: 

H00  H20  H20 

H20     H20     H20 
H20     H20     H20 

In  a  solution  of  an  electrolyte,  many  of  the  molecules  split  into  ions  thus : 

Na*    Cl-    Na+    Cl-    Na*    01- 

Na>     Cl-    Na+     Cl-     Na>     01- 
Na+    Cl-    Na+    Cl-    Na+    01- 

When  an  electric  current  passes  through  a  solution  of  an  electrolyte, 
the  ions  tend  to  arrange  themselves  thus: 

Cathode-  Anode* 

Na+    Na>  Na*  Cl-  Cl-    01- 

Na+    Na+  Na+  Cl-  Cl-    01- 

Na+    Na+  Na*  Cl-  Cl-    01- 

It  follows  from  the  above  considerations  that  the  conductivity  of  a  sub- 
stance in  solution  will  depend  on  the  degree  to  which  it  undergoes  dissocia- 
tion. Furthermore,  if  we  assume  that  in  so  far  as  osmotic  pressure 
phenomena  are  concerned,  each  ion  behaves  in  the  same  way  as  a  mole- 
cule, then  it  follows  that  the  electrical  conductivity  must  be  proportional 
to  the  extent  to  which  the  osmotic  pressure  is  greater  than  we  should  ex- 
pect it  to  be  from  the  amount  of  substance  actually  dissolved. 

In  the  Determination  of  the  Conductivity  it  is  obviously  necessary  to 
use  standard  conditions  of  depth  and  width  of  the  fluid  through  which  the 
current  is  passed,  and  to  have  some  standard  of  comparison.  The  value 
is  then  known  as  the  specific  conductivity,  the  standard  for  comparison 
being  the  conductivity  of  a  hypothetical  liquid  which,  if  enclosed  in  a 
centimeter  cube,  would  offer  a  resistance  of  1  ohm  between  two  opposite 
sides  of  the  cube  acting  as  electrodes.  The  actual  determination  is  usu- 


18 


PHYSICOCHEMICAL   BASIS   OF   PHYSIOLOGICAL   PROCESSES 


ally  made  in  a  cylindrical  vessel  of  hard  glass  (from  soft  glass  enough 
alkali  might  be  dissolved  to  affect  the  results),  the  electrodes  being  circu- 
lar plates  of  platinum  firmly  cemented  at  a  known  distance  from  each 
other  (Fig.  5).*  This  conductivity  cell,  as  it  is  called,  is  connected 
with  a  suitable  apparatus  for  measuring  the  resistance  offered  by  the 


Fig.  5. — Diagram  of  conductivity  cells.  The  platinum  discs  are  represented  by  the  thick 
black  lines.  They  are  held  in  position  by  thick-walled  glass  tubes,  through  which  they  are 
connected  with  the  terminals  by  platinum  wires.  (From  Spencer.) 

solution  to  the  passage  of  an  electric  current  (Wheatstone  Bridge)  (see 
Fig.  6).  The  resistance  is  of  course  inversely  proportional  to  the  con- 
ductivity. 

As  a  saline  solution  is  progressively  diluted,  its  specific  conductivity 
naturally  decreases  (since  there  are  now  fewer  molecules  between  the 


Fig.    6. — Wheatstone    Bridge    for    the    measurement    of    electric    resistance:    a-b,    bridge    wire;     c, 

the    movable    contact. 

two  opposite  faces  of  the  centimeter  cube,  and  the  space  between  ions  or 
molecules  is  increased).  This  result  will  not,  however,  tell  us  whether 
the  salt  itself  is  undergoing  any  alteration  in  conducting  power  as  a  con- 
sequence, for  example,  of  greater  dissociation.  To  ascertain  this  we  must 


*This  distance  is  determined  not  by  direct  measurement  but  by  calculation  from  results  obtained 
by  testing  the  actual  resistance  of  a  solution  whose  specific  resistance  is  accurately  known. 


ELECTRICAL  CONDUCTIVITY,  DISSOCIATION,   IONIZATION  19 

obtain  figures  relating  to  the  same  quantity  of  salt  at  each  dilution.  If 
we  multiply  the  specific  conductivity  by  the  volume  of  solution  in  c.c. 
which  contains  1  gram-equivalent  (see  page  22),  a  value  will  be  secured 
which  represents  the  conducting  power  of  a  gram-equivalent.  This  is 
known  as  the  equivalent  or  molecular  conductivity*  and  is  represented  by 
the  sign  A.  When  it  is  determined  for  progressively  diluted  solutions, 
A  gradually  increases,  indicating  that  the  efficiency  of  the  electrolyte  itself 
as  a  conductor  increases  with  dilution,  because  it  dissociates  more.  The 
extent  of  this  increase  is  found  to  become  less  and  less  as  dilution 
proceeds.  By  plotting  the  values  of  the  molecular  conductivity  of  suc- 
cessive dilutions  as  a  curve,  the  value  at  infinite  dilution  can  be  ascertained 
by  extrapolation.  This  value  is  represented  by  A  a. 

Now,  let  us  see  how  these  facts  bear  out  the  theory  of  electrolytic  dissocia- 
tion. According  to  this  hypothesis  the  conductivity  depends  on  the  num- 
ber of  ions  (see  page  17),  and  since  it  is  at  a  maximum  at  infinite  dilu- 
tion, the  value  A«  must  represent  the  total  number  of  ions  that  can  be  pro- 
duced by  the  dissociation  of  1  gram-equivalent,  and  A  that  at  some  other 
dilution.  If,  therefore,  we  divide  A  by  Ace  we  obtain  a  value  (called  a) 
which  must  represent  the  degree  to  which  the  electrolyte  is  ionized  at  the 
various  dilutions  at  which  A  is  measured.  From  what  has  been  said  re- 
garding the  osmotic  pressure  of  similar  solutions,  it  is  evident  that  the 
value  a  could  also  be  calculated  by  finding  the  extent  to  which  the  de- 
pression of  freezing  point  (A)  is  greater  than  would  be  expected  from  the 
number  of  dissolved  molecules.  As  a  matter  of  fact,  it  has  been  found 
that  the  two  methods  yield  practically  identical  values  for  many  substances, 
thus  furnishing  almost  incontrovertible  proof  in  support  of  the  dissociation 
hypothesis.  In  the  cases  of  weak  acids  and  bases,  it  is  possible  to  secure 
a  value,  called  the  dissociation  constant  (K),  which  represents  the  rela- 
tive values  of  a  at  all  dilutions.  Since  the  activity  of  acids  and  bases 
is  dependent  upon  the  number  of  H-  and  OH-ions,  respectively,  set  free 
by  dissociation,  it  follows  that  it  must  be  proportional  to  K.  It  will  be 
necessary,  however,  to  postpone  a  further  consideration  of  the  application 
of  this  constant  until  we  have  studied  mass  action  (page  23). 

Biological  Applications. — The  practical  value  of  a  knowledge  of  the 
laws  of  electrical  conductivity  rests,  not  so  much  on  any  direct  application 
that  can  be  made  of  it  in  explaining  physiological  processes,  as  on  the  es- 
sentially important  bearing  which  it  has  in  enabling  us  to  understand  the 
nature  and  operation  of  other  physicochemical  laws.  Without  a  clear  com- 
prehension of  the  elemental  laws  of  dissociation,  it  is  impossible  to  con- 
sider such  problems  as  those  which  concern  the  activities  of  enzymes  (mass 

*In  other  words,  the  molecular  conductivity  is  the  specific  conductivity  divided  by  the  number  of 
gram-equivalents  contained  in  1  c.c. 


20  PHYSICOCHEMICAL   BASIS   OF   PHYSIOLOGICAL   PROCESSES 

action,  etc.),  the  occurrence  of  electrical  currents  during  the  physiological 
activity  of  muscles,  glands,  and  nerves,  and  the  all-important  question  of 
the  reaction  or  H-ion  concentration  of  the  body  fluids. 

There  are,  however,  several  instances  in  which  measurements  of  electrical 
conductivity  and  of  dissociation  have  direct  physiological  value.  The  circu- 
lation time  of  the  bloodflow  through  an  organ  can  be  determined  by  first 
finding  the  electrical  resistance  of  a  short  piece  of  the  vein  of  the  organ, 
and  then  observing  the  change  in  resistance  which  is  produced  when  the 
conductivity  of  the  blood  in  the  vein  is  altered  by  the  arrival  in  it  of 
saline  injected  into  the  artery.  The  interval  elapsing  between  the  injec- 
tion into  the  artery  and  the  changes  in  resistance  in  the  vein  equals  the 
circulation  time  (G.  N.  Stewart). 

The  same  investigator  has  used  measurements  by  electrical  conductiv- 
ity to  study  the  passage  of  electrolytes  out  of  the  red  blood  corpuscles  into 
the  serum.  Under  normal  conditions  the  blood  serum  has  a  certain  elec- 
trical conductivity  equal  to  that  of  a  0.9  per  cent  sodium-chloride  solution. 
The  conductivity  of  the  defibrinated  blood  is  only  about  one-half  that  of 
serum,  because  it  contains  corpuscles  which  are  nonconductors  and  there- 
fore obstruct  the  free  passage  of  the  ions,  just  as  a  suspension  of  quartz 
powder  in  a  sodium-chloride  solution  lowers  the  conductivity  of  the  lat- 
ter. If  anything  occurs  therefore  to  occasion  a  passage  of  the  saline  con- 
tents of  the  corpuscles  through  their  walls  into  the  serum,  an  increase  in 
the  electrical  conductivity  will  be  produced.  The  value  of  this  method  in 
the  investigation  of  changes  in  permeability  of  the  red  corpuscles  is  de- 
pendent on  the  fact  that  such  migration  of  electrolytes  out  of  the  cor- 
puscles may  occur  before  any  of  the  less  diffusible  hemoglobin  itself  has 
escaped.  The  rise  in  conductivity  precedes  the  hemolysis  (see  page  7). 

Although  determinations  of  the  specific  conductivity  of  blood  and  urine 
under  various  pathological  conditions  have  also  been  made,  the  results 
have  not  been  found  to  possess  any  diagnostic  value  or  clinical  signifi- 
cance. Measurements  of  the  electrical  conductivity  of  blood  have,  how- 
ever, been  used  by  Wilson7  and  by  Priestley  and  Haldane8  to  detect  the 
degree  of  dilution  when  large  quantities  of  water  are  ingested. 

Another  application  of  conductivity  measurements  in  biochemistry  has 
been  made  in  studying  the  digestive  action  of  proteolytic  enzymes  (Ba}r- 
liss).  The  general  action  of  the  enzymes  is  to  break  the  large  undisso- 
ciated  molecules  of  the  higher  proteins  (albumin,  casein,  etc.),  into 
smaller  molecules  (amino  acids,  etc.),  which  are  partly  ionized.  As  diges- 
tion proceeds,  therefore,  the  conductivity  of  the  digestion  mixture  pro- 
gressively increases,  and  is  a  measure  of  the  rate  of  digestion. 

Applications  of  the  dissociation  hypothesis  in  physiology  concern  the 
explanation  of  such  phenomena  as  the  production  of  electric  currents 


ELECTRICAL  CONDUCTIVITY,  DISSOCIATION,   IONIZATION  21 

during  muscular,  glandular,  and  nervous  activity.  The  exact  details  of 
the  application  are  not  as  yet  sufficiently  understood  to  warrant  our  at- 
tempting to  do  more  than  indicate  the  general  lines  along  which  the 
problems  are  being  investigated.  To  do  so  we  must  delve  a  little  further 
into  physicochemical  research,  when  we  shall  find  that  there  are  two  further 
facts  concerning  ionized  molecules  that  must  be  of  importance  in  connec- 
tion with  our  problem.  The  first  is  that  the  contribution  which  each  ion 
makes  to  the  equivalent  (or  molecular)  conductivity  of  a  solution  is  inde- 
pendent of  the  other  ion  with  which  it  is  associated;  and  the  second,  that 
ions  differ  considerably  in  their  conducting  power.  Since  the  univalent 
ions,  K.,  Na.,  CL',  N03',  carry  charges  of  equal  magnitude,*  and  yet  all  do 
not  conduct  to  the  same  degree,  they  must  move  at  different  velocities 
through  the  solution.  We  are  driven,  therefore,  to  the  conclusion  that, 
exposed  to  the  same  electrical  force,  different  ions  have  different  mobili- 
ties ;  that  is  to  say,  when  an  electric  current  passes  through  a  solution  of 
an  electrolyte,  the  positively  charged  ions  move  towards  the  cathode  at  a 
different  rate  from  that  at  which  the  negatively  charged  ions  move 
towards  the  anode.  Confirmation  of  this  conclusion  is  obtained  by  exam- 
ination of  the  concentration  changes  around  the  two  electrodes  of  an 
electrolytic  cell.  The  actual  velocity  of  each  ion  can  be  determined  by 
experimental  means.  The  inequality  in  concentration  of  ions  in  different 
regions  of  a  tissue  is  no  doubt  the  fundamental  cause  for  the  electrical 
currents  that  are  set  up  by  injury  and  activity. 

*Thus  Faraday  showed  that  the  amounts  of  the  various  ions  liberated  by  electrolysis  are  in  the 
same  ratio  as  their  chemical  equivalents. 


I    I/ 


e^x^U  * 

CHAPTER  IV 

THE  PRINCIPLES  INVOLVED  IN  THE  DETERMINATION  OF  THE 
HYDROGEN-ION  CONCENTRATION 

TITRABLE  ACIDITY  AND  ALKALINITY 

All  acids  have  one  property  in  common — namely,  that  they  contain 
hydrogen — and  when  the  acid  becomes  neutralized,  it  is  this  element 
which  becomes  replaced  by  some  other  cation.  Evidently,  then,  the 
strength  of  an  acid  is  proportional  to  the  number  of  displaceable  hydro- 
gen atoms  which  it  contains.  It  may  contain  other  hydrogen  atoms 
which  are  so  bound  up  in  the  molecule  that  they  do  not  become  displaced 
when  an  alkali  is  mixed  with  the  acid.  For  example,  in  organic  acids 
like  acetic,  CH3COOH,  it  is  only  the  H  atom  attached  to  the  COOH 
group,  but  not  those  attached  to  the  CH3  group,  that  is  replaceable.  It 
must  therefore  be  possible  to  prepare  for  every  acid  a  solution  having 
exactly  the  same  neutralizing  power  as  that  of  any  other  acid;  that  is, 
the  same  volume  of  solution  must  be  required  in  each  case  to  neutralize 
a  given  quantity  of  alkali,  the  point  of  neutralization  being  judged  by 
the  change  in  color  of  indicators.  As  a  standard  a  gram-molecular  solu- 
tion of  an  acid  with  one  displaceable  H  ion,  such  as  hydrochloric,  is 
chosen.  This  we  call  a  "normal  acid"  (N).  To  prepare  a  normal  solu- 
tion of  acids  having  two  displaceable  H  atoms,  such  as  H2S04,  we  can  not 
however  use  a  gram-molecular  quantity,  but  must  take  one-half  of  it; 
and  similarly  in  the  case  of  those  with  three  H  atoms,  such  as  H3P04, 
a  one-third  gram-molecular  solution  will  be  a  normal  acid  solution.  For 
practical  purposes,  use  is  very  generally  made  of  solutions  that  are  some 
fraction  of  the  normal,  e.  g.,  tenth  or  decinormal  (written  N/10),  or  hun- 
dredth or  centinormal  (N/100). 

In  a  similar  way,  alkaline  solutions  can  be  prepared,  a  normal  alkali 
being  one  which  exactly  corresponds  in  strength  with  a  normal  acid 
(i.e.,  can  exactly  neutralize  it).  Now,  the  characteristic  of  alkalies  is 
that  they  produce  in  solution  "OH"  or  hydroxyl  ions;  so  that  the  process 
of  neutralization  must  consist  in  the  union  of  the  H  ions  of  the  acid  with 
the  OH  ions  of  the  alkali  to  form  water:  KOH  +  HC1  =  KC1  +H20.  We 
can,  therefore,  prepare  normal  solutions  of  alkalies  by  dissolving  in  1 
liter  of  water  such  quantities  of  alkali  (in  grams)  as  will  yield  the  OH 
required  to  react  with  the  available  hydrogen  in  normal  acid  solutions. 

22 


HYDROGEN-ION    CONCENTRATION  23 

Actual  Degree  of  Acidity  or  Alkalinity. — According  to  the  foregoing 
method  of  titration  a  normal  solution  of  a  powerful  mineral  acid,  such 
as  hydrochloric,  is  no  stronger  than  a  normal  solution  of  a  weak  acid, 
such  as  acetic  or  lactic.  It  requires  no  fewer  c.c.  of  N  alkali  to  neutralize 
it.  But  the  normal  solution  of  the  powerful  acid  is  more  acid  to  the  taste, 
is  more  toxic,  dissolves  metals  more  readily,  and  in  all  its  other  chemical 
and  physiological  properties  acts  much  more  quickly  than  the  weak  acid, 
so  that  the  titrable  acidity  or  alkalinity  can  not  express  the  real  strength 
of  the  acid  or  alkali,  or  the  actual  degree  of  acidity  or  alkalinity.  It  is 
in  this  connection  that  the  dissociation  hypothesis  aids  us,  for  it  suggests 
that  the  degree  to  which  the  acid  becomes  dissociated  into  H-  and  the 
remainder  of  the  molecule  will  determine  its  real  strength  (see  page  16). 
The  question  is,  how  are  we  to  measure  the  latter?  One  action  of  H  ions 
which  we  may  measure  is  that  known  as  catalytic — that  is,  the  power  to 
accelerate  reactions,  such  as  the  splitting  of  cane  sugar  (C^H^On)  into 
glucose  and  levulose,  which  otherwise  would  proceed  very  slowly  (see 
page  75).  If  then  the  real  strength  of  an  acid  depends  on  the  degree 
of  dissociation  which  it  undergoes,  figures  representing  the  catalytic 
power  should  correspond  with  those  representing  the  relative  conductivi- 
ties of  the  acids  in  equivalent  concentration  (see  page  19).  That  this  is 
actually  the  case  is  shown  in  the  following  table,  in  which  the  above  values 
of  various  acids  are  given  compared  with  HC1,  which  is  taken  as  100. 

ACID  CATALYTIC  POWER  RELATIVE  CONDUCTIVITY 

HC1  100  100 

Dichloracetic  27  25 

Monochloracetic  4.8  4.9 

Formic  1.5  1.7 

Acetic 0.40 0.42 

It  will  be  evident  that,  if  we  could  measure  the  concentration  of  free 
H  ions  in  a  solution — that  is,  of  H  ions  that  are  not  matched  by  OH  ions — 
we  should  have  a  faithful  index  of  its  real  acidity.  This  measurement 
has  been  rendered  possible  by  the  application  of  two  other  physico- 
chemical  principles — namely,  those  of  mass  action  and  electromotive 
force.  Since  the  object  of  this  volume  is  to  present  the  scientific  basis 
for  the  various  methods  that  are  used  in  modern  medicine,  it  will  be  nec- 
essary for  us  to  review  the  main  principles  of  these  two  actions.  We  shall 
see  that  they  apply,  not  only  in  the  measurement  of  H-ion  concentration, 
but  in  many  other  physiological  processes. 

Mass  Action 

When  materials  take  part  in  a  reaction,  some  molecules  are  decom- 
posing  while   others   are  being   formed.     After   some  time,   however,   a 


24  PHYSICOCHKMICAL   BASIS   OF   PHYSIOLOGICAL   PROCESSES 

condition  is  reached  in  which  the  changes  in  one  direction  are  exactly 
offset  by  those  in  the  other.  An  equilibrium  is  said  to  have  become  estab- 
lished between  the  reacting  substances.  Bearing  in  mind  that  the  ions 
and  molecules  entering  into  these  reactions  are  constantly  moving  about 
and  coming  in  contact  with  one  another,  it  is  easy  to  see  that  if  we  were 
to  add  an  additional  quantity  of  one  kind  of  molecule  or  ion,  there  would 
be  a  change  all  along  the  line  until  a  new  equilibrium  was  established. 
If,  on  the  other  hand,  we  were  to  remove  one  kind  of  molecule  or  ion 
as  fast  as  it  was  formed,  the  equilibrium  could  never  be  established,  and 
the  reaction  would  proceed  until  all  of  this  material  had  disappeared. 
The  natural  rate  at  which  any  chemical  reaction  proceeds  is  dependent 
upon  a  number  of  conditions,  such  as  chemical  affinity,  temperature, 
catalysis,  and  concentration.  Of  these  conditions  that  of  concentration 
is  most  readily  measured.  If  we  maintain  all  of  the  conditions  other 
than  that  of  concentration  unchanged,  and  designate  this  combined  in- 
fluence as  K  (constant),  we  shall  find  that  the  speed  of  the  reaction  is 
proportional  to  the  molecular  concentration  of  the  reacting  substances 
(i.  e.,  the  number  of  gram-molecular  weights  per  liter).  In  other  words, 
the  speed  with  which  two  substances,  a  and  b,  unite  to  form  other  sub- 
stances, c  and  d,  will  be  expressed  by  the  equation, 

k  (a)x  (b)   ?±  k'   (c)  x(d)j* 

which  means  that,  when  the  reaction  is  complete,  the  composition  of 
the  mixture  will  be  dependent  upon  the  ratio  between  k  and  k'.  Since 
however  these  are  both  constants,  their  quotient  is  also  constant  (K),  and 

(a)  x (b) 
we  have  the  equation,  -~^ — ~~  =  K,  indicating  that  no  matter  how 

(c)  x  (d) 

the  concentrations  a,  b,  c,  and  d  are  varied,  reaction  will  take  place  in 
one  direction  or  the  other  until  the  concentrations  have  become  adjusted 
so  that  K  remains  unchanged. 

As  an  example  of  the  application  of  these  laws,  let  us  take  the  reaction 
which  occurs  between  alcohols  and  organic  acids  to  form  the  substances 
called  esters — a  reaction  which  is  analogous  to  that  between  mineral 
alkalies  and  acids  to  form  neutral  salts,  and  which  is  of  special  interest 
to  us  because  it  is  the  reaction  involved  in  the  splitting  of  animal  fats. 
The  equation  for  the  reaction  is: 


C2H5OH  +  CHsCOOH  <=*  C2HBOOCCH3  +  H2O. 
(ethyl         (acetic  (ethyl  acetate, 

alcohol)         acid)  an  ester) 

Or  expressed  according  to  the  law  of  mass  action: 

[C2H5OH]  x  [CH3COOH] 
[CaH6OOCCH3]  x  [H.O]    : 

*The   brackets  indicate  that  gram   molecular  quantities   are  used. 


HYDROGEN-ION    CONCENTRATION  25 

Now  it  is  clear  that  if  we  increase,  say,  H20  in  the  above  equation,  then 
in  order  that  K  may  remain  unchanged  C2H5OOCCH3  must  diminish  or 
the  substances  which  form  the  numerator  of  the  equation  must  increase, 
or  both  these  changes  must  occur.  As  a  matter  of  fact,  in  such  a  case  as 
the  above,  both  of  these  adjustments  take  place,  for,  as  the  ester  breaks 
down,  it  must  thereby  increase  the  concentration  of  acid  and  alcohol. 
Since  in  aqueous  solutions  the  reaction  occurs  in  the  presence  of  an  excess 
of  water,  it  is  evident  that  the  tendency  for  an  ester  is  to  break  down  into 
alcohol  and  acid,  and  this  must  occur  in  all  reactions  in  the  body  fluids  in 
which  water  enters  into  the  equation. 

Physiological  Applications.  —  The  application  of  the  law  of  mass  action 
in  the  explanation  of  biochemical  processes  is  very  extensive.  Most  of 
the  reactions  which  enzymes  or  ferments  are  capable  of  influencing  are 
of  the  same  general  nature  as  that  represented  above,  and  the  products 
of  their  activities  are  usually  the  substances  on  the  side  of  the  equation 
in  which  no  water  molecules  appear  —  i.  e.,  they  are  hydrolytic  reactions. 
Enzymes  merely  accelerate  the  reaction  (page  72),  so  that  if  we  start 
with  a  mixture  of  the  substances  on  either  side  of  the  equation,  all  they 
do  is  to  accelerate  the  production  of  a  sufficient  concentration  of  those 
on  the  other  side,  until  the  equilibrium  point  is  reached.  For  example, 
an  enzyme  present  in  pancreatic  juice,  called  lipase,  accelerates  the 
breakdown  of  such  esters  as  neutral  fat,  which  consists  of  the  triatomic 
alcohol,  glycerol,  combined  with  the  fatty  acids  palmitic  (C15H31COOH), 
stearic  (C17H35COOH)  and  oleic  (C7H33COOH): 


CSH5  (O  00  C1THM),  +  3H,0?±3C1THMCOOH  +  q,HII  (OH),. 

(the    neutral   fat,  (the  fatty  acid,     (glycerol) 

tristearin)  stearic) 

Under  ordinary  conditions  the  reaction  proceeds  until  nearly  all  the 
neutral  fat  has  become  decomposed  because  of  the  preponderance  of 
water,  but  if  we  start  with  a  mixture  of  fatty  acid  and  glycerol  with 
just  enough  water  to  permit  the  enzyme  to  act,  the  reaction  will  pro- 
ceed in  the  opposite  direction  —  i.  e.,  so  that  some  neutral  fat  will  be 
synthesized.  This  is  called  the  reversible  action  of  enzymes  (page  77). 

Because  of  the  universal  presence  of  water,  it  is  plain  that  such  re- 
versible reactions  could  not  alone  be  held  responsible  for  the  synthe- 
sis of  neutral  fat  or  of  similar  substances  in  the  animal  body.  The  only 
way  by  which  synthesis  could  occur  under  these  conditions  would  be 
if  the  substance  produced  along  with  the  water  were  removed  from  the 
site  of  the  reaction  as  soon  as  it  was  formed.  This  might  occur  by  the 
precipitation  of  the  substance  or  by  its  becoming  surrounded  by  an  en- 
velope of  some  inert  material.  In  the  synthesis  of  neutral  fat  which 


26  PHYSICOCHKMICAL   BASIS   OF   PHYSIOLOGICAL   PROCESSES 

occurs  in  the  epithelium  of  the  intestine  out  of  the  fatty  acid  and  glycerol 
absorbed  from  the  intestinal  contents,  it  is  possible  that  the  last  men- 
tioned process  occurs.  In  other  cases  the  substance  may  be  carried 
away  by  the  blood  or  lymph  or  urine  as  fast  as  it  is  formed. 

The  Law  of  Mass  Action  as  Applied  to  the  Measurement  of  H-ion 
Concentration.  —  Let  us  now  return  to  the  reaction  or  H-ion  concentration 
of  substances  in  solution.  As  the  standard  of  neutrality,  pure  water  is 
chosen.  Let  us  consider,  then,  how  the  laws  of  mass  action  can  be 
applied  in  order  to  enable  us  to  determine  the  H-ion  concentration  of 
pure  water.  It  has  been  stated  above  that  chemically  pure  water  is  in- 
capable of  conducting  the  electric  current.  This  however  is  not  strictly 
the  case,  for  it  conducts  to  a  very  slight  degree.  According  to  the  dis- 
sociation hypothesis,  it  must  therefore  be  represented  as  containing 
molecules  of  H20  and  ions  of  H  •  and  OH',  and  according  to  that  of  mass 
action  there  must  be  a  balanced  reaction  between  the  molecules  and  ions 
represented  thus: 


. 

Since  the  concentration  of  H-  and  OH'  is  extremely  small,  there  must 
always  be  such  an  overwhelming  preponderance  of  H20  molecules  that 
no  changes  in  the  concentration  of  H  •  and  OH'  will  be  capable  of  appre- 
ciably affecting  the  concentration  of  H20  ;  in  other  words,  one  may  omit 
the  denominator  of  the  equation  and  write  it  [H  •]  x  [OH']  =K.  If 
then  we  know  the  value  of  K,  it  will  only  be  necessary  to  measure  the 
concentration  of  either  H  •  or  OH'  in  order  to  express  in  numerical  terms 
the  reaction  of  the  solution.  It  has  been  found  that  the  value  of  K  is 
about  1  x  10'14,*  and  since  the  concentrations  of  H  •  and  OH'  are  nec- 
essarily equal  in  pure  water,  it  follows  that  [H]  =  [OH]  =  Ix  10~14, 
i.  e.,  each  ion  has  a  concentration  of  1  x  10'7.  This  means  that  water  con- 
tains approximately  1  gram  mol.  each  of  H-  and  OH'  ions,  or  1  gram 
H-  and  17  grams  OH'  ions,  in  10+7  or  10,000,000  liters.  A  consequence 
of  the  above  law  is  that  no  matter  how  much  the  concentration  of  one 
ion  is  increased  by  adding  another  substance,  the  solution  must  still 
contain  some  of  the  other  ion.  Thus,  in  acid  solutions  the  concentration  of 
H  •  must  increase  and  the  concentration  of  OH'  must  decrease  in  such  pro- 
portion that  the  two  multiplied  together  equals  about  1  x  10~14.  The  H-ion 
concentration  can  be  used  therefore  to  express  the  reaction  of  neutral,  acid 
and  alkaline  solutions. 
In  place  of  water,  let  us  substitute  decinormal  hydrochloric  acid 


*The  sign  10-14  is  simply  a  convenient  way  of  expressing  the  degree  of  dilution.  It  gives  the 
number  of  times  the  value  standing  in  front  of  it  must  be  divided  by  10  in  order  to  find  the 
concentration. 


HYDROGEN-ION    CONCENTRATION  27 

(0.1  N  Hd) — that  is,  a  hydrochloric  acid  solution  containing  one  tenth 
of  the  molecular  weight  of  hydrochloric  acid  in  grams  dissolved  in  a 
liter  of  water.  At  this  dilution  HC1  is  91  per  cent  dissociated ;  therefore 
the  H-ion  concentration  (or  CH  as  it  is  written  for  short)  is  0.091  N, 
or,  in  mathematical  notation,  9.1  x  10  2. 

Method  of  Expressing  CH.— To  avoid  the  necessity  of  having  to  use 
several  figures  to  express  CH,  as  has  been  done  above,  Sorenson  has  intro- 
duced a  scheme  by  which  only  one  figure  is  required.  This  figure,  des- 
ignated by  PH,  is  found  by  subtracting  from  the  power  of  ten  (i.  e., 
the  figure  standing  behind  10)  the  common  logarithm  of  the  figure  ex- 
pressing the  normality  of  the  acid.  In  a  decinormal  HC1  solution, 
therefore,  we  must  subtract  from  the  power  2,  the  common  log.  of  9.1, 
which  is  .96  (ascertained  from  logarithm  tables),  leaving  1.04.  .  Take 
another  example:  decinormal  acetic  acid  is  dissociated  only  to  the  ex- 
tent of  1.3  per  cent ;  CH  is  therefore  0.0013  normal,  or  1.3  x  10'3.  Since 
the  logarithm  of  1.3  is  .11,  PH  equals  3-.11,  or  -2.89.* 

The  only  objection  to  the  use  of  the  exponent  PH  as  an  expression  of 
the  H-ion  concentration  is  that  it  increases  in  magnitude  as  the  acidity 
becomes  less;  this  is  because  the  negative  sign  of  the  power  is  disre- 
garded. As  stated  above,  it  is  usual  to  express  the  strength  of  alkalies 
as  well  as  acids  in  terms  of  CH,  or  PH,  because  it  is  easier  to  measure  the 
concentration  of  H  ions  than  of  OH  ions.  A  0.1  NaOH  solution  is  84 
per  cent  dissociated;  therefore  the  "OH"  ion  is  0.084  N  (i.  e.,  0.084  gram 
equivalents  OH  per  liter),  and  since  the  product  of  the  H-  and  OH' 
concentrations  must  always  equal  10'14-14  (at  20°  C.),  it  is  clear  that  as 
the  H  ion  increases  in  concentration,  the  OH  ion  must  reciprocally  de- 
crease. Expressed  according  to  the  above  scheme,  the  0.084  N  NaOH 
solution  gives  PH  13.06;  thus,  0.084  =  8.4  x  10'2;  the  log.  of  8.4  is  .924, 
and  this  subtracted  from  the  power  -2  =  1.08  as  POH,  or  14.14  - 1.08  = 
13.06  as  PH.** 

Similarly,  PH  of  0.1  N  NH4HO  solution  is  11.286.  Its  dissociation  is 
1.4  per  cent;  therefore  the  solution  contains  only  0.0014  gram  equivalents 
HO— i.e.,  1.4  xlO-3  POH  =  3  -  0.146  =  2.854  .-.  PH  14.14-2.854  = 
11.286.f 


*If  we  wish  to  express  the  value  of  PH  in  ordinary  notation,  we  must  find  the  antilogarithm 
of  the  difference  between  the  value  of  PH  and  the  next  higher  whole  number;  e.  g.,  if  PH  =  7.45, 
the  antilogarithm  of  0.55  being  3.55,  the  CH  is  3.55  x  10"8,  or  0.000,000,0355  N,  or  3.55  gm.  mol. 
H  ion  in  100,000,000  liters. 

**It  must  be  remembered  that  the  power  of  a  number  indicates  the  number  of  times  by  which 
that  number  must  be  multiplied  by  ten;  thus,  Pn-6  does  not  mean  that  the  H  ion  is  six  times  less 
than  PH°,  but  1  x  10  x  10  x  10  x  10  x  10  x  10,  or  1,000,000  times  less.  Similarly,  Pn'3  is  1000  times 
as  great  as  Pa-6,  not  twice  as  great. 

A  solution  containing  almost  exactly  1  gram  molecule  of  dissociated  hydrogen  in  10,000,000  fiters 
constitutes  a  neutral  solution  (Pn  =  7). 

tThe  expressions  PH  and  CH  may  be  used  indiscriminately,  but  when  the  numerical  value  is 
given,  it  is  most  convenient  to  use  the  former. 


28  PHYSICOCHEM1CAL   BASIS   OF   PHYSIOLOGICAL   PROCESSES 

Application  of  the  Law  of  Mass  Action  in  Determining  the  Real 
Strength  of  Acids  or  Alkalies. — We  have  seen  that  it  is  the  degree  of 
dissociation  upon  which  the  real  strength  of  an  acid  depends  and  that 
this  varies  with  dilution  (page  19).  The  equilibrium  between  the  un- 
dissociated  and  dissociated  molecules  may  therefore  be  shifted  in  either 
direction  by  changing  the  concentration;  in  other  words,  the  process  of 
dissociation  is  a  reversible  reaction,  and  may  be  represented  as 
AB  ±+  A'  +  B  •.  The  law  of  mass  action  must  apply  in  such  a  case,  and 
as  a  matter  of  fact  it  has  been  found  that  a  constant  can  be  calculated, 
which  is  known  as  the  dissociation  constant.*  It  is  an  expression  of  the 
inherent  ability  of  the  acid  to  dissociate  into  ions,  and  is  therefore  the 
best  measure  of  the  strength  of  the  acid.  This  is  strictly  the  case  for  all 
of  the  weaker  acids,  but  strong  mineral  acids  (and  bases)  do  not  give 
a  satisfactory  constant,  so  that  the  comparison  must  not  be  made  between 
them  and  weaker  ones.  That  the  dissociation  constant  expresses  the  rela- 
tive strength  of  organic  acids  can  be  shown  by  comparing  its  value  with 
that  of  the  rate  at  which  cane  sugar  is  inverted  (see  page  23),  this  being 
proportional  to  the  concentration  of  the  H  ions  present.  K  for  some  or- 
ganic acids  is :  Acetic,  0.000018 ;  Formic,  0.000214 ;  Benzoic,  0.00006 ;  Sal- 
icylic, 0.00102. 


*The  equation  is     yr — yy-    =  K,  where  it  is  supposed  that  in  volume   V  of  the  solution  there   is 

1  gram-equivalent  of  electrolyte,  and  that  the  degree  of  dissociation  is  a;  the  quantity  of  undis- 
sociated  electrolyte  stated  in  a  fraction  of  a  gram-equivalent  will  be  1-a,  and  the  quantity  of  each 
ion  a.  To  illustrate,  let  us  take  acetic  acid  in  various  dilutions: 

V  a  K  x  105 

0.994  0.004  1.62 

2.02  0.00614  1.88 

15.9  0.0166  1.76 

18.1  0.0178  1.78 


CHAPTER  V 

THE  PRINCIPLES  INVOLVED  IN  THE  MEASUREMENT  OF  THE 
HYDROGEN-ION  CONCENTRATION  (Cont'd) 

THE  METHODS  OF  MEASUREMENT 

The  Electrical  Method 

In  order  to  understand  the  principle  of  the  standard  method  used  for 
measuring  the  H-ion  concentration,  it  is  necessary  that  a  few  words  be 
said  concerning  the  factors  governing  the  development  of  electric  cur- 
rents in  chemical  batteries.  There  may  be  a  further  application  of  this 
knowledge  in  connection  with  the  generation  of  the  electric  currents 
which  occurs  during  physiological  activity,  as  in  active  glands  and  muscles. 

When  a  metal  is  immersed  in  a  solution  of  one  of  its  salts,  it  has  a 
tendency  to  give  off  ions  into  the  solution.  Similar  ions  are,  however, 
already  present  in  this  solution,  and  these,  by  their  osmotic  pressure, 
tend  to  oppose  the  passage  of  the  ions  coming  from  the  metal.  The 
force  with  which  the  metal  sends  out  its  ions  into  the  solution  is  called 
the  electrolytic  solution  pressure.  If  this  is  equal  to  the  osmotic  pres- 
sure of  the  metallic  ions  in  the  solution,  there  will  be  no  electric  current 
generated,  but  if  it  is  greater  or  less  than  the  osmotic  pressure  of  the 
metallic  ion,  an  electric  current  will  be  set  up.  When  the  solution  pres- 
sure is  the  greater,  the  metal  will  become  negatively  charged,  because  its 
ions  carry  positive  charges  into  the  solution  (cations) ;  on  the  contrary, 
when  the  osmotic  pressure  is  greater  than  the  solution  pressure,  the  metal 
will  have  a  positive  charge,  owing  to  the  receipt  of  the  positive  cations 
from  the  solution. 

Because  of  a  force  called  electrostatic  attraction,  the  ions  given  off 
from  the  metal  can  not  travel  any  measurable  distance  from  the  oppositely 
charged  mass  of  metal,  so  that  from  one  of  the  electrodes  alone  it  is 
impossible  for  us  to  lead  off  any  electric  current.  For  this  purpose  we 
must  form  a  circuit.  This  is  done  in  the  manner  shown  in  Fig.  7  by 
connecting  side  tubes  coming  from  the  electrode  vessels  with  an  inter- 
mediate vessel  containing  a  solution  of  high  conductivity  and  by  con- 
necting the  metals  by  wires.  If  the  circuit  is  formed  between  the 
same  metals  in  solutions  of  the  same  concentration,  no  electric  cur- 
rent will  be  generated,  because  the  two  electrode  potentials  will  be 

29 


30 


PHYSICOCHEMICAL   BASIS   OF   PHYSIOLOGICAL   PROCESSES 


equal  and  in  opposite  directions  to  each  other.  On  the  other  hand,  should 
the  concentration  of  the  metallic  ion  in  the  solutions  be  unequal,  the 
electromotive  force  will  flow  from  the  one  electrode  to  the  other,  and 
the  pressure  with  which  it  flows  will  be  equal  to  the  difference  in  con- 
centration of  the  two  solutions.  This  is  the  principle  of  a  concentration 
cell,  and  if  we  know  the  concentration  of  one  of  the  solutions  composing 
it,  and  then  proceed  to  measure  the  electromotive  force,  we  can  obtain 
the  concentrations  of  the  other  solution  by  difference.  To  do  this  we 
must  employ  a  formula  which  takes  into  consideration  the  relation  be- 
tween the  potential  and  the  concentration  of  the  solution. 

The  potential  of  an  unknown  electrode  composed  of  a  metal  in  con- 
tact with  a  solution  of  one  of  its  salts  may  also  be  determined  by  making 
it  one  pole  of  a  battery  of  which  the  other  pole  is  composed  of  a  stand- 
ard electrode  of  unchanging  known  potential.  An  electrode  of  the  latter 


Fig.  7. — Diagram  to  show  type  of  electrodes  used  in  studying  electromotive  force.  The 
metal  in  each  electrode  is  connected  (through  a  glass  tube)  with  a  platinum  wire,  to  which 
the  appai-atus  for  measurement  of  the  voltage  is  connected.  The  metal  dips  into  a  solution 
contained  in  the  electrode  vessel  and  filling  the  side  tube.  The  latter  dips  into  an  inter- 
mediate vessel  containing  saturated  KC1  solution.  The  currents  flow  through  the  circuit  under 
the  following  conditions:  (1)  dissimilar  metals  dipping  into  the  same  fluid;  (2)  similar  metals 
dipping  into  different  fluids;  (3)  dissimilar  metals  dipping  into  different  fluids. 

type  can  most  readily  be  made  by  bringing  pure  mercury  in  contact 
with  a  saturated  solution  of  calomel  (Hg2Cl2)  in  normal  potassium  chlo- 
ride solution  (Fig.  8).  Under  suitable  conditions  (i.  e.,  when  the  circuit  is 
completed),  a  potential  of  0.560  v.  is  developed  in  this  so-called  calomel 
electrode* — that  is,  positive  ions  of  mercury  are  deposited  on  the  mercury 
from  the  calomel  solution  at  this  pressure.  Suppose  that  we  connect  a 
calomel  electrode,  through  the  intermediation  of  some  solution  which 


*The  calomel  electrode  consists  of  a  suitably  shaped  glass  vessel  containing  pure  mercury,  con- 
nected by  means  of  a  platinum  wire  with  a  conductor,  and  filled  with  a  saturated  solution  of  pure 
mercurous  chloride  in  normal  KC1  solution  up  to  such  a  level  that  it  also  fills  a  side  tube  connected 
with  a  vessel  containing  a  saturated  solution  of  potassium  chloride.  Into  this  vessel  also  runs  a 
similar  side  tube  from  the  unknown  electrode.  By  having  an  excess  of  utidissolved  calomel  in  the 
solution  in  the  calomel  electrode  its  saturated  condition  is  maintained  during  the  chemical  changes 
which  accompany  the  production  of  the  electric  current. 


HYDROGEN-ION    CONCENTRATION 


31 


will  serve  as  a  good  conductor,  with  another  electrode,  the  two  elec- 
trodes being  also  connected  by  wires  with  electrical  apparatus  for 
measuring  the  total  potential  of  the  battery;  then  by  adding  +0.560  v. 
to  or  subtracting  this  value  from  the  total  potential  (depending  on  the 
sign  of  the  unknown  electrode)  we  can  tell  the  potential  of  the  unknown 
electrode. 

We  have  discussed  these  principles  of  electrochemistry  because  they 
form  the  basis  upon  which  depends  the  standard  method  for  the  deter- 
mination of  the  H-ion  concentration  of  fluids.  Suppose,  for  example, 
that  in  place  of  using  a  metal  in  the  construction  of  one  electrode,  we 
use  an  electrode  consisting  of  a  layer  of  pure  hydrogen  gas  in  contact 
with  a  solution  in  which  are  free  H  ions;  then  the  rate  at  which  H  ions 


Fig.  8. — Diagram  of  apparatus  for  the  measurement  of  the  H-ion  concentration.  The  cur- 
rent generated  in  the  battery  (composed  of  calomel  electrode,  connecting  vessel  with  KC1  solu- 
tion, and  the  H  electrode)  or  that  from  the  normal  element  is  transmitted  through  a  reversing 
key  to  the  bridge  wire,  where  the  voltage  is  compared  with  a  steady  current  flowing  through  the 
bridge  wire  from  an  accumulator.  The  capillary  electrometer  is  used  to  detect  the  flow  of 
current  at  various  positions  of  the  movable  contact  on  the  bridge  wire.  (Modified  from 
Sorensen.) 

become  added  to  the  solution  from  the  H  layer,  or  taken  from  it,  will  de- 
pend on  the  concentration  of  H  ions  in  solution.  In  order  to  secure  a 
hydrogen  electrode  fulfilling  the  above  requirements,  it  is  necessary  to 
employ  some  means  by  which  a  layer  of  hydrogen  may  be  furnished,  and 
fortunately  this  can  be  done  by  taking  advantage  of  the  property  which 
spongy  platinum  possesses  of  absorbing  large  quantities  of  this  gas.  It 
is  also  necessary  to  keep  an  atmosphere  of  pure  H  in  contact  with  the 
fluid. 

As  is  the  case  of  the  simpler  cells  described  above,  there  are  two 
types  which  we  might  use  for  measuring  the  electromotive  force  gen- 
erated in  the  unknown  electrode:  a  concentration  cell  composed  of  two 


32  PHYSICOCHEMICAL  BASIS   OF   PHYSIOLOGICAL  PROCESSES 

hydrogen  electrodes,  of  which  one  contains  a  solution  of  known  H-ion 
concentration,  and  the  other  the  solution  in  which  this  is  unknown; 
and  a  cell  of  which  one  electrode  is  a  standard  calomel  electrode  and 
the  other,  a  hydrogen  electrode  containing  the  unknown  solution. 

The  exact  arrangement  of  the  apparatus  in  which  the  calomel  elec- 
trode is  used  will  be  seen  in  the  accompanying  sketch.  The  hydrogen 
electrode,  it  will  be  noticed,  is  a  very  small  V-shaped  tube,  in  which  is 
suspended  a  platinum  wire  coated  with  spongy  platinum  and  dipping 
into  a  solution  which  nearly  fills  the  tube.  The  space  above  the  solution 
is  filled  with  pure  hydrogen.  This  and  the  calomel  electrode  are  con- 
nected with  suitable  electric  measuring  instruments,  and  the  circuit  is 
completed  by  connecting  the  two  electrodes  by  means  of  an  intermediate 
vessel  containing  a  saturated  solution  of  potassium  chloride.  This  con- 
necting solution  is  used  because  it  has  been  found  that  the  electric  cur- 
rents set  up  at  the  contact  between  different  solutions  are  so  small  that 
they  can  be  disregarded.* 

As  outlined  above,  the  hydrogen  electrode  is  that  which  is  used  to 
determine  the  H-ion  concentration  of  blood,  the  particular  point  about 
it,  in  comparison  with  the  apparatus  used  for  simpler  solutions,  being 
that  the  hydrogen  is  not  changed  in  the  course  of  the  experiment.  This 
precaution  is  to  prevent  the  carbon  dioxide  of  the  blood  from  being 
" washed  out'*  of  it  by  a  frequently  changing  atmosphere  of  hydrogen. 
Many  inaccuracies  in  the  earlier  results  obtained  by  this  method  were 
due  to  the  removal  of  carbon  dioxide,  which,  as  we  shall  see  later,  is 
one  of  the  chief  acids  contributing  to  the  H-ion  concentration  of  blood. 

The  Indicator  Method 

As  pointed  out  in  a  previous  chapter  (page  22),  the  method  of  titra- 
tion  for  acidity  or  alkalinity  in  which  a  standard  solution  of  alkali  or 
acid  is  added  until  a  certain  change  in  the  color  of  a  suitable  indicator 
is  detected,  does  not  afford  any  information  regarding  the  H-ion  con- 
centration actually  present  in  the  solution.  It  tells  us  the  total  con- 
centration of  available  acid  or  base,  both  dissociated  and  undissociated. 
By  modification  of  the  method  of  procedure,  however,  we  may  also  use 
indicators  for  determining  the  H-ion  concentration.  The  principle  of 
this  method  depends  on  the  fact  that  there  are  certain  dyes  which 
change  quite  distinctly  in  tint  with  very  slight  changes  in  the  H-ion 
concentration,  so  that  if  we  use  dyes  which  possess  this  property  at  a 
point  near  that  of  neutrality  (i.  e.,  between  PH6.5  and  PH8),  we  can  es- 


*A  description  of  the  technic  for  measuring  the  electric  potential  developed  by  the  cell  would 
be  out  of  place  here.  Suffice  to  say  that  the  strength  of  the  current  is  compared  with  that  of  a 
current  of  known  strength  furnished  by  a  normal  cell,  the  comparison  being  made  by  a  bridge  wire 
F,  a  capillary  electrometer  H  being  employed  to  detect  the  direction  and  degree  of  current. 


HYDROGEN-ION    CONCENTRATION 


33 


timate  the  H-ion  concentration  of  the  body  fluids  with  very  remarkable 
accuracy,  provided  certain  precautions  are  taken  to  circumvent  the 
disturbing  influence  which  the  protein  and  salts  in  these  fluids  may  have 
on  the  color  change. 

To  understand  this  use  of  indicators,  it  is  important  to  bear  in  mind 
that  one  solution  reacting  neutral  to  one  indicator  may  have  a  H-ion 
concentration  which  differs  very  markedly  from  that  of  another  solu- 
tion reacting  neutral  to  another  indicator.  This  is  because  indicators 
react  to  different  H-ion  concentrations.  A  solution  that  is  neutral  to 
phenolphthalein  has  a  PH  of  about  9,  whereas  one  neutral  to  methyl  or- 
ange has  a  PH  of  about  4.  This  can  be  very  clearly  shown  by  titrating 
a  solution  of  phosphoric  acid  with  decinormal  alkali.  After  a  certain 
amount  of  alkali  has  been  added  it  will  be  noticed  that  methyl  orange 
changes  from  red  to  yellow,  but  after  it  has  changed  and  is  therefore 
alkaline  as  judged  by  this  indicator,  it  still  remains  distinctly  acid  to- 
wards phenolphthalein  (shows  no  red  tint)  even  though  considerably 
more  alkali  is  added.  The  methyl  orange  is,  therefore,  itself  unrespon- 
sive to  weak  acids  such  as  remain  after  the  greater  part  of  the  phos- 
phoric acid  has  been  neutralized  by  the  alkali. 

The  series  of  indicators  which  has  been  employed  for  this  purpose  is 
given  in  the  accompanying  table,  along  with  the  PH  limits  through  which 
they  change  in  color. 

LIST  OF  INDICATORS 


CHEMICAL  NAME 

COMMON 

NAME 

CONCEN- 
TRATION 

COLOR 

CHANGE 

RANGE 
PH 

Thymol    sulfon    phthalein 

per  cent 

(acid  range) 

Thymol  blue 

0.04 

Red-yellow 

1.2-2.8 

Tetra  bromo  phenol   sul- 

fon phthalein 

Brom  phenol 

blue 

0.04 

Yellow-blue 

3.0-4.6 

Ortho  carboxy  benzene 

azo  di  methyl 

aniline 

Methyl  red 

0.02 

Red-yellow 

4.4-6.0 

Ortho  carboxy  benzene 

azo  di  propyl 

aniline 

Propyl  red 

0.02 

Red-yellow 

4.8-6.4 

Di  bromo  ortho  cresol 

sulfon  phthalein 

Brom  cresol 

purple 

0.04 

Yellow- 

purple 

5.2-6.8 

Di  bromo  thymol  sulfon 

Brom  thymol 

phthalein 

blue 

0.04 

Yellow-blue 

6.0-7.6 

Phenol  sulfon  phthalein 

Phenol  red 

0.02 

Yellow-red 

6.8-8.4 

Ortho  cresol  sulfon 

phthalein 

Cresol  red 

0.02 

Yellow-red 

7.2-8.8 

Thymol   sulfon  phthalein 

Thymol  blue 

0.04 

Yellow-red 

8.0-9.6 

(see  above) 

Ortho   cresol   phthalein 

Cresol 

phthalein 

0.02 

Colorless-red 

8.2-0.8 

These  dyes  may   now  be   obtained   in   this  country. 


(W.  M.  Clark  and  H.  A.  Lnbs.)9 


34  PHYSICOCHEMICAL   BASIS   OF   PHYSIOLOGICAL  PROCESSES 

Briefly  stated  the  method  for  measuring  the  H-ion  concentration  con- 
sists in  preparing  a  series  of  solutions  containing  known  concentrations 
of  H-ion — that  is  to  say,  of  known  PH — and  adding  to  each  solution  an 
equal  amount  of  an  indicator  which  exhibits  easily  distinguishable 
changes  in  tint  at  H-ion  concentrations  approximating  those  believed 
to  be  present  in  the  unknown  solution.  The  same  indicator  is  added  to 
the  unknown  solution,  which  is  then  placed  side  by  side  with  the  stand- 
ards to  find  with  which  of  them  it  most  closely  matches.  The  series 
of  solutions  of  known  H-ion  concentration  is  prepared  by  mixing  fif- 
teenth normal  solutions  of  Na2HP04  and  KH2P04  in  varying  propor- 
tions as  given  in  the  following  table: 

PREPARATION  OF  STANDARD  SOLUTIONS 
The  solutions  are  mixed  in  the  proportions  indicated  below  to  obtain  the  desired   PH:* 

PH  6.4      6.6     6.8      7.0     7.1      7.2      7.3      7.4      7.S      7.6      7.7      7.8      8.0      8.2      8.4 

Primary    Potas.  73       63       51        37        32        27       23        19        15.8    13.2    11         8.8      5.6      3.2      2.0 

Phos.,  c.c. 
Secondary   Sodium  27       37       49       63       68       73       77       81       84.2    86.8    89       91.2    94.4    96.8    98.0 

Phos.,  c.c. 

(From  Levy,  Rowntree  and  Marriott.) 

*Standard  phosphate  mixtures  are  prepared   according  to   Sorensen's  directions  as   follows: 
1/15    mol.    acid    or    primary    potassium    phosphate. — 9.078    grams    of    the    pure    recrystallized    salt 
(KH2PO4)    are  dissolved  in  freshly  distilled  water  and   made  up   to   1   liter. 

1/15  mol.  alkaline  or  secondary  sodium  phosphate. — The  pure  recrystallized  salt  (Na2HPC>4. 12H2O) 
is  exposed  to  the  air  for  from  ten  days  to  two  weeks,  protected  from  dust.  Ten  molecules  of  water 
of  crystallization  are  given  off  and  a  salt  of  the  formula!  NaoHPO4.2H2O  is  obtained;  11.876  grams 
of  this  are  dissolved  in  freshly  distilled  water  and  made  up  to  1  liter.  The  solution  should  give  a 
deep  rose  red  color  with  phenolphthalein.  If  only  a  faint  pink  color  is  obtained,  the  salt  is  not 
sufficiently  pure. 

The  indicator  method  is  extremely  accurate  when  used  with  pure 
solutions  of  acids,  but,  as  mentioned  above,  it  is  apt  to  be  inaccurate,  at 
least  with  most  indicators,  when  protein  or  inorganic  salts  are  pres- 
ent in  the  solution,  and  of  course  it  is  quite  unusable  with  colored 
fluids  such  as  blood.  In  order  to  overcome  these  difficulties,  the 
dialysis  method  has  recently  been  evolved.  It  consists  in  placing  the 
fluid — blood,  for  example — in  a  dialyser  sac  composed  of  celloidin  and 
about  as  large  as  a  small  test  tube.  The  sac  is  placed  in  a  wider  test 
tube  of  hard  glass  containing  an  isotonic  solution  of  sodium  chloride 
that  has  been  carefully  tested  to  ascertain  that  it  is  strictly  neutral. 
The  amount  of  blood  or  serum  required  for  this  method  is  only  2  or 
3  c.c.,  and  the  amount  of  salt  solution  placed  outside  the  sac  should  be 
about  the  same.  It  takes  only  from  five  to  ten  minutes  for  dialysis  to 
occur.  The  celloidin  sac  is  then  removed,  a  few  drops  of  the  indicator 
are  thoroughly  mixed  with  the  dialysate,  and  the  tube  compared  with 
the  series  of  standards  until  the  corresponding  tint  is  matched.  This 
indicates  the  H-ion  concentration  in  the  dialysate.  The  tints  produced 
by  using  sulphonephenolphthalein  are  reproduced  as  nearly  as  possible 


PH7-0  PH7-/  PH7-2  PH7-3  P 


U 


Fig.   9. — Chart  showing  approximately  the  tints  produced  by  adding  sulphophenolphthalein  to  a  series 
of  phosphate  solutions  of  the  H-ion  concentrations  indicated  in  each  case  by   PH. 


HYDROGEN-ION    CONCENTRATION 


35 


in  the  accompanying  chart.  The  H-ion  concentration  of  the  unknown 
solution  is  that  of  the  tint  with  which  it  matches  in  the  series. 

It  might  be  thought  that  this  method  would  be  inaccurate  because  of 
the  loss  of  carbon  dioxide  from  the  blood.  By  actual  experiment,  how- 
ever, it  has  been  found  that,  if  the  blood  is  collected  with  certain  pre- 
cautions, the  error  is  negligible.  The  method  is,  therefore,  a  most  useful 
one  clinically. 

To  minimize  the  chances  of  loss  of  free  C02,  S.  H.  Dale  and  Evans  have 
elaborated  the  technic  of  the  dialysis  method  by  tying  the  sac  onto  an 
ebonite  perforated  stopper  which  exactly  fits  the  mouth  of  the  test  tube 
containing  the  neutral  saline  solution.  The  blood  is  delivered  directly 
from  the  blood  vessel  by  a  narrow  glass  tube  which  passes  to  the  bottom 
of  the  sac  through  the  hole  in  the  stopper.  After  enough  blood  has  been 
collected  the  tube  is  withdrawn  and  the  hole  in  the  stopper  is  tightly 
closed  by  a  piece  of  cork.  We  have  found  this  a  useful  method  but  we 
do  not  believe  that  the  further  modification  described  in  their  paper  for 
determination  of  the  PH  of  the  dialysis  is  as  reliable  as  that  described 
above.20 

The  following  table  gives  the  hydrogen-ion  concentration  or  true 
reaction  of  the  body  fluids. 


FLUID 


PH 


FLUID 


PH 


Blood  7.4 

Urine  6.0 

Saliva  6.9 

Gastric  juice  (adult)  0.9-1.6 

Gastric  juice  (infant)  5.0 

Pancreatic  juice   (dog)  8.3 

Small  intestinal  contents  8.3 
Small  intestinal  contents  (infant)      3.1 

Bile  from  liver  7.8 

Bile  from  gall  bladder  5.3-7.4 

Perspiration  7.1 

Perspiration  4.5 

Tears  7.2 


Muscle  juice  (fresh)  6.8 

Muscle  juice  (autolyzed)  Variable 

Pancreas  extract  5.6 

Peritoneal  fluid  7.4 

Pericardial  fluid  7.4 

Aqueous  humor  7.1 

Vitreous  humor  7.0 

Cerebrospinal  fluid    (fresh)  7.4 
Cerebrospinal  fluid  (after  standing)     8.3 

Amniotic  fluid  7.1 

Amniotic  fluid  8.1 

Milk  (human)  7.0-7.2 

Milk  (cow)    '  6.6-6.8 

Milk  (goat)  6.6 

Milk  (ass)  7.6 


(W.  M.  Clark  and  H.  A.  Lubs.) 


a 


TER  VI 

THE   REGULATION    OF   NEUTRALITY   IN   THE   ANIMAL   BODY 

*~AND  ACIDOSIS 

Nothing  is  more  constant  in  the  animal  economy  than  the  H-ion  con- 
centration (CH)  of  the  fluids  which  bathe  the  tissues.  This  regulation 
is  fundamentally  of  a  physicochemical  nature,  depending  on  the  inter- 
action of  alkalies  with  acids,  of  which  c#tobo*iic  and  phosphoric  acids 
are  the  most  important.*  When  different  amounts  of  acids  or  al- 
kalies are  added  to  water,  the  rajige  of  variation  in  H  ion  is 
very  extensive,  whereas  in  blood  the'range  is  very  limited  indeed,  not 
extending  beyond  PH7  and  PH7.52  (i.  e.,  CH^)ever  goes  above  that  of  a 
0.000,000,1  N  solution  or  below  that  of  a  0.000,000,03  N  solution).  In 
other  words  blood  can  withstand  considerable  additions  of  acid  or  al- 
kali without  much  change.  • 

Buffer  Substances.  —  The  chemical  reactions  upon  which  this  remark- 
able constancy  in  reaction  depends  have  been  explained  by  Lawrence 
J.  Henderson.10  The  fundamental  equations  are  as  follows: 

M.HPO,  +  HA  —  MH2PO4  +  MA,  and 
MHC03  +  HA  =  H2C03  +  MA, 
when  M  =  a  basic  radicle,  and  A,  an  acid  radicle. 

Now  it  has  been  discovered  that  weak  acids,  like  carbonic  and  phosphoric, 
possess  the  remarkable  property  of  maintaining  the  reaction  tolerably 
constant  when  they  are  present  in  a  solution  which  also  contains  an 
excess  of  their  salts.  Under  these  circumstances  the  concentration  of 
ionized  hydrogen  is  almost  exactly  equal  to  the  product  of  the  dissocia- 
tion constantf  of  the  acid  (see  page  19)  multiplied  by  the  ratio  be- 
tween free  acid  and  salt;  in  other  words, 

[HA] 


If  carbonic  acid  is  present  in  a  solution  of  bicarbonates  so  that  there 


"Under  certain  circumstances,  proteins  may  also  act  either  as  acids  or  as  alkalies.  They  are 
therefore  calhd  amphoteric.  The  neutralizing  properties  of  proteins  are,  however,  of  little  conse- 
quence in  the  neutrality  regulation  in  the  animal  body  (Bayliss20). 

tThe  dissociation  constant  tms  already  been  referred  to  as  a  figure  which  expresses  the  tendency 
of  a  weak  acid  or  base  to  dissociate  in  an  aqueous  solution.  "It  expresses  the  proportion  in  which 
the  nondissociated  part  is  capable  of  existing  in  the  presence  of  its  ions,"  and  therefore  is  a  gauge 
of  the  strength.  The  dissociation  constant  amounts  to  about  0.000,000,5  for  carbonic  acid;  that  is, 
the  dissociation  of  HoCOs  into  H'-f-HCO^'  at  room  temperature  will  be  such  that  the  concentra- 
tion of  H-ion  equals  a  0.000,000,5  N  solution. 

36 


ACIDOSIS  37 

are  equivalent  quantities  of  free  H9C03  and  bicarbonate  —  i.  e.,  | 


—  the  H-ion  concentration  will  be  exactly  the  same  as  the  dissociation  con- 
stant of  carbonic  acid  (i.e.,  5  x  1O7)  ;  therefore  0.000,000,5  N  (PH  =  6.3)*, 
or  about  five  times  the  value  of  neutrality,  0.000,000,1  N  (PH  =  7).  If  ten 
times  as  much  free  carbonic  acid  as  bicarbonate  is  present,  then  the  H-ion 

concentration  will  be  fifty  times  that   of  neutrality,   i.  e., 


x  0.000,000,5  =  0.000,005  (PH  =  5.31)  ;  if  there  is  ten  times  less  carbonic 
acid  than  bicarbonate,  the  H-ion  concentration  will  be  one-half  that  of 

neutrality,  i.  e.,  4wTT  =  T7i  x  0.000,000,5  =  0.000,000,05)  (PH  =  7.31)  ;  or 


if  twenty  times  less,  one  fourth  (PH  =  7.6).  Since  a  large  amount  of 
bicarbonate  is  actually  present  in  blood  (enough  to  yield  from  50  to  65  c.c. 
C02  per  100  c.c.  of  blood),  and  the  free  carbonic  acid  undergoes  fluctua- 
tions which  are  only  trivial  when  compared  with  those  which  have  been 
chosen  in  the  above  examples,  it  is  clear  that  there  must  be  very  little 
change  in  the  H-ion  concentration  of  the  blood  in  comparison  with  the 
variations  which  would  occur  were  no  bicarbonate  present. 

Another  weak  acid  which  acts  like  carbonic  in  maintaining  neutral- 
ity is  acid  phosphate  (MH2P04),  and  for  the  same  reason  —  namely,  that 
its  dissociation  constant  is  of  similar  magnitude  to  the  H-ion  concen- 
tration. Although  the  blood  plasma  itself  contains  much  less  phosphate 
than  bicarbonate,  the  tissues  contain  a  considerable  amount,  which  en- 
ables them  to  maintain  their  neutrality.  This  action  of  bicarbonates  and 
phosphates  is  styled  the  buffer  action,  meaning  that  it  serves  to  damp 
down  the  effect  on  the  H-ion  concentration  which  additions  of  acids  or 
alkalies  would  otherwise  have.  As  pointed  out  by  Bayliss,  however,  a 
better  word  to  use  would  be  "tampon  action,'*  since  the  substances 
actually  soak  up  much  of  the  added  H-  or  OH'  ions.  It  is  not  confined 
to  the  fluids  of  the  higher  animals,  but  is  very  widely  distributed 
throughout  nature  ;  for  example,  in  the  ocean  and  in  the  fluids  of  marine 
organisms  and  animalcules  (see  L.  J.  Henderson).11 

Although  the  actual  reaction  by  which  neutrality  is  maintained  is 
purely  of  a  physicochemical  nature,  some  provision  must  obviously  be 
made  so  that  the  acid  and  basic  substances  that  take  part  in  it  may  be 
supplied  and  those  produced  by  the  reactions  removed  as  occasion  re- 
quires. The  source  of  supply  is  partly  exogenous  and  partly  endogenous. 
The  exogenous  source  is  the  basic  and  acid  substances  present  in  the 
food;  and  although  we  do  not  ordinarily  attempt  to  control  the  amounts 
of  these  substances  ingested,  we  may  do  so,  as,  for  example,  by  the 
persistent  administration  of  soda  in  cases  of  pathological  acidosis.  The 
endogenous  source  depends  on  the  constant  production  in  metabolism 

*For  calculating  this  value  see  p.  27 


38  PHYSICOCHEMICAL   BASIS   OF   PHYSIOLOGICAL   PROCESSES 

of  acids  such  as  carbonic,  phosphoric,  lactic,  and  sulphuric,  and  of 
alkalies  such  as  ammonia  and  fixed  alkali,  a  considerable  reserve  of  which 
is  undoubtedly  available  in  the  animal  organism. 

The  removal  is  affected  by  three  pathways:  (1)  through  the  lungs 
gaseous  carbonic  acid  is  eliminated;  (2)  through  the  kidneys,  the  fixed 
acids;  and  (3)  through  the  intestines,  some  of  the  phosphoric  acid. 

Carbonic  acid  is  produced  in  large  amounts  in  the  normal  process  of 
metabolism,  and  is  excreted  in  a  gaseous  condition  by  the  lungs.  Varia- 
tion in  its  excretion  is  the  most  important  mechanism  for  controlling 
fl 'temporary  changes  in  CH.  In  order  to  make  this  clear,  it  may  be  well  to 
revert  for  a  moment  to  the  physicochemical  equation  by  which  carbonic 

acid  is  enabled  to  maintain  neutrality.     This  may  be  written:     CH  = 
TT  r*o 

molecular  ratio  ^-^r^    •    Tne  rati°  mav  De  increased  either  by  adding 
JMaxlbUg 

free  carbonic  acid  to  the  blood  (as  by  causing  an  animal  to  respire  some 
of  the  gas),  or  by  the  addition  of  some  other  acid  (e.  g.,  oxybutyric,  as  in 
diabetes)  which  will  decompose  some  of  the  NaHC03  and  produce 
H2C03.  The  increase  which  these  changes  would  cause  in  CH  of  the 
blood  is  prevented  by  the  remarkable  sensitivity  of  the  respiratory  cen- 
ter to  changes  in  CH.  An  increase  which  is  much  less  than  can  be 
measured  by  physicochemical  means  stimulates  the  center,  causing  in- 
creased pulmonary  ventilation,  so  that  the  carbonic  acid  is  immediately 
eliminated  through  the  lungs.  This  elimination  does  not  stop  when  the 

old  level  of  carbonic-acid  concentration  is  reached,  but  proceeds  until 
TT  p<r\ 

the  original  ratio        TrA   *s  again  attained  in  the  blood,  and  CH  is 


restored  exactly  to  its  original  value.    If  it  stopped  at  the  old  CO,  con- 
centration, the  ratio  would  be  too  high  because  there  is  less  NaHC03. 

THE  THEORY  OF  ACIDOSIS 

Although  these  considerations  indicate  that  variations  may  occur  in 
the  bicarbonate  content  of  the  blood  without  any  significant  change  in 
CH,  they  also  show  that  the  bicarbonate  content  must  be  a  criterion  of 
the  acid-base  balance  of  the  blood,  and  probably  of  the  body  fluids  in 
general.  As  pointed  out  by  Van  Slyke,12  bicarbonate  represents  the  ex- 
cess of  base  which  is  left  over  after  all  the  fixed  acids  have  been  neu- 
tralized. It  represents  the  base  that  is  available  for  the  neutralization  of 
any  excess  of  such  acids  that  may  appear — a  measure  of  the  reserve  of 
"buffer  substance"  or,  more  specifically,  the  alkaline  reserve  of  the  body. 
Under  normal  conditions  the  amount  of  NaHCO3  in  blood  plasma  is  very 
constant  (amounting  to  50-65  vols.  per  cent  C02),  and  when  it  is  reduced, 
it  indicates  that  an  excess  of  fixed  acid  must  be  present.  This  is  taken 


ACIDOSIS  39 

by  Van  Slyke  and  others  to  constitute  the  real  definition  of  acidosis  — 
namely,  "a  condition  in  which  the  concentration  of  bicarbonate  in  the 
blood  is  reduced  below  the  normal  level.  "  If  the  respiratory  center 
for  any  reason  should  not  respond  promptly  enough  to  an  increase  in 

TT    QQ 

the  molecular  ratio         TTTT  >  an(i  CH  consequently  become  greater,  the 


condition  is  called  uncompensated  acidosis,  but  if  the  center  does  respond 
so  that  CH  is  held  constant  (although  NaHC03  is  decreased),  the  condition 
is  one  of  compensated  acidosis. 

For  practical  reasons,  therefore,  the  study  of  pathological  acidosis  de- 
pends on  an  estimation  of  the  bicarbonate  content  of  the  blood  or,  since 
it  is  simpler  to  carry  out  and  is  of  equal  value,  of  the  plasma.  When 
plasma  is  obtained  by  removing  blood  from  a  vein  of  the  arm  and  cen- 
trifuged  immediately  out  of  contact  with  air  (so  that  C02  may  not  be 
lost  from  it)  it  contains  approximately  60  vols.  per  cent  of  C02.  Since 
we  know  that  the  partial  pressure  of  C02  in  blood  is  equal  to  42  mm.  Hg 
(ascertained  from  determinations  of  the  alveolar  C02)  (see  page  361), 
we  can  calculate  how  much  of  the  60  vols.  per  cent  must  be  in  simple 
solution  by  application  of  the  law  of  solution  of  gas  in  a  liquid  (page 
353').  One  cubic  centimeter  of  plasma  at  body  temperature  and  at 
760  mm.  Hg  (atmospheric  pressure)  dissolves  0.54  c.c.  C02,  so  that  at 

42 

42  mm.  it  will  dissolve  7^7-  x  100  x  0.54  =  3  vols.  per  cent.   Transcribing 

ToU 

[H2C03]          3  1 

the  figures  to  our  equation  we  get 


[NaHC03]      60         20 

This  definition  of  acidosis  leaves  out  of  regard  all  conditions  that  may 
TT  pr\ 

raise  the  ratio       -^rrf  by  the  addition  of  H2C03  without  decomposing 
JNaJtLvjUs 

any  of  the  NaHC03,  such,  for  example,  as  occurs  when  an  excess  of  free 
carbonic  acid  is  present  in  the  blood  plasma.  Since  increases  in  free 
C02  are  not  infrequent  in  both  health  and  disease  —  e.  g.,  asphyxial  con- 
ditions —  the  above  definition  is  not  sufficiently  comprehensive.  When 
we  come  to  study  the  control  of  the  respiratory  center,  we  shall  see  that 

FT  PO 

an  increase  in  the  ratio       -A-^rf  °^  sufficient  magnitude  to  cause  an 

actual  increase  in  CH  can  be  brought  about  by  causing  an  animal  to  respire 
air  containing  an  excess  of  C02  —  a  true  acidosis,  but  one  for  which  no 
place  is  found  in  the  above  definition. 

*This   agrees   sufficiently   with   the   result   as   calculated   from    the    known   values   of   the   equation 
2  Thus,    if   we   take    CH    as   0.35  x  1Q-7,    X    as   0.605    for    blood    conditions,    and 


K. 

s  4.4X10- 
49.) 


K  as  4.4X10-    (Michaelis  and   Rona),    we  get  '     =    0.605  x  0.35  x  10-'  =     1         (gee  a]go  p 

4.4  X  10   '  21 


40  PHYSICOCHEMICAL   BASIS   OF   PHYSIOLOGICAL   PROCESSES 

Nevertheless,  Van  Slyke's  definition  has  a  real  value,  because  it  em- 
phasizes the  importance  of  a  determination  of  the  bicarbonate  as  a  cri- 
terion of  the  degree  of  the  forms  of  acidosis  usually  met  with  in  disease. 
The  bicarbonate  under  such  conditions  may  become  reduced  either  be- 
cause of  the  appearance  of  improperly  oxidized  fatty  acids,  like  /?-oxy- 
butyric  and  acetoacetic,  when  carbohydrate  metabolism  is  upset  as  in 
diabetes  or  starvation,  or  because  the  acids  produced  by  a  normal 
metabolism  are  inadequately  eliminated  by  the  kidneys,  as  in  nephritis. 

Accordingly,  if  the  respiratory  mechanism  and  increased  mass  move- 
ment of  the  blood  (for  an  increase  in  CH  accelerates  this  also)  should 

TT    pA 

fail  to  eliminate  C02  quickly  enough  so  as  to  keep  the       JL  ^  ratio  at 


one  twentieth,  then  CH  will  rise.  This  is  not  likely  to  happen  until  a 
large  part  of  the  NaHC03  has  been  used  up,  so  that  an  estimation  of  that 
actually  present  must  be  a  reliable  index  of  the  proximity  to  this 
condition. 

A  sustained  increase  in  CH  is  incompatible  with  life.  The  NaHC03  is 
the  buffer,  the  factor  of  safety  which  prevents  its  occurrence.  Although 
it  is  only  in  arterial  blood  (i.  e.,  after  elimination  of  excess  of  C02  by 
the  lungs  has  been  accomplished)  that  constancy  in  the  ratio 


NaHCO, 

can  be  expected,  it  is  fortunate,  for  practical  reasons,  that  venous  blood 

collected  during  muscular  rest  and  without  stasis  should  be  only  slightly 
different. 

When  acids  are  added  to  the  blood,  they  will  first  of  all  be  neutralized 
by  the  "buffers"  of  the  plasma — namely,  NaHC03  (and  protein),  as  we 
have  seen.  But  this  is  only  the  first  line  of  defense  against  acidosis,  for 
buffer  substances  present  in  the  corpuscles  may  also  be  used.  This  intra- 
corpuscular  reserve  of  base  is  rendered  available  by  transference  of  HC1 
from  the  plasma  into  the  corpuscle  so  releasing  base  in  the  former  to 
combine  with  the  added  acid  (e.g.,  H2C03),  according  to  the  equation: 
H2C03  +  NaCl  ±5  NaHC03  +  HC1.  The  HC1  on  entering  the  corpuscle 
combines  with  alkali  which  it  receives  from  the  hemoglobin  and  also  from 
phosphates  according  to  the  equation:  HC1  +  Na2HP04  ±^  NaH2P01  + 
NaCl.  This  is  a  particularly  important  detail  of  the  buffer  action  of  the 
blood,  not  only  because  it  shows  us  how  the  hemoglobin  and  phosphates 
of  the  corpuscles  are  rendered  available  for  neutralizing  acids  added  to 
the  plasma,  but  also  because  the  transference  of  acid  must  go  on  with  the 
other  cells  of  the  body  so  that  the  plasma,  itself  rather  poor  in  buffer 
substances,  has  all  those  of  the  body  at  its  disposal. 


ACIDOSIS  41 

THE  MEASUREMENT  OF  THE  RESERVE  ALKALINITY  OF  THE 

BODY  FLUIDS 

Titration  Methods 

There  are  several  methods  by  which  the  reserve  alkalinity  of  the  blood 
may  be  measured.  The  simplest  in  theory  consists  in  seeing  how  much 
standard  acid  must  be  added  to  a  measured  quantity  of  blood  plasma  in 
order  to  reach  the  neutral  point  as  judged  by  change  in  tint  of  some 
indicator.  The  indicators  employed  (e.  g.,  methyl  orange)  are  such  as 
change  their  tints  at  H-ion  concentrations  that  are  well  to  the  acid  side 
of  neutrality  (i.  e.,  at  a  high  CH  or  low  PH).  To  bring  the  plasma  to  this 
point  of  neutrality  the  added  acid  will  need  to  neutralize,  not  only  the 
bicarbonate  of  the  plasma,  but  other  acid-binding  substances  as  well. 
This  will  give  us  a  false  impression  of  the  acid-binding  powers  of  the 
plasma,  since,  at  the  normal  CH  of  the  blood,  proteins  do  not  absorb  acids 
to  anything  like  the  extent  they  do  at  higher  degrees  of  CH.  Another 
objection  to  the  method  is  that  the  proteins  interfere  with  the  sensitive- 
ness of  the  indicators. 

The  objections  can  be  removed  by  determining  the  end  point  electro- 
metrically  or  by  indicators  that  change  tint  at  about  PH7.  The  most 
practical  way  is  to  determine  the  change  in  CH  produced  by  adding  a 
known  volume  of  standard  acid  to  blood  plasma.  The  resulting  change 
in  CH  will  then  be  greater  the  less  the  alkaline  reserve.  In  the  electro- 
metric  method  irregularities  that  might  be  caused  by  variable  amounts 
of  carbonic  acid  in  the  blood  to  start  with  are  best  controlled  by  removing 
the  C02  from  the  plasma  after  adding  the  standard  acid.  The  procedure 
therefore  consists  in  mixing  1  c.c.  plasma  with  2  c.c.  N/50  HC1  in  a  small 
separating  funnel,  which  is  then  evacuated  so  as  to  remove  the  C02, 
after  which  the  fluid  is  transferred  to  a  hydrogen  electrode  and  CH 
measured  (see  page  29).  In  normal  blood  this  should  be  10  5-6  (PH5.6). 
In  acidosis,  where  there  is  a  depleted  alkaline  reserve,  the  2  c.c.  of  acid 
will  cause  a  much  greater  change  in  CH — in  diabetic  blood  to  below  5 
or  lower. 

The  technic  involved  in  the  above  method  is,  however,  too  exacting  for 
routine  clinical  work.  For  such  purposes  the  colorimetric  method  of  Levy 
and  Eowntree  may  be  employed. 

The  Method  of  Levy  and  Eowntree.is — A  test  tube  made  of  hard  ("nonsol")  glass 
of  about  20  c.c.  capacity,  containing  about  a  gram  of  powdered  neutral  potassium  oxa- 
late,  is  filled  with  newly  drawn  blood,  immediately  stoppered  and  placed  on  ice.  Quan- 
tities of  2  c.c.  each  of  the  blood  are  then  placed  in  a  series  of  seven  small  (nonsol)  test 
tubes  and  allowed  to  stand  for  five  to  six  minutes  in  order  to  permit  a  narrow  layer 
of  plasma  to  separate  on  the  surface  (this  prevents  laking  of  the  blood  during  the  sub- 


42  PHYSICOCHEMICAL   BASIS   OF   PHYSIOLOGICAL   PROCESSES 

sequent  addition  of  acid  or  alkali).  The  blood  in  the  first  tube  is  used  for  the  de- 
termination of  the  normal  H-ion.  In  each  of  the  next  three  tubes  are  added  respec- 
tively 0.1,  0.2  and  0.3  c.c.  N/50  HC1,  and  to  the  last  three,  similar  quantities  of  N/50 
NaOH.  After  inverting  the  tubes  so  as  to  mix  the  contents,  the  blood  in  each  is  trans- 
ferred to  celloidin  sacs  and  the  CR  determined  according  to  the  method  described  else- 
where (page  32). 

The  tubes  are  noted  in  which  a  change  in  tint  from  that  of  the  normal  blood  is 
evident,  and  the  results  are  expressed  as  the  c.c.  of  N/50HC1  or  NaOH  which  must 
be  added  to  blood  to  change  its  0R.  Thus,  the  alkali  buffer  is  the  c.c.  of  N/50  NaOH 
which  can  be  added  to  2  c.c.  of  blood  without  change  of  CH  of  the  dialysate,  and 
the  acid  luffer  the  c.c.  of  N/50  HC1. 

The  method  suffers  from  the  following  drawbacks: 

1.  Very  small  quantities  of  acid  and  alkali  are  employed. 

2.  It  is  often  difficult  to  tell  just  exactly  when  a  slight  difference  in  tint  has  been 
produced. 

3.  Even  with  the  precautions  described  above,  it  is  impossible  to  be  sure  that  the 
amount  of  CO    in  the  different  samples  of  blood  is  the  same,  which  means,  of  course, 
that  some  bloods  will,  on  this  account  alone,  be  able  to  bind  more  alkali  than  others. 

The  Method  of  Van  Slyke. — A  method  based  on  somewhat  the  same  principle,  but 
which  is  more  accurate  because  it  meets  the  above  objections,  is  that  suggested  by  Van 
Slyke,  Stillman  and  Cullen.i*  Plasma  is  freed  of  CO2  by  placing  it  in  a  vacuum, 
and  is  then  mixed  with  an  equal  volume  of  N/50  HC1  (or  NaOH)  and  the  CH  deter- 
mined by  the  electric  method  (see  page  29).  In  the  case  of  normal  blood,  after  such 
an  addition  of  acid,  a  practically  normal  CH  will  be  found,  whereas  in  the  blood  of 
cases  of  acidosis  it  will  be  very  distinctly  increased  (i.e.,  PH  lower). 

Total  CO, -combining  Power 

The  above  objections  to  the  titration  of  blood  plasma  or  dialysate 
with  standard  solutions  of  acids  are  removed  if  we  measure  the  com- 
bining power  of  the  blood  alkali  towards  carbonic  acid  itself  at  normal 
blood  reaction.  This  may  be  done  either  in  blood  immediately  after  its 
removal  from  the  animal  or  in  blood  that  has  been  first  of  all  saturated 
outside  the  body  with  carbonic  acid  at  a  partial  pressure  equal  to  that 
existing  in  the  body.  Since  for  practical  reasons  venous  blood  must  be 
used — in  the  clinic  at  least — the  former  of  these  methods  suffers  from 
the  fault  that  varying  amounts  of  carbonic  acid  will  be  added  to  the 
blood  during  its  passage  through  the  tissues,  and  the  error  thereby 
incurred  will  become  greatly  aggravated  if  venous  stasis  has  been  pro- 
duced in  drawing  the  specimen  for  analysis.  But  the  chief  reason  why 
this  method  has  not  been  extensively  employed,  as  pointed  out  by  Van 
Slyke,  is  the  technical  difficulty  of  making  the  necessary  analysis. 

It  is  most  satisfactory  to  collect  venous  blood  after  a  period  (one  hour  at  least) 
of  muscular  rest  (so  that  there  is  no  excess  of  COo)  and  without  venous  stasis,  and 
to  centrifuge  without  permitting  any  considerable  loss  of  carbonic  acid.  The  latter 
precaution  is  necessary  because  there  is  a  migration  of  acid  radicles,  e.  g.,  HC1,  from 
plasma  into  corpuscles  when  the  COo  of  the  former  is  increased,  and  in  the  reverse 


ACIDOSIS 


43 


direction  when  the  CO2  is  decreased.  If  the  CO2  in  the  blood  were  not  the  same  dur- 
ing centrifuging  as  it  is  in  the  body,  the  separate  plasma  would  not  contain  the  same 
amount  of  alkali — i.  e.,  its  reserve  alkalinity  would  be  altered.  Although  theoretically, 
therefore,  centrifuging  should  be  performed  in  an  atmosphere  containing  the  same 
partial  pressure  of  CO*  as  exists  in  the  body  (i.  e.,  the  alveolar  air)  (see  page  361), 
this  has  been  found  impracticable  for  general  use,  and  is  unnecessary  if  loss  of  CO2 
from  the  specimen  of  blood  is  prevented  by  allowing  it  to  flow  into  the  syringe  very 
slowly  (without  any  suction).  It  is  mixed  in  the  syringe  with  powdered  (neutral) 
potassium  oxalate  (enough  to  make  a  1  per  cent  solution  with  the  blood),  and  imme- 
diately delivered  into  a  centrifuge  tube  under  paraffin  oil,  which  by  floating  on  its 
surface  serves  to  diminish  free  diffusion  of  CO2  to.  the  outside  air  (even  though  such 
oils  dissolve  more  CO9  than  water).  To  mix  the  blood  with  the  oxalate,  the  syringe 
should  be  moved  backward  and  forward  several  times,  but  it  must  not  be  shaken. 

After  centrifuging,  about  3  c.c.  of  plasma  are  removed  and  saturated  with  CO2  at 
the  same  tension  as  in  alveolar  air  (i.  e.,  5.5  per  cent).  This  is  done  by  placing  the 
plasma  in  a  separating  funnel  of  300  c.c.  capacity,  laying  the  funnel  on  its  side  and 
displacing  the  air  in  it  by  alveolar  air  secured  by  quickly  making  as  deep  an  inspira- 


Fig.  10. — Diagram  of  apparatus  for  saturating  blood  or  plasma  with  expired  air.  _  The  glass 
beads  in  the  bottle  condense  excess  of  moisture.  The  separating  funnel,  as  soon  as  it  has  been 
filled  with  expired  air,  should  be  closed  by  a  stopper  and  the  stopcock  turned  off.  It  is  then 
rotated  so  that  the  blood  forms  a  film  on  its  walls. 

tion  as  possible  through  the  tube  and  bottle  containing  glass  beads  (Fig.  10).  The 
glass  beads  remove  excess  of  water  vapor  from  the  air.  The  funnel  must  be  restop- 
pered  before  the  end  of  the  expiration,  so  that  no  outside  air  enters.  It  is  then  ro- 
tated, for  about  two  minutes,  in  such  a  way  that  the  plasma  forms  a  film  on  its  walls. 
If  it  is  necessary  to  postpone  the  saturating  of  the  plasma,  this  should  me  pipetted  off 
from  the  corpuscles  and  preserved  in  hard  glass  test  tubes  coated  with  paraffin.  From 
ordinary  glass  enough  alkali  is  soon  dissolved  out  to  vitiate  the  results.  After  satura- 
tion of  the  plasma  with  CO^,  the  funnel  is  placed  in  the  upright  position  and  the 
plasma  allowed  to  collect  in  "the  narrow  portion,  after  which  1  c.c.  is  removed  with 
an  accurate  pipette  and  analyzed  for  CO  . 

The  analysis  may  be  done  by  using  either  the  Van  Slyke  or  the  Haldane-Barcroft 
apparatus.  The  Van  Slyke  method  is  as  follows: 

The  apparatus  is  filled  to  the  top  of  the  graduated  tube  with  mercury  (Fig.  11) 
by  raising  the  mercury  reservoir  F,  care  being  taken  that  D  and  E  are  also  filled. 
One  c.c.  of  the  COo-saturated  plasma  is  then  delivered  into  A  (which  has  been  rinsed 
out  with  CO2-free  ammonia  water),  and  the  stopcock  I  turned  so  that  by  cautiously 
lowering  the  level  of  the  reservoir  F,  the  plasma  runs  into  B  (but  no  trace  of  air). 


44 


PHYSICOCHEMICAL   BASIS   OF   PHYSIOLOGICAL   PROCESSES 


The  same  procedure  is  repeated  with  1  c.c.  water,  so  as  to  wash  in  all  of  the  plasma/ 
arid  finally  0.5  c.c.  of  5  per  cent  H  SO  is  sucked  in,  after  which  stopcock  I  is  turned 
off.  The  reservoir  F  is  then  lowered  sufficiently  to  allow  all  of  the  mercury,  but  none 
of  the  blood,  to  run  out  of  B  and  C.  A  vacuum  is  thus  produced  in  B  and  C. 

As  the  level  of  the  mercury  falls  in  B  and  C,  the  plasma  effervesces  violently,*  be- 
cause it  is  exposed  to  a  vacuum.  To  be  certain  that  all  traces  of  CO  have  been 
dislodged  from  the  solution,  the  apparatus  is  inverted  several  times.  To  ascertain  how 
much  CO2  has  been  liberated,  stopcock  II  is  now  turned  so  as  to  bring  C  and  E  into 
communication,  and  by  cautiously  lowering  the  reservoir  the  fluid  in  C  is  allowed  to 
run  into  the  bulb  E.  Stopcock  II  is  thereafter  turned  so  as  to  connect  C  and  D,  and 
the  reservoir  raised  so  that  the  mercury  runs  into  C  as  far  as  the  CO  that  has  col- 


Fig.   11. — Van  Slyke's  apparatus  for  measuring  the  CDs-combining  power  of  blood  in  blood  plasma. 
For   description,   see   context. 


lected  in  the  burette  will  permit  it  to  go.  After  bringing  the  level  of  the  mercury 
ir.  F  to  correspond  to  that  in  the  burette,  the  graduation  at  which  this  stands  is  read. 
It  gives  the  c.c.  of  CO  liberated  from  the  plasma.  Under  the  above  conditions  normal 
plasma  binds  about  75  per  cent  of  its  volume  of  CO2 ;  therefore,  since  the  total  capacity 
of  the  pipette  is  50  c.c.,  the  mercury  should  stand  at  0.375  c.e.  on  the  burette.  For 
accurate  measurement  it  is  necessary  to  allow  for  the  CO2  that  remains  dissolved  in 
the  water,  etc.,  as  well  as  for  barometric  pressure  and  temperature.  This  is  best  done 
by  the  use  of  a  table  based  on  the  known  solubility  of  CO.,  under  the  various  condi- 
tions obtaining,  which  is  given  in  'van  Slyke's  paper.12 


*This  may  be  prevented  by  adding  a  small  drop  of  caprylic  alcohol. 


ACIDOSIS  45 

The  Haldane-Bar  croft  apparatus  that  is  most  suitable  for  the  above  analysis  is 
shown  in  Fig.  136,  page  395.*  One  c.c.  of  CO2-free  ammonia  water  is  placed  in  the 
bottle  and  the  1  c.c.  of  plasma  delivered  beneath  it.  The  bottle  is  then  connected 
with  the  manometer  with  the  precautions  described  elsewhere  in  this  volume.  When 
temperature  conditions  have  been  allowed  for,  saturated  tartaric  acid  is  mixed  with 
the  plasma  solution  and  the  gas  evolved  measured  by  the  displacement  of  the  fluid 
in  the  manometer.  The  apparatus  may  also  be  used  with  blood  in  place  of  plasma. 
In  this  case,  however,  it  is  necessary  that  the  oxygen  be  removed  before  adding  the 
tartaric  acid.  This  precaution  is  necessary,  since  acid  can  dislodge  some  of  the  H2  from 
hemoglobin.  The  blood  is  therefore  first  of  all  laked  with  ammonia  containing  some 
saponin,  then  shaken  with  0.25  c.c.  saturated  potassium  ferricyanide  solution,  and 
finally  with  the  saturated  acid  solution.  If  blood  is  used,  the  estimations  must  be 
made  on  strictly  fresh  blood,  since  on  standing  the  CO2  combining  power  greatly  de- 
teriorates. 

From  what  has  been  said  in  the  introductory  part  of  this  chapter  it  is 
clear  that  the  plasma  furnishes  only  the  first  line  of  defense  of  the  body 
against  excess  of  acid;  the  corpuscles  form  the  second  line  of  defense,  so 
that  a  much  truer  estimate  of  the  ' '  reserve  alkalinity ' '  is  afforded  when  the 
C02-combining  power  of  whole  blood  rather  than  that  of  separated  plasma 
is  used.  The  C02-combining  power  of  the  whole  blood  has  been  studied 
by  Christiansen,  Haldane  and  Douglas,22  by  Morawitz  and  Walker,23  and 
more  recently  by  Haggard  and  Henderson,21  Van  Slyke,28  and  Joffe  and 
Poulton.29 

Another  question  remains  to  be  considered,  namely,  whether  arterial  or 
venous  Hood  should  be  employed.  For  various  reasons  arterial  blood  is 
preferable.  In  the  first  place  the  percentage  of  C02  actually  present  in  it 
is  proportionate  to  the  alkaline  reserve,  because  the  respiratory  center  is 
so  sensitive  to  the  slightest  excess  of  this  acid  (see  page  353)  that  it  stimu- 
lates respiration  so  as  to  remove  the  excess  and  thus  maintain  the  C02  of 
the  arterial  blood  at  exactly  the  point  which  corresponds  to  its  alkaline 
reserve.  It  is,  therefore,  unnecessary -to  expose  the  blood  to  an  atmosphere 


*This  form  of  Haldane-Barcroft  apparatus  is  not  quite  the  same  as  the  differential  manometer 
that  is  used  for  measurement  of  the  O2-combining  power  of  hemoglobin  (page  395).  In  the  form 
used  for  the  present  purpose,  a  side  tube  at  the  bend  of  the  U-tube  is  connected  with  a  small  rub- 
ber bag,  which  can  be  compressed  by  a  screw.  When  the  gas  is  evolved  in  the  bottle,  it  presses 
down  the  fluid  in  the  proximal  limb  of  the  manometer  correspondingly  and  raises  that  in  the  distal 
limb.  Since  the  calculation  of  the  amount  of  gas  evolved  depends  on  finding  the  pressure  produced 
without  any  change  in  volume,  it  is  necessary  after  the  gas  has  been  evolved  to  compress  the  rubber 
bag  until  the  meniscus  of  fluid  in  the  proximal  limb  of  the  manometer  is  brought  back  to  its  original 
level.  The  height  at  which  the  fluid  stands  in  the  distal  limb  then  obviously  corresponds  to  the 
pressure  created  by  the  evolved  gas. 

The  equation  for  determining  the  amount  of  gas  evolved  depends  on  the  gas  Jaw,  which  states 
that  the  pressure  of  a  gas  is  inversely  proportional  to  its  volume  (page  353).  Suppose  that  the 
volume  of  gas  evolved  was  equal  to  the  volume  of  the  bottle,  then,  since  the  volume  has  been 
kept  constant,  the  pressure  would  be  doubled — that  is,  the  fluid  in  the  distal  limb  would  equal  that 
of  1  atmosphere,  or  10,400  mm.  of  water  or  10,000  of  clove  oil,  which  is  the  fluid  actually  used  to 
fill  the  manometer.  Any  other  observed  pressure  would  therefore  correspond  to  the  volume  of 
evolved  gas  according  to  the  equation, 

V  =    V01'  °f  b°ttle   (and  tubi"g  t0  meni8CU8>     X    mm.      Pressure  in   Manometer. 
10,000  (when  clove  oil  is  used) 

In  using  the  apparatus  in  the  above  manner,  only  one  of  the  bottles  is  employed,  and  the  tartaric 
acid  is  added  from  a  pocket  in  the  stopper  by  a  simple  manipulation. 


46  PHYSICOCHEMICAL   BASIS   OF   PHYSIOLOGICAL   PROCESSES 

containing  C02  before  measuring  the  C02  content.  In  the  second  place, 
the  arterial  blood  represents  the  mixed  blood  of  the  body,  and  not  that  of 
one  locality  only,  as  is  the  case  with  blood  removed  from  a  peripheral  vein. 
If  venous  blood  is  collected  with  the  precaution  that  the  muscles  in  the 
corresponding  area  have  been  at  rest  for  some  time  it  appears  that  there  is 
practically  no  difference  between  the  alkaline  reserve  of  arterial  and  ve- 
nous blood;  but  if  there  has  been  any  muscular  contraction,  the  venous 
blood  will  have  a  lower  reserve  than  the  arterial,  because  of  the  lactic  acid 
thrown  into  it  by  the  active  muscles.  But  even  when  we  take  the  precau- 
tion of  avoiding  muscular  action  it  is  probable  that  there  is  not  a  strict 
parallelism  between  the  buffer  action  of  arterial  and  venous  blood,  as  in 
cases  in  which  the  demands  on  the  alkaline  reserves  are  such  that  those  of 
the  tissues  are  being  called  on  as  well  as  those  of  the  blood  itself. 

Even  when  the  whole  blood  is  used,  however,  we  do  not  necessarily 
measure  the  total  reserve  of  tlie  ~body,  a  final  reserve  being  afforded  by  the 
alkalies  and  possibly  certain  of  the  proteins  of  the  tissue  cells.  Now  it  is 
clear  that  there  can  be.  no  test  tube  method  by  which  measurement  of  the 
magnitude  of  all  of  these  defensive  agencies  is  possible;  and  we  are  there- 
fore compelled  to  supplement  them  by  certain  indirect  methods. 

Indirect  Methods 

The  chief  criticism  against  the  use  of  the  C02  carrying  power  of  blood 
or  blood  plasma,  is  therefore,  that  it  tells  little  if  anything  concerning  the 
acid-absorbing  powers  of  the  tissues.  Is  there  not,  therefore,  some  test  of 
the  acid  buffer  which  can  be  applied  to  the  intact  animal  ?  One  such  is  the 
percentage  of  C02  in  alveolar  air  (see  page  361). 

1.  Determination  of  the  Tension  of  C02  in  Alveolar  Air. — Since  this 
method  is  employed  more  particularly  in  investigating  the  hormone  con- 
trol of  the  respiratory  center,  we  shall  defer  a  description  of  it  until  later 
(page  361).  For  the  present,  however,  it  should  be  remarked  that  the  alve- 
olar C02  can  be  a  precise  gauge  of  the  acid-base  equilibrium  only  provided 
that  the  respiratory  center  is  perfectly  normal,  and  that  there  is  no  in- 
terference with  the  diffusion  of  C02  from  the  blood  into  the  alveolar  air. 
In  order  to  place  an  estimate  on  the  relative  value  of  this  method  com- 
parisons have  been  made  between  the  C02  tension  of  the  alveolar  air  and 
the  C02  absorbing  power  of  the  blood.  This  has  been  done  both  in  nor- 
mal and  pathological  subjects.  In  normal  subjects  the  comparisons  have 
been  made  under  conditions,  such  as  the  taking  of  food  and  during  mus- 
cular exercise,  in  which  slight  alterations  in  the  acid-base  equilibrium  are 
known  to  occur.  Van  Styke,  Stillman  and  Cullen9b  found  that  the  ratio 

plasma  C°2 varies  from  1.27  to  1.80  in  different  resting  individu- 

mm.  alveolar  C02 

als,  there  being  apparently  a  characteristic  ratio  for  each  individual,  and 


ACIDOSIS  47 

that  the  taking  of  food  invariably  raises  the  alveolar  OCX-combining  power. 
This  would  seem  to  indicate  that  it  must  be  the  excitability  of  the  'respi- 
ratory center  rather  than  the  acid-base  equilibrium  that  becomes  altered 
so  as  to  cause  variations  in  alveolar  C02. 

Technical  difficulties  have  also  to  be  overcome  in  the  collecting  of  the 
alveolar  air,  for  it  is  now  well  established  that  the  original  method  of  Hal- 
dane  and  Priestley  is  approximately  accurate  only  when  it  is  carried  out 
under  strictly  controlled  conditions — so  strict  that  they  can  not  be  prac- 
tised in  the  clinic — and  even  then,  as  R.  G.  Pearce,  Carter,  Krogh,  Sie- 
beck  and  others  have  shown,  we  can  not  be  certain  of  the  results.  At  best, 
therefore,  the  alveolar  C02  can  serve  as  an  accurate  index  of  the  acid-base 
equilibrium  of  the  blood  only  under  strictly  controlled  conditions. 

2.  The  Measurement  of  the  Acid  Excretion  by  the  Kidney, — As  might 
be  expected,  the  acid-base  equilibrium  of  the  body  may  also  be  gauged  by 
measurement  of  the  acid  excretion  of  the  urine,  in  which  the  acids  are 
contained  partly  in  combination  with  ammonia  or  a  fixed  base,  and  partly 
in  a  free  state.  We  shall  first  of  all  consider  the  methods  of  acid 
excretion  and  then  examine  the  evidence  showing  that  the  total  acid 
excretion  is  proportional  to  the  alkaline  reserve  as  measured  by  the 
above  described  methods. 

EXCRETION  OF  ACID  IN  COMBINATION  WITH  AMMONIA. — The  production 
of  ammonia  is  essentially  an  endogenous  process,  and  when  excessive 
quantities  of  acid  make  their  appearance  in  the  organism,  the  fixed  alkali 
may  not  be  sufficient  to  neutralize  it  all,  so  that  ammonia,  derived  from 
the  breakdown  of  ammo  acids  (page  650),  instead  of  being  converted 
into  urea  is  employed  to  neutralize  the  excess  of  acid.  Most  workers 
have  in  this  way  explained  the  very  large  ammonia  excretion  that  has 
long  been  known  to  occur  in  such  conditions  as  diabetic  acidosis.  Some 
recent  workers  are,  however,  inclined  to  question  the  significance  of 
ammonia  in  this  connection,  believing  that  the  increased  ammonia  ex- 
cretion is,  like  the  acetone  bodies  themselves,  a  product  of  perverted 
metabolism.  Be  this  as  it  may,  it  is  no  doubt  true  that  ammonia  is  used 
for  neutralizing  acid  in  disease,  although  it  may  not  be  an  important 
factor  in  the  maintenance  of  neutrality  under  normal  conditions.  It  is 
a  factor  of  safety,  in  that  it  helps  to  care  for  an  increase  in  acid  when 
the  normal  mechanism  of  the  body  is  overtaxed. 

EXCRETION  OF  PHOSPHATES. — The  more  permanent  control  of  neutrality 
depends  on  the  excretion  of  phosphates  by  the  kidney.  The  principle 
governing  this  process  is  exactly  the  same  as  that  already  discussed  in 
connection  with  carbonic  acid.  In  the  one  case  it  is  the  volatile  acid 
C02,  and  in  the  other,  the  fixed  phosphoric  acid  that  is  concerned  in  the 
reaction.  The  ratio  between  the  acid  salts  of  phosphoric  acid,  MH2P04, 


48  PHYSICOCHEMICAL   BASIS   OF   PHYSIOLOGICAL   PROCESSES 

and  the  alkaline  salts,  M2HP04,  in  blood  is  approximately  1  to  5,  but  in 
the  urine  this  ratio  varies  according  to  the  amount  of  H  ion  that  must 
be  eliminated  from  the  blood.  In  other  words,  a  definite  amount  of  phos- 
phoric acid  is  enabled  to  carry  variable  amounts  of  H  ion  out  of  the  body 
by  causing  the  amount  of  alkali  excreted  in  combination  with  it  to  be- 
come altered.  For  example,  in  the  form  of  MH2P04  a  given  amount  of 
P04  obviously  carries  out  more  H  ion  than  when  it  is  excreted  as 
M2HP04.  The  adjustment  between  these  two  salts  is  a  function  of  the 
kidney.  We  may  accordingly  measure  the  amount  of  alkali  retained  by 
the  organism  by  finding  how  much  standardized  alkali  must  be  added 
to  a  given  quantity  of  urine  until  the  reaction  of  the  blood  is  obtained. 
Since  the  latter  value  is  constant,  the  titration  can  be  done  simply  by 
titrating  the  urine  with  an  indicator  such  as  sulphonephenolphthalein, 
which  changes  tint  at  about  PH  of  blood. 

A  more  serviceable  indicator  to  use,  however,  is  phenolphthalein,  be- 
cause its  end  point  is  such  that  when  human  urine  just  reacts  neutral 
to  it — that  is,  when  the  titrable  acid  approaches  zero — the  C02-absorb- 
ing  power  of  the  plasma  is  at  its  maximum  of  80  vols.  per  cent  and  the 
ammonia  excretion  by  the  urine  is  zero  (Van  Slyke).  It  is  advantageous, 
therefore,  to  use  this  indicator,  because  it  happens  to  have  its  turning 
point  situated  for  a  reaction  which  is  well  to  the  alkaline  side  of  neu- 
trality, and  which  is  reached  in  urine  when  the  blood  is  at  its  maximal 
acid-combining  power  and  no  ammonia  is  being  used  for  neutralization 
purposes.  As  the  C02-combining  power  of  the  blood  decreases,  there 
should,  therefore,  be  a  proportionate  increase  in  ammonia  and  in  the 
titrable  acidity  of  the  urine. 

3.  Determination  of  Alkali  Retention. — Another  valuable  criterion  of 
the  alkaline  reserve  is  the  amount  of  alkali  required  to  change  the  re- 
action of  the  urine.  In  health  the  CH  of  the  urine  varies  from 
0.000,016  N  (PH  =  4.8)  to  about  0.000,000,035  N  (PH  =  7.46)  with  a  mean 
of  about  0.000,001  N  (PH  =  6).  These  extremes  are  rarely  overstepped 
in  disease,  but  frequently  the  average  is  considerably  different.  In  car- 
dio-renal  disease,  for  example,  the  mean  acidity  may  be  approximately 
0.000,005  N  (PH  =  5.3),  or  five  times  the  normal  value,  A  certain  de- 
gree of  acidosis  is  therefore  common  enough  in  this  condition — a  fact 
which  has  indicated  the  advisability  of  administering  sodium  bicarbon- 
ate. It  has  been  found  that  5  grams  or  less  of  soda,  given  by  mouth  to 
a  normal  person,  causes  a  distinct  diminution  in  tHe  CH  of  the  urine, 
whereas  in  pathologic  cases  it  may  be  necessary  to  give  more  than  100 
grams  before  a  similar  effect  is  observed  (L.  J.  Henderson  and  Palmer15 
and  Sellards16). 

This  test  has  been  found  of  particular  value  in  the  diagnosis  of  acidosis 


ACIDOSIS  49 

accompanying  certain  forms  of  renal  disease  (chronic  interstitial  nephri- 
tis), which  raises  the  question  as  to  whether  the  retention  may  not  be 
due  to  faulty  elimination  of  the  bicarbonate  rather  than  to  its  retention,  in 
order  that  a  deficient  alkaline  reserve  maybe  corrected.  It  has  not  been  a 
very  simple  matter  to  disprove  entirely  this  possible  explanation,  and  ex- 
periments of  a  variety  of  types  have  had  to  be  devised  in  connection  with 
the  problem.  One  of  them  consists  in  determining  the  effect  of  a  second 
dose  of  bicarbonate  administered  to  an  acidosis  patient  to  whom  a  suffi- 
cient amount  had  previously  been  given  to  render  the  urine  just  alkaline. 
It  has  been  found  that  a  few  grams  now  suffice,  indicating,  apparently, 
that  the  alkaline  reserve  must  have  been  restored  to  its  normal  level. 
Even  to  this  experiment  the  objection  can  be  raised,  however,  that  the 
large  doses  were  retained  because  the  threshold  of  the  kidney  for  the  ex- 
cretion of  bicarbonate  was  a  Very  high  one,  and  that  the  second,  smaller 
administration  just  sufficed  to  overstep  this  threshold. 

Sellards'  careful  work  with  this  method  seems  quite  clearly  to  establish 
its  value,  however,  and  for  practical  purposes  it  is  probably  the  most  prac- 
ticable test  -of  acidosis  at  present  available  in  routine  clinical  work.  It 
has  the  important* advantage,  furthermore,  of  being  simple  and  of  requir- 
ing no  elaborate  apparatus. 

It  may  be  advantageous  in  this  place  to  classify  the  possible  causes 
which  might  lead  to  a  want  of  stability  in  th'e  CH  of  the  blood ;  that  is, 
to  threatened  acidosis  or  alkalosis,  not  of  acidosis  in  the  narrow  sense  im- 
pliecl  in  Van  Slyke's  definition,  but  in  the  broader  sense  of  any  disturb- 
ance in  the  acid-base  equilibrium. 

Relationship  Between  OCX-content  of  Blood  and  Hydrogen-ion 

Concentration 

From  the  equation  given  on  page  39,  it  is  evident  that  PH  can  be  cal- 
culated for  each  partial  pressure  of  C02  at  which  blood  is  equilibrated, 
provided  we  know  the  total  C02-combining  power  and  the  H2C03.  We 
have  seen  how  the  former  may  be  determined  (page  42).  The  free  H2CO:J 
is  determined  by  multiplying  the  mm.  of  C02  pressure  by  the  factor  0.0672 

which  is  derived  from  the  equation    _-.    x  -— —  in  which  0.511  is  the 

7bU  1 

coefficient  of  solubility  of  C02  in  blood  at  3'8°  C.  (cf.  gas  laws,  page  354). 
If  blood  be  exposed  to  various  C02  tensions  which  are  placed  on  the 
abscissa  of  a  chart,  as  in  Fig.  128,  page  363,  and  the  total  C02  with  which 
it  combines  at  each  tension  be  placed  on  the  ordinates,  a  curve  (C02-dis- 
sociation  curve)  is  obtained  and  a  slanting  line  may  also  be  drawn  on 
the  chart  to  show  the  C02  in  simple  solution  (i.e.,  as  H2C03).  Now  CH 
at  each  C02  tension  will  be  proportional  to  the  ratio  between  the  dis- 


50  PHYSICOCHEMICAL   BASIS   OF   PHYSIOLOGICAL   PROCESSES 

tances  of  the  curves  and  the  slanting  line  from  the  abscissa;  i.e.,  PH,  since 
it  is  the  reciprocal  of  CH,  will  be  inversely  proportional.  Lines  repre- 
senting PH  may  therefore  be  drawn  across  the  chart,  their  exact  position 
being  most  conveniently  calculated  from  the  equation  PH  =  6.10  +  log 
(total  C02  -  0.0672p)  (a  modification  of .  that  already  given  on  page  39, 

0.0672p 

and  in  which  p  is  the  partial  pressure  of  C02  and  0.0672  the  factor  by 
which  it  is  necesary  to  multiply  the  tension  in  order  to  find  the  volume 
per  cent  of  C02  in  simple  solution).  As  a  practical  detail  in  determining 
the  curve  it  may  be  mentioned  that  the  blood  should  be  exposed  to  C(X 
tensions  of  40,  72  and  18  m.m.,  in  the  order  given  (Haggard  and  Hender- 
son). If  the  lowest  tension  is  used  first  there  is  danger  of  laking  of  the 
blood  with  consequent  error  because  of  the  acid  qualities  of  hemoglobin. 


CHAPTER  VII 

COLLOIDS 

Substances  which  can  be  obtained  in  the  crystalline  state  and  which, 
when  in  solution,  are  capable  of  readily  diffusing  through  membranes, 
are  designated  as  crystalloids,  and  are  to  be  distinguished  from  another, 
larger  group  of  substances  not  having  these  characteristics  or  having 
them  only  in  very  minor  degree — the  colloids.  In  every  field  of  chem- 
istry the  properties  of  colloids  have  been  studied  extensively  during 
recent  years,  but  in  no  field  more  than  in  that  which  covers  the  chem- 
istry of  biological  fluids  and  tissues,  into  whose  composition  colloids 
enter  much  more  extensively  than  crystalloids.  The  subject  of  colloidal 
chemistry  has  indeed  become  so  extensive  that  an  attempt  to  do  more 
than  indicate  some  of  the  most  important  characteristics  of  colloids 
would  take  us  far  beyond  the  limitations  of  this  book.  The  far-reaching 
applications  of  the  subject  in  physiology  and  medicine  are  only  begin- 
ning to  be  realized. 

The  term  "colloid,"  or  "colloidal,"  does  not  refer  to  a  class  of  chemical 
substances,  but  rather  to  a  state  of  matter  which  is  quite  independent 
of  the  chemical  composition  of  the  substance.  We  are  familiar  with 
more  colloids  in  the  organic  than  in  the  inorganic  world,  yet  they  are 
plentiful  in  both,  and  the  same  substance  may  at  one  time  be  colloidal 
and  at  another  noncolloidal.  Indeed,  under  appropriate  conditions  prob- 
ably all  substances  may  assume  the  colloidal  state — not  solids  and  liq- 
uids alone,  but  gases  as  well.  It  is  mainly  with  liquids,  however,  that 
we  are  concerned  in  biochemistry. 


CHARACTERISTIC  PROPERTIES 

The  distinction  between  molecular*  and  colloidal  solutions  is  a  rela- 
tive one.  Suppose,  for  example,  that  we  take  a  piece  of  gold  in  water 
and  divide  it  up  into  smaller  and  smaller  parts.  At  a  certain  stage,  the 
particles  will  be  so  fine  that  they  will  remain  in  suspension  and  be  in- 
visible by  ordinary  means.  They  are  then  said  to  be  in  the  colloidal 
state.  If  we  divide  them  further  until  they  become  molecules  of  gold, 
a  molecular  solution  will  be  obtained.  In  the  colloidal  state,  there  are 

*Molecular  solutions  include  those  of  nonelectrolytes,  such  as  sugar,  and  electrolytes,  such  as 
inorganic  salts. 

51 


52  PHYSICOCHEMICAL   BASIS   OF   PHYSIOLOGICAL   PROCESSES 

two  distinct  phases  in  the  solution,  one  solid  and  the  other  liquid,  and 
between  the  two,  because  of  the  great  subdivision  of  the  original  par- 
ticle, is  an  enormous  surface  of  contact.  The  solution  is  heterogeneous, 
and  at  the  interface  between  the  two  "phases"  the  physical  forces  which 
depend  on  surface — e.  g.,  surface  tension  (see  page  65) — are  enormously 
developed,  and  are  responsible  for  the  peculiar  properties  of  colloidal 
solutions  as  compared  with  those  of  molecular  solutions,  which  may, 
therefore,  be  styled  homogeneous.  The  solutions  of  crystalline  substances 
which  we  have  hitherto  been  concerned  with,  are  homogeneous. 

Between  these  two  groups  of  solutions  is  an  intermediate  one — namely, 
suspensions  (as  suspensions  of  quartz  or  carbon,  or  oil  emulsions).  Be- 
sides being  turbid  in  transmitted  light,  the  solutions  may  be  seen  by 
means  of  the  ultramicroscope  to  contain  particles.  These  can  be  sepa- 
rated by  filtration  from  the  fluid  they  are  suspended  in,  except  in  the 
case  of  many  emulsions  in  which  the  particles  can  squeeze  their  way 
through  the  filter  pores  by  changing  their  shape.  On  standing  or  being 
centrifuged  suspensions  may  also  separate  into  their  constituents,  al- 
though this  can  be  greatly  hindered  by  the  addition  of  a  suspending 
substance  such  as  gelatin  or  certain  bodies  having  a  so-called  protec- 
tive action  (as  peptone,  proteose,  etc.). 

True  Colloidal  Solutions 

1.  The  Solution  Is  More  or  Less  Turbid. — Frequently  this  can  be  recog- 
nized by  holding  the  solution  in  a  thin-walled  glass  vessel  against  a 
dark  background,  but  the  turbidity  may  be  so  slight  that  it  requires 
for  its  detection  the  use  of  the  Tyndall  phenomenon.     This  is  familiar 
to  all  in  the  effect  of  a  beam  of  sunlight  let  in  through  a  small  aperture 
into  an  otherwise  darkened  room.    In  the  course  of  the  beam  suspended 
dust  particles,  which  are  invisible  in  an  equally  illuminated  room,  be- 
come visible,  and  thus  render  very  distinct  the  pathway  of  the  beam. 
If  a  colloidal  solution  contained  in  a  glass  vessel,  preferably  with  paral- 
lel sides,  is  held  in  the  course  of  such  a  beam,  the  Tyndall  phenomenon 
will  be  seen  in  the  liquid,  which  is  not  the  case  with  molecular  solutions. 
Focused  artificial  light  may  be  employed  for  intensifying  the  effect. 
The  light  that  is  sent  out  at  right  angles  to  the  beam  is  plane-polarized, 
which  means  that  the  particles  reflecting  the  light  must  be  smaller  than 
the  mean  wave  length  of  the  light  forming  the  beam.    It  should  be  under- 
stood that  the   individual  particles  themselves  may  not   be  rendered 
visible  to  the  naked  eye  by  the  beam,  although  in  such  cases  they  can 
often  be  seen  by  using  intense  illumination  and  a  dark-field  (ultramicro- 
scope) combined  with  suitable  magnification  (Fig.  12). 

2.  Colloids  Do  Not  Readily  Diffuse. — To  demonstrate  this,  test  tubes 


COLLOIDS  53 

are  half  filled  with,  a  5  per  cent  solution  of  pure  gelatin  or  a  1  per  cent 
solution  of  pure  agar,  and,  after  the  jelly  is  set,  the  solution  under 
examination  is  poured  on  the  surface;  or,  when  it  is  of  high  spe- 
cific gravity,  the  tube  of  gelatin,  etc.,  is  placed  mouth  downwards  in 
the  solution.  In  the  case  of  colloidal  solutions  very  little  if  any  diffu- 
sion into  the  gelatin  or  agar  will  occur,  even  after  several  days;  whereas 
true  molecular  solutions  will  diffuse  for  a  considerable  distance.  When 
colored  solutions  are  used,  the  diffusion  can  readily  be  recognized  by 
inspection  (see  Fig.  13),  but  when  they  are  colorless,  the  presence  or 
absence  of  diffusion  must  be  determined  by  removing  the  column  of 
gelatin  or  agar  and  dividing  it  into  slices  of  equal  size,  which  are 
then  examined  chemically  for  the  substance  in  question. 

A  further  test  is  afforded  by  the  failure  of  colloids  to  diffuse  through 
membranes  [dialysis).  This  was  the  method  originally  used  by  Thomas 
Graham  to  distinguish  between  molecular  and  colloidal  solutions.  The 
solution  under  examination  is  placed  in  a  dialyzer,  which  is  then  im- 
mersed in  a  wide  vessel  containing  the  pure  solvent.  The  older  forms 


Fig.  12. — Ultramicroscope  (slit  type)  for  the  examination  of  colloidal  solutions.  The  arrange- 
ment of  diaphragms,  etc.,  in  this  form  removes  the  absorptive  effects  of  the  surfaces  of  the  glass 
vessel  or  slide  used  to  contain  the  colloidal  solutions. 

of  dialyzer  consisted  in  general  of  a  bell-shaped  glass  vessel  closed  be- 
low with  parchment  paper,  but  more  recently  so-called  diffusion  sacs 
have  been  adopted.  These  consist  of  pig  or  fish  bladders  or  of  col- 
lodion sacs.  The  latter  are  made  by  placing  some  collodion  dissolved 
in  ether  in  a  test  tube,  which  is  then  tilted  so  that  the  collodion  runs 
out  except  for  a  thin  layer  which  remains  adherent  to  the  walls.  When 
the  collodion  has  set,  the  sac  can  be  removed  after  loosening  it  by  allow- 
ing a  little  water  to  flow  between  the  sac  and  the  walls  of  the  test  tube. 
The  sac  containing  the  colloidal  solution  is  then  suspended  in  water 
or  some  of  the  solvent  used  in  preparing  the  colloidal  solution,  care 
being  taken  that  the  menisci  of  the  fluids  inside  and  outside  of  the  sac 
stand  at  the  same  level.  Sometimes,  especially  when  collodion  sacs  are 
used,  some  colloid  may  at  first  diffuse  through,  but  if  the  outer  fluid 
(the  dialysate)  is  renewed  and  the  dialysis  allowed  to  proceed,  this 
ceases. 


54  PHYSICOCHEMICAL   BASIS   OF   PHYSIOLOGICAL   PROCESSES 

When  a  fluid  solution  exhibits  both  of  the  above  properties  (i.  e.,  the 
Tyndall  phenomenon  and  indiffusibility),  there  can  be  no  doubt  as  to  its 
being  in  a  true  colloidal  state,  but  there  are  substances,  such  as  congo 
red,  or  protein  solutions  of  certain  strengths,  which  may  exhibit  a  very 
slight  diffusibility  in  a  dialyzer  but  not  show  the  Tyndall  phenomenon. 
Substances  of  this  group  constitute  transitional  types  between  molecular 
and  colloidal  solutions,  and  to  determine  their  true  nature  it  is  neces- 


Fig.    13. — To    show    diffusion    into    gelatin    of    a    crystalloid    stain    in    b    and    the    nondiffusion    of    a 
colloid    stain    in    a.      (From    W.    Ostwald.) 

sary  to  employ  refined  methods  such  as  those  of  ultramicroscopy,  ultra- 
filtration,  etc.,  which  can  not  be  described  here. 

3.  The  Size  of  Colloidal  Particles. — It  will  be  apparent  that  the  essential 
property  upon  which  the  above-mentioned  phenomena  depend  is  the  size 
of  the  particle.  Particles  which  can  still  be  seen  under  the  microscope 
are  called  microns.  They  have  been  computed  to  have  a  dimension  of 
0.1  fj.  (0.001  mm.)  or  more,  and  they  form  suspensions.  Particles  which 
are  invisible  microscopically  under  the  ordinary  conditions  of  illumina- 


COLLOIDS 


55 


tion,  but  are  still  visible  when  the  ultrainicroscopic  illumination  is 
used,  are  called  submicrons.  They  have  a  dimension  between  0.1  p  and 
1  pp  (0.000,001  mm.),*  and  they  constitute  the  colloids.  Particles  smaller 
than  1  pp  are  called  amicrons,  this  term  being. used  to  include  the  mol- 
ecules and  ions  present  in  molecular  solutions.  (The  amicron  of  hydro- 
gen is,  for  example,  computed  to  be  0.067  to  0.159  pp,  and  that  of  water 
vapor,  0.113  pp.)  This  classification  of  dissolved  substances  according 
to  the  size  of  the  particles  and  molecules  shows  the  relationship  of  one 


Fig.    14. — Diagram    from    W.    Ostwald    showing   the    relative    size    of   various    particles    and    colloidal 
dispersoids    compared    with    a    red    blood    corpuscle    and    an    anthrax    bacillus. 

class  of  substances  to  others.  An  idea  of  the  relative  sizes  of  colloidal 
particles  and  molecules  in  comparison  with  such  familiar  objects  as  a 
blood  corpuscle  and  an  anthrax  bacillus  is  given  in  Fig.  14.  The  fluid 
in  which  the  "particle"  is  suspended  is  called  the  dispersion  medium,  or 
external  phase,  and  the  particle  itself  the  dispersoid,  or  internal  phase. 
It  is  the  enormous  development  of  surface  which  determines  the  dif- 

*M  —  0.001    mm.,  and  /*/*•  =  0.000,001   mm. 


56  PHYSICOCHEMICAL   BASIS   OF   PHYSIOLOGICAL   PROCESSES 

ference  in  the  properties  of  a  colloidal  solution  from  those  of  a  suspen- 
sion of  the  same  substance.  Thus,  the  difference  between  a  colloidal 
solution  of  platinum  (prepared  by  allowing  an  electric  arc  to  form  be- 
tween platinum  electrodes  in  water)  and  pieces  of  platinum  in  water 
depends  on  the  fact  that  the  surface  of  the  platinum  in  the  former  case 
has  been  increased  many  million  times.  When  the  subdivision  becomes 
still  greater  and  the  particles  gain  the  size  of  molecules,  the  phenomena 
due  to  surface  development  become  suppressed  and  those  due  to  con- 
centration in  unit  volume  become  accentuated.  The  properties  depend- 
ent on  osmotic  pressure,  diffusibility,  etc.,  are  exhibited  by  all  dispersoids, 
whether  ions,  molecules  or  particles,  but  some  of  these  properties  are 
much  more  pronounced  when  the  dispersoids  are  of  large  dimensions, 
and  others  when  they  are  small.  In  other  words,  the  phenomena  due  to 
surface,  such  as  those  of  surface  tension  (see  page  65),  become  apparent 
only  when  the  dispersoids  have  the  properties  of  matter  in  mass;  when 
the  dispersoids  become  molecular  in  size,  they  manifest  the  properties 
characteristic  of  true  solutions. 

4.  Electrical  Properties  of  Colloids. — Most  colloids  carry  a  charge,  which 
may  be  either  positive  or  negative  toward  the  dispersion  medium.  Both 
crystalloids  and  colloids  therefore  carry  electric  charges;  in  the  former 
case,  however,  the  charge  does  not  reveal  itself  until  the  molecules  in 
solution  have  become  dissociated,  when  each  ion  carries  a  charge  of 
opposite  sign  (see  page  16),  whereas1  in  the  case  of  colloids,  each  col- 
loid particle  usually  carries  a  charge  which  is  always  of  one  sign,  either 
positive  or  negative.  Colloids  may  therefore  be  grouped  into  positive 
and  negative,  according  to  the  charges  which  they  carry,  and  there  is 
a  third  group  in  which  the  charge  may  be  either  positive  or  negative  ac- 
cording to  the  nature  of  the  dispersion  medium. 

A  colloid  not  carrying  a  charge  to  begin  with  can  be  caused  to  assume 
one  by  the  action  of  electrolytes,  for  the  electrical  properties  of  colloids, 
as  well  as  those  of  inert  powders  suspended  in  water,  are  readily  in- 
fluenced by  the  charges  present  in  the  ions  of  the  dispersion  medium. 
The  H-  and  OH'  ions  are  especially  liable  to  exert  this  influence.  The 
particles  of  inert  powders  in  suspensions  (kaolin,  sulphur,  etc.)  carry 
a  positive  charge  when  the  water  in  which  they  are  suspended  is  acidi- 
fied, and  a  negative  charge  when  it  is  made  alkaline.  In  general,  it  may 
be  said  that  suspensions  of  most  powders  and  of  insoluble  organic  acids 
in  water  (e.  g.,  charcoal,  cellulose,  kaolin,  caseinogen,  mastic,  free  acid 
of  congo  red,  etc.)  are  electro-negative.  Of  true  colloids  ferric  hydrox- 
ide (ferrum  dialysatum)  and  serum  globulin  are  positive  in  acid  solu- 
tions; arsenious  sulphide  and  serum  globulin  are  negative  in  alkaline 
solution,  and  serum  globulin  in  neutral  solutions  has  no  charge. 


COLLOIDS 


57 


To  ascertain  the  nature  of  the  charge  various  methods  may  be  em- 
ployed, of  which  the  following  are  important: 

1.  The  method  of  electrophoresis.  The  colloid  solution  is  placed  in  a 
U-tube,  each  side  of  which  carries  a  platinum  electrode  dipping  into  the 
solution.  After  a  strong  continuous  electric  current  has  been  allowed 
to  pass  for  some  time  through  the  solution,  it  will  be  found  that  the 
colloid  collects  at  the  anode  (where  the  current  enters)  when  it  is  a 
negative  colloid  (since  unlike  electric  charges  attract  each  other),  and 
at  the  cathode  when  it  is  positive.  In  the  case  of  colored  solutions,  the 
migration  can  be  readily  seen,  but  otherwise  it  may  be  necessary  to  ana- 
lyze the  solution  at  the  two  poles. 


Fig.  15. — Capillary  analysis  of  colloids.  Strips  of  filter  paper,  after  being  suspended  with 
the  lower  ends  dipping  into  colloidal  solutions.  Those  on  the  right  hand  were  positive  colloids, 
which  did  not  rise  in  the  strips,  but  formed  a  sharp  line  of  demarcation  at  the  lower  end  on 
account  of  precipitation.  Those  on  the  left  hand  were  negative  colloids.  (From  W.  Ostwald.) 

2.  The  method  of  capillary  analysis.    For  this  purpose  a  long  strip  of 
filter  paper  is  arranged  vertically  over  the  solution,  with  its  lower  end 
dipping  into  it.    In  the  case  of  negative  colloids  the  colloid,  as  well  as 
the  dispersion  medium,  rises  uniformly  on  the  strip  of  paper  (it  may  be 
to  a  height  of  20  cm.) ;  whereas  with  positive  colloids  the  dispersion 
medium  alone  rises,  the  colloid  itself  doing  so  only  to  a  very  slight  ex- 
tent, but  becoming  so  highly  concentrated  at  the  interface  between  the 
solution  and  the  paper  that  it  coagulates  on  the  end  of  the  strip  of  paper, 
where  it  forms  a  sharp  line  of  demarcation  (Fig.  15). 

3.  The  method  of  mutual  precipitation  of  colloids.     When  a  positive 


58  PHYSICOCHEMICAL   BASIS    OF   PHYSIOLOGICAL   PROCESSES 

and  a  negative  colloid  are  mixed  in  such  proportions  that  the  electric 
charges  are  neutralized,  precipitation  usually  occurs.  When  it  does  so, 
we  can  tell  the  nature  of  the  electric  charge  of  an  unknown  colloid  by 
its  behavior  when  a  colloid  of  known  electric  sign  is  added  to  it.  For 
example,  if  ferric  hydroxide  (positive)  causes  a  precipitate  to  form 
when  it  is  added  to  an  unknown  colloidal  solution,  the  electric  charge 
of  the  latter  must  be  negative;  if  it  does  not  precipitate  with  ferric 
hydroxide,  but  does  so  with  arsenious  sulphide  (negative),  it  must  be 
positive. 

5.  Brownian  Movement. — Like  the  particles  in  fine  mechanical  suspen- 
sions,   those    of   colloidal   solutions,    especially   when    examined    ultra- 
microscopically,  exhibit  the  so-called  Brownian  movements,  which  have 
been  described  as  "dancing,  hopping  and  skipping."    These  movements 
occur  in  straight  lines,  which  are  suddenly  changed  in  direction  and 
are  quite  independent  of  external  sources  of  energy,  such  as  change  in 
temperature  (although  they  become  quicker  as  the  temperature  of  the 
solution  is  raised),  earth  vibrations,  chemical  changes,  or  the  electric 
charge  of  the  colloid.    The  movements  become  more  rapid  the  smaller  the 
particles,  and  they  become  sluggish  as  the  viscosity  of  the  solution  in- 
creases.   Addition  of  electrolytes  decreases  the  movement  by  causing  the 
particles  to  clump  together.     The  density  and  viscosity  of  the  disper- 
sion medium,  the  electric  charge  of  the  dispersoid  and  the  presence  of 
Brownian  movements,  are  the  forces  which  operate  together  to  prevent 
sedimentation  of  the  particles  in  a  colloidal  solution. 

6.  Osmotic  Pressure. — As  one  of  the  distinguishing  properties  of  col- 
loids we  have  seen  that  their  diffusibility,  as  into  gelatin  or  agar  jel- 
lies, is  extremely  slow  when  compared  with  that  of  a  molecular  solution. 
This  does  not  mean,  however,  that  colloids  are  possessed  of  no  power  of 
diffusibility  if  left  long  enough.     Indeed  the  existence  of  the  Brownian 
movement  indicates  that  such   diffusion  must   occur,   and  therefore   it 
should  be  possible,  by  the  application  of  the  same  principles  as  those 
which  govern  molecular  solutions  (e.  g.,  by  using  a  semipermeable  mem- 
brane), to  measure  the  osmotic  pressure. 

Many  studies  of  the  osmotic  properties  of  colloidal  solutions  have  been 
undertaken,  especially  by  those  who  are  interested  in  the  possibility 
that  the  colloids  of  blood  serum  (serum  albumin  and  globulin)  may  cre- 
ate an  osmotic  pressure.  If  this  should  prove  to  be  the  case,  it  would 
be  necessary  for  the  osmotic  pressure  to  be  overcome  by  mechanical 
pressure  such  as  that  supplied  by  the  heart  (i.  e.,  the  blood  pressure)  in 
the  various  physiological  processes  of  filtration  and  diffusion  taking  place 
through  cell  membranes  (as  in  the  formation  of  urine  in  the  kidney). 

For  measuring  the  osmotic  pressure  of  colloids,   osmometers  similar 


COLLOIDS  59 

to  those  already  described  (page  4)  can  be  employed.  Most  of  the 
recent  work  has  been  done  either  with  collodion  sacs,  or  with  unglazed 
clay  cups  impregnated  with  some  gel,  such  as  silica  or  gelatin.  When 
such  an  osmometer,  filled  with  some  colloidal  solution  (like  a  solution  of 
pure  albumin)  and  provided  with  a  vertical  glass  tube,  is  placed  in  an 
outer  vessel  containing  water,  the  fluid  will  be  seen  to  rise  in  the  ver- 
tical tube,  the  height  to  which  it  rises  being  proportional  to  the  osmotic 
pressure. 

But  the  observed  pressure  does  not  necessarily  give  us  the  osmotic  pressure  of 
the  pure  colloid,  for  to  this,  even  when  highly  purified,  there  is  almost  certain  to 
be  attached  a  considerable  amount  of  inorganic  salt,  which  may  be  responsible  for 
the  osmosis.  It  has  indeed  been  maintained  by  some  observers  that  electrolytes  form 
an  integral  part  of  certain  colloids,  being  bound  to  them  perhaps  by  adsorption  (see 
page  66),  and  that  they  are  essential  to  the  maintenance  of  the  colloidal  state.  In 
any  case,  since  electrolytes  are  always  present,  the  osmotic  pressure  of  the  pure 
colloid  can  be  measured  only  when  means  are  taken  to  discount  their  influence.  Sev- 
eral devices  have  been  used,  of  which  the  following  may  be  mentioned: 

1.  Addition  to  the  fluid  outside  the  osmometer  of  a  percentage  of  salt  equal  to  that 
found  by  chemical  analysis  to   be   present   in  the   colloid.     (This  method  is  untrust- 
worthy.) 

2.  The  use  of  a  limited  quantity  of  fluid  on  the  outside  of  the  osmometer  so  that 
equality  of  saline  content  soon  becomes  established,  by  diffusion,  in  the  fluids  on  the 
two  sides  of  the  membrane. 

3.  The  use  of  a  membrane  which  is  permeable  to  electrolytes  but  not  to  colloids. 
Even  when  the  greatest  care  is  taken  in  its  measurement,  the  osmotic  pressure  of 

a  given  colloid  has  been  found  to  vary  considerably  not  only  according  to  the  method 
used  in  its  preparation,  but  also  according  to  the  amount  of  mechanical  agitation 
(shaking,  stirring,  etc.)  to  which  the  colloid  solution  has  been  subjected.  Eegarding 
the  influence  of  the  method  of  preparation,  it  was  found  in  one  series  of  experiments 
that  albumin  that  had  been  repeatedly  washed  (but  still  contained  considerable  ash) 
gave  no  osmotic  pressure,  whereas  another  preparation  that  had  been  purified  by  crystal- 
lization twice  (and  contained  much  less  ash)  had  a  pressure  of  3.38  mm.  Hg.  Ac- 
cording to  these  results  the  ash  content  of  the  colloid  is  not  fundamentally  responsible 
for  its  osmotic  pressure.  As  to  the  influence  of  mechanical  agitation,  the  osmotic  pres- 
sure of  a  gelatin  solution  is  increased  by  shaking,  while  that  of  a  solution  of  egg  albu- 
min is  decreased. 

The  property  upon  which  the  osmotic  pressure  depends  is  undoubtedly  the  state  of 
dispersion  of  the  colloid  particles,  and  until  we  know  all  of  the  factors  which  may  in- 
fluence this,  measurements  of  osmotic  pressures  of  colloids  can  scarcely  be  of  very 
much  value.  Nevertheless,  that  this  property  has  some  physiologic  bearing  is  clear 
from  the  effect  which  colloids  have  in  restoring  the  blood  pressure  after  hemorrhage 
(page  141). 

Further  evidence  that  the  osmotic  pressure  of  colloids  has  not  the  significance  that 
it  has  in  the  case  of  molecular  solutions  is  furnished  by  the  fact  that  the  osmotic  pres- 
sure is  only  approximately  proportional  to  the  concentration  of  the  solution;  it  may 
either  increase  or  decrease  relatively  to  the  strength  of  the  solution.  Temperature  also 
has  quite  a  different  influence  on  the  osmotic  pressure  of  colloids  from  that  which  ^ 
has  on  the  osmotic  pressure  of  molecular  solutions,  and  it  frequently  has  an  influence 
which  persists  after  the  solution  is  brought  back  to  its  original  level. 


60  PHYSICOCHEMICAL   BASIS   OF   PHYSIOLOGICAL  PROCESSES 

The  influence  of  added  substances  on  the  osmotic  pressure  of  colloidal  solutions 
is  of  considerable  interest  to  the  biologist,  for,  whereas  in  the  case  of  molecular  solu- 
tions this  is  purely  additive,  in  the  case  of  colloids  the  added  substance  may  at  one 
time  cause  the  osmotic  pressure  to  increase,  at  another,  to  decrease.  It  has  been  found 
that  the  osmotic  pressure  of  gelatin  solutions  at  first  decreases,  then  rapidly  increases 
as  the  H-ion  concentration  is  raised.  The  addition  of  alkali  increases  the  osmotic 
pressure  until  a  maximum  is  reached,  beyond  which  it  begins  to  fall.  Both  acids  and 
alkalies  lessen  the  osmotic  pressure  of  egg  albumin.  Electrolytes  always  decrease  the 
osmotic  pressure  of  gelatin  and  albumin  solutions,  and  the  degree  to  which  they  exert 
this  influence  depends  on  the  nature  of  the  cation  and  anion  composing  the  electrolyte. 
In  the  order  of  their  depressing  influence  the  cations  arrange  themselves: 

Heavy  metals  >  alkaline   earths  >  alkalies ; 
and  the  anions: 

SO4  >  01  >  NO2  >  Br  >  I  >  CNS. 

The  influence   of  a  given   electrolyte  varies   extraordinarily  with  the   reaction   of   the 
eolloid,  a  fact  which  must  be  carefully  regarded  in  all  work  in  this  field. 


CHAPTER  VIII 
COLLOIDS  (Cont'd) 

SUSPENSOIDS  AND  EMULSOIDS 

According  to  whether  colloids  form  solutions  that  are  more  or  less 
viscid  than  the  suspension  medium,  they  are  divided  into  emulsoids  and 
suspensoids.  Examples  of  the  former  class  are  silicates  and  gelatin,  and 
of  the  latter,  dialyzed  iron  and  arsenious  sulphide.  The  following  char- 
acteristics are  used  to  distinguish  between  suspensoids  and  emulsoids: 

1.  Measurement  of  the  time  it  takes,  at  a  standard  temperature,  for  a 
given  volume  of  the  fluid  to  flow  out  of  a  standard  pipette  (10  c.c.)  shows 
the  viscosity  to  be,  roughly,  inversely  proportional  to  the  time  of  outflow. 
In  the  case  of  suspensoids  the  viscosity  is  no  different  from  that  of  the 
dispersion  medium  alone,  and  does  not  vary  much  when  the  solution  is 
cooled.    The  viscosity  of  emulsoids  even  in  very  dilute  solutions  is,  on 
the  other  hand,  considerably  greater  than  that  of  the  dispersion  medium 
itself,  and  it  becomes  greatly  increased  by  cooling. 

2.  Suspensoids  are  much  more  readily  coagulated  by  the  addition  of 
electrolytes  than  emulsoids.     This  is  particularly  true  when  water  is 
the  dispersion  medium  (so-called  hydrosols),  and  when  electrolytes  hav- 
ing a  polyvalent  ion  (such  as  Al  or  Mg.)  are  employed.    Thus,  practically 
all  suspensoids  are  coagulated  in  the  presence  of  1  per  cent  of  alum, 
which  has  no  influence  on  emulsoids.    We  shall  return  to  this  phase  of 
our  subject  later  on. 

The  division  of  colloids  into  emulsoids  and  suspensoids  is  more  or  less 
arbitrary,  since  one  class  may  be  changed  into  the  other,  the  determining 
factor  being  the  water  content  of  the  dispersoid.  The  water  content  of 
suspensoids  is  low  (lyophobe),  while  that  of  emulsoids  is  high.  By 
changing  the  relative  amounts  of  water  and  solid  of  which  a  colloidal 
solution  is  composed,  the  nature  of  the  dispersoid  may  be  changed.  If 
the  water  is  diminished,  the  dispersoid  behaves  as  a  suspensoid  and  be- 
comes readily  precipitated.  The  practical  importance  of  this  fact  is 
that  it  explains  the  salting  out  of  proteins — a  process  extensively  used 
in  their  separation.  Ordinarily  these  behave  as  emulsoids,  but  the  addi- 
tion of  salt  raises  the  osmotic  pressure  of  the  dispersion  medium,  and 
thus  attracts  water  from  the  dispersoids,  with  the  result  that  they  come 

61 


62 


PHYSICOCHEMICAL   BASIS   OF   PHYSIOLOGICAL   PROCESSES 


to  behave  as  suspensoids,  and  are  accordingly  precipitated  by  the  elec- 
trolytes. 

Another  property  of  emulsoids  of  biological  importance  is  the  pro- 
tection which  they  can  afford  against  the  precipitating  influence  of 
electrolytes  on  suspensoids.  If  a  colloidal  solution  of  gold  is  mixed  with 
a  trace  of  gelatin,  the  subsequent  addition  of  salts  will  be  found  to 
produce  no  precipitation.  The  explanation  of  this  is  that  the  emulsoid 
becomes  distributed  as  a  film  on  the  suspensoid  particles,  thus  practically 
converting  them  into  emulsoids. 

Gelatinization 

One  of  the  best  known  properties  of  emulsoids  is  that  of  gelatiniza- 
tion,  which  has  an  interesting  bearing  on  many  problems  of  biology. 
After  the  gel  has  set,  an  enormous  pressure  is  required  to  squeeze  out 


any  water  from  it,  indicating  that  the  water  no  longer  forms  the  con- 
tinuous phase  but  must  be  enclosed  in  vesicles  formed  of  more  solid 
material. 

By  observing  solutions  of  pure  soaps  under  the  ultramicroscope  it  has 
been  noted  that  as  the  solution  cools,  the  gel  at  first  forms  a  polarized  cone 
of  light,  but  the  very  fine  particles  which  are  responsible  for  this  effect 
soon  increase  in  number  and  size  so  that  they  obstruct  one  another  in 
their  Brownian  movements  and  adhere,  giving  an  appearance  of  fine 
felt-like  threads  throughout  the  solution.25  A  sort  of  impervious  sponge 
work  of  the  more  solid  phase  is  therefore  formed,  the  more  fluid  phase 
being  inclosed  in  the  meshes. 

If,  as  in  the  accompanying  diagram,  the  dispersion  medium  is  repre- 
sented by  white  and  the  dispersoid  in  black,  the  relationship  between 
the  two  in  a  suspensoid  is  as  in  B,  and  that  in  a  gel  as  in  A.  To  express 


COLLOIDS  63 

any  of  the  dispersion  medium  in  A,  it  will  require  a  pressure  sufficient  to 
cause  the  more  fluid  phase  to  penetrate  the  more  solid.  If  the  gel  is 
treated  with  reagents  like  formaldehyde,  the  liquid  can  be  readily  pressed 
out.  This  occurs  during  fixation  for  histological  purposes. 

Imbibition 

Closely  related  to  gel  formation  is  the  process  of  imbibition — the 
power  of  taking  up  large  quantities  of  water  without  actually  forming 
liquid  solutions.  Besides  gelatin  the  dried  tissues  pf  plants  and  animals 
exhibit  the  phenomenon,  and  it  is  undoubtedly  of  importance  in  many 
physiological  processes  such  as  growth  and  the  passage  of  water  into 
cells,  etc.  The  materials  present  as  vacuoles  in  plant  cells  attract  water 
from  the  environment  of  the  cell  by  imbibition,  and  thus  exert  on  the 
cell  wall  a  pressure  which,  acting  along  with  the  osmotic  pressure, 
maintains  the  turgor  of  the  cell.  The  initial  growth  of  pollen  is  also 
dependent  upon  imbibition,  and  important  observations  on  this  process., 
under  varying  conditions,  are  likely  to  furnish  us  with  useful  informa- 
tion concerning  the  significance  of  imbibition  in  connection  with  growth 
of  cells  in  general. 

By  measuring  the  rate  of  increase  in  length  of  long,  narrow  strips  of  gelatin  placed 
in  Petri  dishes  containing  solutions  of  varying  composition,  the  factors  that  influence 
the  imbibition  process  can  be  quantitatively  investigated.  Working  in  this  way,  F.  H. 
Lloyd"  has  found  that  for  all  acids  there  is  a  certain  concentration  (about  N/320 
H2S04)  which  induces  a  maximum  rate  of  swelling,  and  another,  much  weaker  (N/2800 
H2SO4),  in  which  the  rate  of  swelling  is  even  less  than  in  pure  water.  In  higher  con- 
centrations of  acid  than  N/320,  the  gelatin  at  first  swells  very  quickly;  but  the  rate 
slows  off  so  that  it  soon  comes  to  be  less  than  that  with  intermediate  concentrations. 
Regarding  alkalies,  at  high  concentrations  the  effect  is  similar  to  that  of  acids.  Salts 
alone  seem  to  repress  the  swelling  below  that  of  water.  It  should  be  pointed  out 
that  the  concentrations  of  acid  and  alkali  in  the  above  observations  are  much  greater 
than  those  that  could  occur  in  the  animal  body.  The  experiments  recall  the  attempts 
made  some  years  ago  by  Martin  Fischer  to  explain  edema  as  due  to  excessive  imbibition 
of  water  by  the  proteins  of  the  tissues  because  of  increased  acidity  of  the  blood  and 
tissue  fluids.  That  imbibition  might  possibly  play  some  role  in  such  processes  is  not 
denied,  but  Fischer  disregards  entirely  the  now  well-established  facts  that  hydrogen- 
ion  concentration  is  one  of  the  most  constant  properties  of  the  blood,  that  very  low 
concentrations  of  acid  may  diminish  rather  than  increase  imbibition,  and  that  it  is 
manifested  only  in  the  absence  of  inorganic  salts.*  Moreover,  the  fluid  in  edema  can 
often  be  drained  off  by  hollow  needles,  and  it  passes  by  gravity  from  one  part  of 
the  body  to  another,  neither  of  which  processes  would  be  possible  if  imbibition  were 
the  essential  factor  concerned.  If  further  evidence  against  this  hypothesis  should  be 
demanded,  it  might  be  found  in  the  utter  failure  of  the  therapeutic  measures — alkali 
administration — that  are  recommended  to  combat  the  edema. 

Action  of  Electrolytes  on  Colloids  (apart  from  their  effect  on  osmotic 
pressure). — It  has  been  stated  above  that  the  charge  which  a  colloidal 

*Determinations  of  the  hydrogen-ion  concentration  of  the  blood  recently  published  from  Fischer's 
laboratory  do  not  inspire  confidence. 


64  PHYSICOCHEMICAL   BASIS   OF   PHYSIOLOGICAL   PROCESSES 

particle  assumes  may  be  neutralized  by  a  charge  of  opposite  sign  car- 
ried by  an  ion  present  in  the  dispersion  medium.  The  neutralization 
of  the  electric  charge  causes  coagulation  of  the  suspensoids  but  not  of 
the  emulsoids.  Of  the  positive  and  negative  ions  into  which  the  elec- 
trolytes dissociate,  the  one  producing  the  coagulation  is  that  which  is 
opposite  in  sign  to  the  electric  charge  of  the  colloidal  particle. 

A  quantity  of  electrolyte  which  is  capable  of  producing  complete  pre- 
cipitation when  added  all  at  once  to  suspensoids  will  be  ineffective  when 
added  in  small  quantities  at  a  time.  This  phenomenon,  which  is  also 
known  to  be  exhibited  when  toxins  and  antitoxins  are  mixed  together,  is 
probably  owing  to  the  fact  that  precipitation  depends  on  inequality  and 
irregular  distribution  of  electric  charges,  a  condition  which  becomes 
established  when  the  electrolyte  is  suddenly  added,  but  not  so  when  it 
is  gradually  added.  The  particles  in  the  latter  case  become,  as  it  were, 
acclimated  to  the  electric  charges  introduced  by  the  addition  of  the 
electrolyte. 

Proteins  as  Colloids.— The  most  prominent  colloids  in  the  field  of  bio- 
chemistry are  the  proteins.  On  account  of  complexity  of  structure, 
however,  certain  factors  intervene  which  render  the  investigation  of 
their  behavior  very  difficult.  As  we  shall  see  later,  proteins  are  made 
up  of  combinations  of  amino  acids,  each  of  which  contains  basic  (NH2) 
and  acid  groups  (COOH).  The  various  amino  acids  are  linked  together 
in  protein  by  the  COOH  of  one  uniting  with  the  NH2  of  another,  with 
the  elimination  of  water — thus,  CO  !  OH  +  H  i  HN — but  some  NH2  and 
COOH  groups  are  left  uncombined.  According  to  the  relative  number 
of  these  uncombined  radicles,  the  protein  (or  polypeptid,  see  page  636) 
will  exhibit  faintly  acid  or  basic  or  neutral  properties.  With  acids,  for 
example,  a  salt  will  be  formed  by  union  with  the  NH2  groups,  which  will 
dissociate  into  the  anion  of  the  acid  and  a  large  organic  cation;  whereas 
with  alkalies  union  will  occur  with  the  COOH  group,  and  the  salt  on 
dissociating  will  form  a  small  cation  of  the  metal  of  the  salt  and  a  large 
complex  anion.  We  may  therefore  obtain  the  protein  with  either  a- 
positive  or  a  negative  electric  charge  by  altering  the  chemical  nature  of 
the  fluid  in  which  it  is  dissolved,  so  that  the  reaction  towards  other 
colloids  and  towards  electrolytes  will  vary. 

One  feature  of  proteins  of  importance  in  this  connection  is  that  known 
as  the  isoelectric  point,  at  which  the  protein  exists  with  a  maximum  of 
electrically  neutral  molecules.  This  point  is  reached  by  adding  acid  to 
a  protein  solution.  The  acid  represses  the  dissociation  of  the  protein 
acting  as  an  acid,  and  therefore  diminishes  the  number  of  free  hydrogen 
ions;  and  at  the  same  time  a  salt  is  formed  which  then  dissociates  to 


COLLOIDS  65 

produce  cations.  The  sum  of  the  cations  and  anions  therefore  becomes 
a  minimum,  the  concentration  of  the  two  being  equal,  and  this  point — 
the  protein,  being  electrically  neutral,  has  its  solubility  reduced  to  a 
minimum. 

SURFACE  TENSION 

Before  we  consider  a  very  important  property  of  colloids  known  as 
adsorption,  by  means  of  which  they  are  able  to  perform  many  reactions 
that  do  not  conform  with  the  laws  of  mass  action,  it  will  be  well  to 
say  a  few  words  concerning  the  physical  phenomenon  upon  which  this 
depends — namely,  surface  tension.  The  creation  of  this  force  is  due 
to  the  fact  that,  whereas  the  molecules  within  a  liquid  are  subjected  to 
equal  forces  of  attraction  on  all  sides,  at  the  surface  these  forces  act  on 
one  side  of  the  molecules  only,  and  therefore  tend  to  pull  them  inwards. 
This  causes  the  surface  to  pull  itself  together  so  as  to  occupy  the  least 
possible  area,  and  it  is  this  force  which  constitutes  surface  tension. 
The  surface  behaves  as  if  stretched.  There  are  various  simple  experi- 


A. 


Fig.  17. — Diagram  to  illustrate  surface  tension.  The  rings  A  and  B  inclose  soap  films  in 
which  a  very  fine  loop  of  silk  is  suspended.  In  A  it  is  loose  but  in  B,  where  the  film  inclosed 
in  the  loop  has  been  broken,  it  is  drawn  into  a  circle  by  the  tension  of  the  soap  film.  (From 
Bayliss.) 

ments  that  reveal  the  presence  of  surface  tension.  If  a  film  is  made  on 
a  loop  of  wire  by  dipping  it  in  soap  solution,  a  fine  silk  thread  can  be 
floated  in  the  film,  so  that  it  forms  a  loop  that  is  quite  loose.  If  the 
portion  of  the  film  inside  the  loop  is  destroyed  by  touching  it  with  filter 
paper,  the  film  will  break  in  the  loop,  which  will  now  be  pulled  into  a 
circular  shape  by  the  tension  of  the  film  around  it  (Fig.  17). 

For  the  measurement  of  surface  tension,  various  methods  are  used. 
The  size  of  drops  of  liquid  falling  from  an  orifice  is  dependent  on  sur- 
face tension;  the  larger  the  drops,  the  greater  the  surface  tension.  If 
the  number  of  drops  obtained  by  allowing  a  liquid  to  drop  from  a  stand- 
ard orifice  in  a  given  time  is  counted,  we  have  a  measure  of  the  surface 
tension.  Account  must  of  course  also  be  taken  of  the  specific  gravity 
of  the  liquid.  The  instrument  used  for  this  purpose  is  called  a 
stalagmometer  (Fig.  18).  Another  method  depends  on  the  fact  that 
the  height  to  which  a  i\uid  rises  in  a  capillary  tube  is  dependent  on 


66 


PHYSICOCHEMICAL   BASIS   OF   PHYSIOLOGICAL   PROCESSES 


surface  tension  (and  inversely  on  the  diameter  of  the  capillary).  The 
difference  in  the  heights  to  which  two  liquids  rise  in  capillary  tubes  of 
known  bore  permits  us  to  compare  their  surface  tensions,  and  if  this 
is  known  for  one  of  the  solutions,  it  can  be  determined  for  the  other. 
Besides  existing  between  liquid  and  air,  surface  tension  also  exists  at 


Fib.  18. — Traube's  stalagmometer.  The  surface  tension  is  proportional  to  the  number  of 
drops  formed  in  a  given  time.  The  right-angled  tubes  are  for  thin  liquids,  and  the  straight 
one  for  blood  and  other  viscous  fluids. 

the  interface  between  two  immiscible  liquids,  and  at  that  between  sus- 
pended solid  particles  and  liquid,  as  in  colloidal  solutions.  Since,  as 
we  have  seen,  the  surface  area  (interface)  is  enormously  increased  in 
these  solutions,  a  very  great  surface  energy  is  present,  for  this  is  equal 
to  the  surface  tension  multiplied  by  the  surface  area. 


ADSORPTION 

The  surface  tension  between  liquid  and  air  is  lowered  when  organic 
substances  are  dissolved  in  the  liquid,  but  is  slightly  raised  when  inor- 
ganic salts  are  dissolved.  The  degree  of  lowering  varies  markedly  ac- 
cording to  the  organic  substance  dissolved,  being  very  pronounced  with 
bile  salts,  upon  which  fact  the  well-known  (Hay)  test  for  the  presence 
of  bile  in  urine  is  based.  Between  liquid  and  liquid,  as  well  as  between 
solid  and  liquid,  the  surface  tension  is  always  lowered  "by  dissolving  sub- 
stances in  the  liquid.  Now,  at  the  interfaces  between  solid  particles  and 
liquid  there  must  be  a  local  accumulation  of  free  surface  energy,  which 
will  be  equal  to  the  surface  tension  multiplied  by  the  surface  (inter- 
face) area.  A  constant  tendency  exists  for  such  free  energy  to  be  de- 
creased and,  since  dissolved  substances  have  this  effect,  they  will  become 
concentrated  at  the  interface.  This  is  known  as  the  principle  of  Willard 
GMs,  and  it  is  of  fundamental  importance  to.  the  biochemist,  because 


COLLOIDS  67 

on  it  depends  the  phenomenon  known  as  adsorption,  which  in  the  case 
of  colloidal  solutions  may  therefore  be  defined  as  the  local  concentra- 
tion or  condensation  of  dissolved  substances  at  the  interface  between 
the  two  phases.  The  amount  of  substance  concentrated  at  the  interface 
can  be  calculated  by  a  formula  which  takes  into  account  the  concentra- 
tion of  the  dissolved  substance,  the  temperature,  and  the  surface  tension 
at  the  interface  (the  Gibbs  formula).  After  adsorption  has  occurred,  vari- 
ous reactions  of  a  chemical,  electrical  or  purely  physical  nature  (e.  g.,  dif- 
fusion) may  follow  at  a  rate  which  depends  on  the  amount  of  the 
condensation.  A.  P.  Matthews  has  recently  challenged  this  view  of 
adsorption.30 

Reactions  Which  Depend  on  Adsorption 

1.  Decolorization  of  liquids  by  charcoal.     That  no  chemical  reaction  occurs  in  such 
a  case  is  readily  shown  by  the  ease  with  which  the  pigment  can  be   extracted  from 
the  charcoal. 

2.  Adsorption  of  gases  by  such  solids  as  charcoal  and  spongy  platinum.     In  these 
cases  there  must  be  great  condensation,  even  a  liquefaction  of  the  gas,  during  which 
heat  must  be  evolved.     By  adsorbing  oxygen  and  hydrogen,   spongy  platinum  causes 
these    gases   to    combine    and    form    water.     The   hemoglobin    of    blood    may    take    up 
oxygen  by  a  similar  process. 

3.  Formation  of  solid  surface  films  on  solutions  of  protein,  saponin,  etc.     The  con- 
densation may  lead  to  coagulation,  which  explains  why,  if  the  froth  produced  by  beat- 
ing the  white  of  an  egg  is  allowed  to  stand,  it  can  not  be  again  beaten  into  a  froth, 
the  albumin  having  gone  out  of  solution  by  surface  coagulation. 

An  interesting  phenomenon  depending  on  the  surface  tension  occurs 
when  the  protoplasmic  contents  of  a  ciliated  infusorian  is  pressed  out  in 
water.  A  new  membrane  forms  on  the  protoplasm  because  of  surface  con- 
centration of  all  constituents  which  lower  surface  energy.  By  application 
of  the  principle  of  Willard  Gibbs,  A.  B.  Macallum18  concludes  that  not  only 
adsorption,  as  exhibited  in  a  colloidal  solution,  but  also  the  local  accumula- 
tions of  material  often  seen  in  cells,  are  associated  with  changes  in  sur- 
face energy.  His  conclusions  are  based  largely  on  microscopic  studies 
of  various  forms  of  cell  exhibiting  different  degrees  and  types  of  activity, 
and  ingeniously  stained  for  potassium  by  cobalt  hexanitrite.  By  such 
a  means  the  potassium  stains  intense  black.  In  vegetable  cells,  local 
accumulations  of  potassium  occur  either  near  the  interface  between  the 
clear  and  the  chlorophyl-containing  parts  of  the  cell  (spirogyra)  or 
under  a  portion  of  the  cell  wall  from  which  later  a  protrusion  grows  out 
to  form  the  first  stage  in  conjugation.  The  outgrowth  from  the  cell, 
as  well  as  the  accumulation  of  potassium,  may  be  the  result  of  a  low 
surface  tension.  In  unicellular  animal  organisms,  such  as  Vorticella, 
much  less  potassium  is  present,  being  confined  to  the  base  of  the  cilia, 
which  Macallum  believes  indicates  that  the  structures  are  produced  as 
an  outcome  of  low  surface  tension. 


68  PHYSICOCHEMICAL   BASIS   OF   PHYSIOLOGICAL   PROCESSES 

In  the  cells  of  higher  animals,  deposits  of  potassium  are  also  localized ; 
in  striated  muscle,  for  example,  they  occur  in  a  zone  at  each  end  of  the 
doubly  refractive  band  and  immediately  adjacent  to  the  singly  refrac- 
tive band.  Changes  in  surface  tension,  associated  with  changes  in  the 
distribution  of  potassium,  are  believed  by  many  to  be  responsible  for 
muscular  contraction.  In  nerves  and  nerve  cells,  potassium  is  concen- 
trated at  the  axon  and  at  the  surfaces  of  the  cells.  Interesting  sugges- 
tions are  offered  to  explain  the  relationship  among  changes  in  surface 
tension  at  the  terminations  of  axons  (synapses,  terminations  in  gland  and 
muscle  cells)  brought  about  by  the  nerve  impulse  acting  as  a  change  in 
electric  potential.  Surface  condensation  of  potassium  has  also  been 
observed  at  the  lumen  border  of  gland  cells  (pancreas),  and  on  the  lu- 
men surface  of  the  cells  of  the  renal  tubules.  Such  observations  indicate 
in  what  way  surface  tension  may  be  called  into  play  to  control  cellular 
activities.  The  field  is  new  and  almost  unexplored,  but  there  is  already 
much  to  indicate  that  surface  energy  plays  a  most  important  role  in  the 
performance  of  many  cellular  activities. 

Conditions  That  Influence  or  Are  Influenced  by  Adsorption 

Electrical  Changes. — Besides  mere  concentration,  other  forces  come  into  play  to  assist 
or  retard  adsorption.  One  of  the  most  important  of  these  is  electrical.  Most  solids 
\vhen  present  as  particles  in  a  fluid  carry  a  negative  charge  of  electricity,  some  a  posi- 
tive one.  In  conformity  with  the  Willard  Gibbs  law,  a  constant  tendency  will  exist 
for  this  free  energy  to  be  diminished  by  the  neutralization  of  the  electric  charge. 
This  can  occur. by  deposition  on  the  interface  of  other  particles  carrying  an  electric 
charge  of  opposite  sign  or  by  the  action  of  that  present  on  ions.  Charcoal  in  suspen- 
sion in  water,  for  instance,  has  a  negative  charge.  If  colloidal  iron,  which  has  a  pos- 
itive charge,  is  added  to  the  solution,  it  will  become  deposited  on  the  charcoal,  as  will 
also  the  cations  of  an  inorganic  salt.  On  account  of  electric  adsorption,  dyestuffs  and 
bile  salts  are  adsorbed  much  more  freely  than  they  would  be  if  the  process  depended 
solely  on  surface  condensation;  that  is,  if  the  Gibbs  formula  is  used  to  calculate  the 
adsorption,  it  will  give  values  that  are  much  below  those  actually  found. 

If  the  dissolved  substance  and  the  particles  both  have  the  same  electric  sign,  ad- 
sorption will  not  occur.  Filter  paper,  for  example,  has  a  negative  charge  and  can  not 
therefore  adsorb  a  negative  dye  such  as  congo  red  (as  shown  by  the  depth  to  which 
it  becomes  stained) ;  whereas  it  readily  adsorbs  night  blue,  which  is  positively  charged. 
If  the  negative  charge  of  the  paper  is  lowered,  it  becomes  capable  of  adsorbing  some 
of  the  negative  congo  red.  This  can  be  effected  either  by  placing  the  paper  in  al- 
cohol or  by  adding  inorganic  salts  (NaCl)  to  the  water  with  which  it  is  in  contact. 
The  positive-charged  ions  of  Na,  produced  by  dissociation,  neutralize  some  of  the  nega- 
tive charge  on  the  paper,  and  allow  a  certain  amount  of  adsorption  of  the  negative- 
charged  congo  red  to  occur.  As  would  be  expected,  acids  and  alkalies  are  capable  of 
greatly  altering  the  electric  charges  by  the  II  and  OH  ions  which  they  contribute. 

Chemical  Forces. — If  the  nature  of  the  phase  at  the  surface  of  which  adsorption 
occurs  is  such  that  it  can  enter  into  chemical  combination  with  the  substance  ad- 
sorbed, reactions  will  occur  that  do  not  obey  the  laws  of  mass  action.  By  adsorption, 


COLLOIDS  69 

reactions  of  a  certain  type  may  be  encouraged  over  other  reactions,  even  although,  the 
necessary  reacting  substances  may  be  present  in  the  solution  (specific  adsorption).  The 
adsorbing  substance  itself  is  not,  however,  usually  susceptible  of  chemical  change 
even  when  it  exists  as  very  minute  particles,  as  in  the  case  of  colloidal  solutions. 
Nevertheless,  adsorption  may  accelerate  chemical  reactions  by  bringing  together  in 
concentrated  form  substances  of  high  chemical  reactivity.  In  such  cases  the  adsorbing 
substance  itself  does  not  enter  into  the  chemical  reaction,  and  can  be  recovered  at  the 
end  in  an  unchanged  condition.  It  acts  as  a  catalyst  (page  72).  As  we  shall  see 
later,  enzymes  act  in  this  way — i.  e.,  their  rate  of  reaction  is  controlled  by  adsorp- 
tion.* 

The  distinguishing  feature  of  such  adsorption  phenomena  is  that  a  curve  of .  the 
reaction  (drawn  by  plotting  amount  of  chemical  change  against  concentration  of  react- 
ing substances)  is  a  parabola,  indicating  that  the  laws  of  mass  action  (page  23)  are 
no  longer  followed.  In  order  to  be  able  to  determine  whether  some  particular  process 
— as,  for  example,  a  fermentation  process,  or  the  absorption  of  oxygen  by  blood — is 
caused  by  adsorption,  we  must  compare  its  curves,  constructed  according  to  the  same 
principles,  with  the  typical  adsorption  curve.  A  formula  may  be  used  in  constructing 
the  curves.  In  arriving  at  this  formula,  two  facts  have  to  be  remembered:  (1)  As  ad- 
sorption proceeds  and  less  and  less  of  the  free  energy  on  the  adsorbing  surface  re- 
mains to  be  neutralized,  the  reaction  slows  off,  until  equilibrium  is  reached.  The  more 
dilute  the  solution,  the  greater  is  the  proportion  of  its  contents  to  be  adsorbed,  which 
means  that  if  a  is  the  amount  of  substance  adsorbed  from  a  certain  solution,  then, 
from  a  solution  of  twice  that  strength,  somewhat  less  than  2  a  will  be  adsorbed — i.  e., 
a  multiplied  by  some  root  of  2.  Although  the  formula  is  one  belonging  to  the  class 
known  as  parabolic,  it  must  not  be  assumed  that  every  reaction  which  happens  to  give 
such  a  parabolic  curve  (such  as  the  combination  of  O  with  hemoglobin  under  certain 
conditions)  (see  page  396)  must  be  one  dependent  on  adsorption. 

It  must  be  understood  that  although  the  substance  that  is  removed  from  a  solution 
by  adsorption  is  no  longer  capable  of  contributing  to  the  conductivity  or  the  osmotic 
pressure  of  the  solution,  it  is  nevertheless  not  so  firmly  fixed  that  it  can  not  be  set 
free  again  by  purely  mechanical  means,  as  by  constant  dilution  of  the  fluid.  If  char- 
coal which  has  adsorbed  sugar  is  placed  in  a  dialyzer  made  of  membrane,  the  pores  of 
which  allow  sugar  but  not  charcoal  to  pass  through,  the  sugar  will  gradually  be  re- 
moved if  the  dialyzer  is  immersed  in  running  water.  A  certain  equilibrium  exists  be- 
tween the  substance  adsorbed  and  the  same  substance  still  remaining  in  solution.  If 
the  latter  is  constantly  diminishing  by  dialysis,  the  adsorption  compound  must  break 
down  to  maintain  the  equilibrium.  It  is  clear,  however,  that  the  process  of  removal 
will  be  extremely  slow.  The  ability  of  adsorbed  substances  to  withstand  removal  by 
washing  is  taken  advantage  of  by  nature  in  holding  back  foodstuffs  in  the  soil. 

*Another  instance  of  the  influence  of  surface  energy  on  the  course  of  chemical  reactions  is  seen 
in  the  accelerative  influence  of  charcoal  on  such  reactions  as  the  oxidation  of  formic  acid,  glycerol, 
etc.  Surface  tension  may  also  cause  retardation  of  chemical  reactions,  as  is  seen  in  the  turbidity 

(due  to  the  separation  of  chloroform)  which  gradually  develops  when  a  — ^ —  NagCOs  solution  is 
mixed  with  a -^-chloral  hydrate  solution.  The  surface  remains  clear,  because  surface  energy  has 
prevented  the  reaction. 

An  important  effect  of  surface  tension  on  chemical  reactions  is  also  seen  in  the  relationship 
between  it  and  the  absorption  coefficient  of  gases  (volume  of  gas  dissolved  by  unit  volume  of 
liquid).  The  lower  the  surface  tension,  the  greater  the  solubility  of  the  gas.  Oxygen  and  nitrogen 
are,  for  example,  much  more  soluble  in  alcohol,  hydrocarbons  or  oil  than  in  water.  This  shows 
the  futility  of  attempting  to  prevent  the  loss  of  gases  from  fluids  such  as  blood  by  covering  them 
with  oils  or  hydrocarbons. 


70  PHYSICOCHEMICAL   BASIS   OF   PHYSIOLOGICAL   PROCESSES 

Biological  Processes  Depending  on  Adsorption 

Instances  in  which  adsorption  undoubtedly  plays  a  most  important 
part  in  physiological  processes  are  as  follows: 

1.  The  action  of  enzymes  (see  page  71). 

2.  The  combination  of  toxin  with  antitoxin  occurs  according  to  the  laws 
of  adsorption  rather  than  those  of  mass  action.     In  this  case  it  is  im- 
portant to  note  that  when  the  toxin  of  diphtheria  is  added  in  small  suc- 
cessive quantities  to  diphtheria  antitoxin,  more  toxin  is  neutralized  than 
when  the  toxin  is  all  added  at  once.    A  similar  phenomenon  can  also  be 
observed  by  adding  filter  paper  to  congo  red,  more  of  the  pigment  being 
adsorbed  when  the  paper  is  added  in  small  quantities  than  when  added 
all  at  once.     The  explanation  is  that  relatively  more  adsorption  of  a 
given  substance  occurs  from  a  dilute  than  from  a  strong  solution  (cf. 
page  69). 

3.  The  sensitizing  of  leucocytes  by  opsonins,  as  well  as  the  subsequent 
ingestion  of  bacilli  by  the  sensitized  leucocytes,  both  of  which  follow  the 
course  of  an  adsorption  reaction. 

4.  The  formation  of  adsorption  compounds,  such  as  the  inorganic  salts 
and  proteins  and  the  complex  lecithin  compounds  that  can  be  extracted 
from  egg  yolk  or  brain  tissue.    In  such  compounds  the  laws  of  chemical 
proportion  no  longer  hold,  and  properties  may  be  exhibited  that  are  quite 
different  from  those  of  either  one  of  its  components.    When  yolk  of  egg 
is  extracted  with  ether,  for  example,  a  compound  of  lecithin  with  vitellin 
goes  into  solution,  although  vitellin  itself  is  quite  insoluble  in  ether.* 
There  can  be  no  doubt  that  adsorption  compounds  of  this  character  are 
very  abundant  in  living  cells,  and  that  they  are  constantly  being  formed 
and  broken  down. 

5.  It  is  possible  that  the  distribution  of  a  substance  in  protoplasm  is 
largely  dependent  on  the  influence  which  it  has  on  the  surface  tension 
at  the  boundary  of  different  phases  in  the  protoplasm. 

*By  mixing  solutions  of  egg  albumin,  congo  red  and  a  dye  called  fustic  in  the  presence  of 
alum,  the  colloidal  particles  of  which  each  is  composed  run  together  to  form  larger  colloidal  ag- 
gregates, which  by  ultramicrosconic  examination  can  be  seen  to  be  composed  of  a  red,  a  yellow 
and  a  green  colloidal  particle.  The  attractive  force  holding  the  particles  together  is  electric  in 
this  case. 


CHAPTER  IX 

FERMENTS,  OR  ENZYMES 

One  of  the  most  striking  developments  of  modern  research  in  biochem- 
istry concerns  the  nature  of  enzyme  action.  So  remarkable  are  many  of 
the  facts  that  have  been  brought  to  light  that  it  can  not  fail  to  interest 
every  one  engaged  in  the  study  of  life  phenomena — whatever  the  nature 
of  that  study  may  be — to  know  something  of  the  main  questions  at 
present  occupying  the  attention  of  investigators  in  this  field.  In  this 
chapter  a  brief  survey  will  be  given  of  some  of  these  questions;  no  at- 
tempt will  be  made  at  completeness,  and  only  where  necessary  for  the 
sake  of  example  will  reference  be  made  to  individual  types  of  enzyme 
action. 

The  discovery  by  Buchner  that  an  enzyme  can  be  expressed  from  yeast 
cells  which  is  capable  of  instantly  bringing  about  the  alcoholic  fermen- 
tation of  dextrose  solutions  has  been  responsible  for  a  great  deal  of  the 
modern  advance.  Formerly,  yeast  cells  were  believed  to  bring  about 
alcoholic  fermentation  as  a  result  of  their  growth:  it  was  believed  to  be 
a  life  phenomenon,  or  "vital  process."  Now  we  know  that  yeast  cells 
produce  an  intracellular  ferment  or  endo-enzyme*  to  which  its  sucroclastic 
properties  are  due  and  which  can  act  apart  from  the  cells  that  produce  it. 
It  is  no  great  stretch  of  imagination  to  think  of  all  chemical  reactions 
mediated  by  cellular  activity  as  due  to  a  similar  mechanism,  and  this  thought 
has  led  to  the  hypothesis  that  all  processes  of  intermediary  metabolism  in 
the  animal  and  plant  are  caused  by  enzyme  action.  Before  Buchner 's 
day  we  knew  only  of  the  extracellular  enzymes  (such,  for  example,  as 
the  digestive  ferments),  that  is  to  say,  of  enzymes,  produced  indeed  by 
cells,  but  secreted  from  them  and  acting  outside  their  protoplasm;  now 
we  must  recognize  intracellular  enzymes  acting  where  they  are  produced, 
in  the  protoplasm  of  the  cell.  But  we  must  not  permit  this  conception  to 
carry  us  too  far.  Without  further  investigation  we  must  not  imagine 
that  the  riddle  of  life  is  thus  solved. 

As  an  example  of  the  role  which  extra-  and  intracellular  enzymes  are 
supposed  to  play  in  the  animal  economy  may  be  cited  the  metabolism  of 
protein.  Proteolytic  enzymes  are  very  widely  distributed  in  the  active 
tissues  of  the  animal  and  plant.  By  their  agency  in  animal  life,  the  com- 

*The  terms  "ferment"  and  "enzyme"  are  synonymous,  but  the  latter  is  preferable  as  the  noun, 
leaving  the  former  to  be  used  as  the  verb. 

71 


72  PHYSICOCHEMICAL   BASIS   OF   PHYSIOLOGICAL   PROCESSES 

plex  protein  molecule  is  split  up  to  render  it  absorbable  from  the  intes- 
tine, and  the  tissues  appropriate  from  the  blood  those  of  the  degradation 
products  that  they  require  for  the  construction  of  protoplasm,  which, 
later,  they  decompose  so  as  to  utilize  the  energy  which  the  organism 
demands.  All  these  processes  are  believed  to  be  the  work  of  enzymes. 

The  Nature  of  Enzyme  Action 

The  changes  brought  about  by  enzymes  can  also  be  accomplished  by 
ordinary  chemical  means,  but  these  have  often  to  be  of  a  very  energetic 
nature  to  accomplish  what  the  enzyme  can  so  quickly  and  quietly 
perform. 

It  is  the  custom  to  regard  enzymes  as  catalysts.  A  catalyst  is  a  sub- 
stance which  accelerates  (or  retards)  a  chemical  reaction  which  in  its 
absence  could  proceed  at  a  different  (usually  slower)  pace.  The  action 
of  catalysts  has  been  aptly  likened  to  that  of  a  lubricant.  A  weight 
placed  at  the  top  of  an  inclined  plane,  so  held  that  the  weight  only  slowly 
slips  down,  has  its  velocity  greatly  increased  if  its  under  surface  be 
oiled.  The  oil  accelerates  the  action  but  does  not  affect  the  ultimate 
result.  Catalysts  do  not  combine  with  the  final  products  of  the  reaction, 
these  being,  as  a  rule,  the  same  as  they  would  have  been  had  no  catalyst 
been  added.  Another  characteristic  is  the  tremendous  amount  of  chem- 
ical change  which  even  a  trace  of  catalyst  can  induce.  There  are  many 
examples  of  catalysts  in  the  inorganic  world,  among  which  may  be  cited 
the  action  of  spongy  platinum  on  hydrogen  peroxide.  This  substance 
normally  tends  to  decompose  into  water  and  oxygen,  but  if  a  small 
amount  of  spongy  platinum  is  added  to  it,  the  decomposition  is  greatly 
accelerated:  H202  =  H20  +  0. 

A  very  good  example  of  the  action  of  an  inorganic  catalyst  is  that  of 
the  hydrogen  ion  on  cane  sugar,  or  other  disaccharides,  in  the  presence 
of  water.  It  accelerates  the  hydrolysis.  Cane  sugar  solution  at  room 
temperature  does  not  indeed,  in  sterile  solution,  undergo  any  appreciable 
hydrolysis,  but  at  100°  C.  it  does,  which  leads  us  to  believe  that,  though 
inappreciable,  the  action  also  occurs  at  room  temperature.  By  adding 
a  little  hydrochloric  acid,  or  other  acid  not  having  an  oxidizing  effect 
on  sugar,  we  greatly  accelerate  the  hydrolysis  because  of  the  hydrogen 
ions  present  in  the  acid  solution.  "Within  certain  limits  the  rate  of  hy- 
drolysis is  proportional  to  the  amount  of  catalyst  present- 
Enzymes,  like  other  catalysts,  produce  their  action  when  present  in 
very  small  amounts  (e.  g.,  sucrase  can  hydrolyze  200,000  times  its  weight 
of  cane  sugar;  diastase  can  convert  starch  to  sugar  in  a  dilution  of 
1-1,000,000)  and  there  is  a  distinct  relationship  between  the  amount  of 
enzyme  present  and  the  rate  of  the  reaction.  The  final  product  of  the 


FERMENTS,    OR   ENZYMES  73 

reaction  is,  however,  the  same  at  whatever  rate  it  proceeds,  and  the 
enzyme  does  not  appear  in  the  final  products.  Many  enzymes  such  as 
diastase  can  be  found  unaltered  in  amount  after  they  have  completed 
their  action.  This  is  determined  by  adding  a  fresh  supply  of  substrate 
(that  is,  of  material  to  be  acted  on),  when  the  enzymic  action  proceeds 
again  in  the  usual  way.  The  same  is  no  doubt  true  for  all  enzymes, 
though  as  yet  it  can  actually  be  proved  for  only  a  few  of  them.  Enzymes, 
therefore,  may  be  defined  as  catalysts  produced  by  living  organisms. 

The  Properties  of  Enzymes 

Although  enzymes  are  examples  of  catalysts,  they  exhibit  many  proper- 
ties that  appear  to  differ  from  those  of  inorganic  catalysts.  It  will, 
therefore,  be  advisable  in  considering  each  quality  to  compare  it  in 
catalysts  and  enzymes,  for  by  this  method  a  much  clearer  conception  of 
the  nature  of  enzyme  action  can  be  gained  (Bayliss19).  Those  properties 
that  are  strictly  peculiar  to  enzymes  we  shall  consider  later. 

1.  Most  enzymes  are  remarkably  specific  in  their  action,  whereas  inor- 
ganic catalysts  are  very  much  less  so.  Thus,  in  the  case  of  the  enzymes 
which  bring  about  inversion  of  disaccharides,  this  specificity  is  clearly 
shown.  There  is  a  special  enzyme  for  each  of  the  three  disaccharides — 
maltose,  lactose  and  cane  sugar — and  one  of  these  can  not  replace 
another. 

Still  more  strikingly  is  this  specificity  of  enzyme  action  demonstrated 
in  the  fact  that  certain  enzymes,  such  as  zymase  (expressed  from  yeast), 
will  act  only  on  bodies  having  a  certain  configuration,  that  is,  having 
their  side  chains  arranged  in  a  certain  way.  Thus,  there  are  two  varie- 
ties of  dextrose  (a  and  /?),  which  differ  from  each  other  solely  in  the 
fact  that  the  side  chains  are  arranged  in  different  positions  with  rela- 
tion to  the  central  chain  of  carbon  atoms.  This  form  of  isomerism  is 
called  stereoisomerism  because  the  two  bodies  rotate  the  plane  of  polar- 
ized light  to  an  equal  degree  in  opposite  directions.  Zymase  acts  on  one 
of  these  but  not  on  the  other,  and  there  are  innumerable  examples  of  the 
same  kind.  Indeed,  of  all  bodies  that  exist  in  two  stereoisomers  only 
one  is  found  in  living  cells  and  it  is  on  this  variety  alone  that  the  enzymes 
in  animals  can  act.  A  similar  specificity  exists  between  certain  drugs  and 
their  pharmacological  action. 

Specificity  of  action  is  explained  by  supposing  that  a  union  occurs 
between  the  substrate  and  the  enzyme,  and  for  this  union  to  take 
place  the  enzyme  must  possess  a  configuration  which  corresponds  accu- 
rately with  that  of  the  substrate.  The  process  has  been  compared  to  a 
lock  and  key;  the  key  must  be  shaped  to  fit  the  lock,  or  it  can  not 
operate.  The  specificity  does  not,  however,  in  itself  disprove  the  close 


74  PHYSICOCHEMICAL   BASIS   OF   PHYSIOLOGICAL   PROCESSES 

relationship  between  enzymes  and  inorganic  catalysts,  for  on  the  one 
hand  there  are  several  enzymes  which  do  not  exhibit  this  property,  and 
on  the  other,  there  are  inorganic  catalysts  which  do.  For  example, 
lipase,  the  fat-splitting  enzyme  of  pancreatic  juice,  decomposes  not  only 
fats  but  to  a  greater  or  less  degree  a  number  of  bodies  of  the  same  gen- 
eral build  (esters),  and  tyrosinase  can  decompose,  not  tyrosin  alone, 
but  all  phenol  compounds.  Conversely,  the  hydrogen  ion — to  the  pres- 
ence of  which  acids  owe  their  catalytic  powers — can  decompose  the  ordi- 
nary esters  (that  is,  of  acids  containing  the  carboxyl  or  COOH  group) 
but  it  has  no  action  on  the  sulphonic  esters.  However,  enzymes  are  cer- 
tainly much  more  specific  in  their  action  than  inorganic  catalysts. 

2.  Temperature  does  not  influence  catalysis  and  enzyme  action  in  the 
same  way.    As  the  temperature  is  raised  in  the  case  of  inorganic  catalysts, 
the  reaction  becomes  about  doubled  in  rapidity  for  each  rise  of  10°  C., 
whereas  in  the  case  of  enzymes  it  becomes  increased  up  to  a  certain  opti- 
mum temperature,  beyond  which,  as  the  temperature  rises,  the  reaction  is 
first  slowed  and  then  disappears  altogether. 

This  peculiarity  of  enzymes  as  compared  with  inorganic  catalysts  need 
not  in  itself  disprove  the  analogy  between  the  two,  because  enzymes  do 
not  form  true,  but  colloidal  solutions.  Colloidal  solutions,  as  we  have 
seen,  are  really  fine  suspensions  of  ultramicroscopic  particles ;  there  is  no 
splitting  into  ions  of  the  dissolved  substance,  as  is  the  case  with  true 
(molecular)  solutions,  but  the  colloid  is  suspended  in  the  water  or  other 
solvent  to  form  a  heterogeneous  system  (page  52),  on  which  account 
the  surface  area  of  the  menstruum  is  enormously  increased.  Rise  in 
temperature  alters  the  extent  of  the  surface  area,  and  thereby  intro- 
duces an  influence  which  progressively  opposes  catalysis. 

Although  inorganic  catalysts  in  molecular  solution  show  no  optimum 
temperature  but  increase  in  activity  in  proportion  as  the  temperature  is 
raised,  inorganic  colloidal  catalysts  may  show  an  optimum  temperature. 
Thus,  spongy  platinum  shows  an  optimum  temperature  in  its  action  on  a 
mixture  of  hydrogen  and  oxygen.  It  has  therefore  been  suggested  that 
it  is  because  they  are  colloids  that  enzymes  exhibit  this  property. 

3.  Inorganic  catalysts  frequently  carry  the  reaction  to  a  further  stage 
than  that  attained  by  the  action  of  enzymes.    For  example,  acid  breaks 
down  the  protein  molecule  niuch  more  completely  than -do  the  proteolytic 
enzymes.    This  difference  is  perhaps  explained  by  the  fact  that  enzymes 
are  retarded  in  their  activities  when  there  comes  to  be  a  certain  accumu- 
lation of  the  products  of  the  reaction  present.     The  final  stages  in  the 
reaction  may  become  so  slow  as  to  be  almost  inappreciable.     This  de- 
crease in  activity  is  partly  due  to  a  union  between  the  enzyme  and  the 
products  of  its  activity. 


FERMENTS,    OR   ENZYMES  75 

4.  The  velocity  constant  in  the  case  of  inorganic  catalysts  remains  un- 
changed throughout  the  reaction,  whereas  in  the  case  of  enzymes  it  be- 
comes either  less  or  greater  as  the  process  proceeds.  When  a  substance  is 
changed  by  catalytic  action,  it  is,  of  course,  constantly  being  diminished 
in  concentration  so  that  less  and  less  of  it  remains  to  be  acted  on.  This 
implies  that  there  are  fewer  molecules  present  for  the  same  amount  of 
catalyst  to  act  on  and  consequently  that  the  amount  changed  in  a  unit 
of  time  is  progressively  less.  At  any  moment,  therefore,  the  rate  of 
catalysis  will  be  proportional  to  the  amount  of  substance  (substrate) 
left.  To  understand  this  we  must  refer  back  to  what  we  have  learned  about 
mass  action.  If  we  suppose  that  two  substances  A  and  B  react  to  form 
two  other  substances  C  and  D,  then,  by  the  law  of  mass  action,  the  reac- 
tion will  not  go  on  to  completion  but  will  stop  when  a  certain  equilibrium 
is  reached.  The  reaction  can  be  represented  by  the  equation 
A  +  B  +±  C  +  D,  which  means  that  it  proceeds  at  a  rate  proportional  to 
the  reacting  molecules.  In  some  cases  this  reaction  goes  on  until  either 
A  or  B  has  practically  disappeared  (that  is,  the  equilibrium  point  is  very 
near  the  right  of  the  equation),  as  is  the  case  in  the  inversion  of  cane 
sugar: 

C12  H22  On  +  H20  =  C6  H12  06  +  C6  H12  06 

Taking  place  as  it  does  in  an  excess  of  water,  and  there  being  very 
little  tendency  for  the  reaction  to  go  in  the  opposite  direction  (cf.  re- 
versible action  page  25),  the  only  thing  which  will  influence  its  velocity 
is  the  concentration  of  cane  sugar;  in  other  words,  the  velocity  of  the 
reaction  at  any  moment  will  depend  on  the  concentration  of  the  cane 
sugar  still  left  undecomposed.  This  can  be  determined  by  means  of 
an  equation.* 

The  value  of  such  an  equation  is  that  it  gives  us  a  figure  K,  represent- 
ing the  amount  of  inversion  that  would  occur  in  each  unit  of  time  if  the 
cane  sugar  were  kept  in  constant  concentration.  When,  for  example, 
it  is  stated  that  K  for  a  particular  strength  of  acid  acting  on  cane  sugar 

*If  x  be  the  amount  of  sugar  inverted  in  time  t,  C,  the  concentration  of  the  sugar  not  yet  in- 
verted, and  if  we  use  a  figure  called  a  constant  (K)  to  express  the  fundamental  rate  of  the  reaction 

(which  will  therefore  be  different  for  different  reactions),  then  —  r=  KC.  But  C  can  not  be  the  same 
at  any  two  consecutive  periods  of  time,  because  the  reaction  is  going  on  continuously.  This  renders 

it  necessary  to  use  the  notation  of  the  differential  calculus,   and  we  have  -=— •  =    KC.      The    sign   8 

ot 

indicates  that  the  reaction  is  a  constantly  changing  one  so  that  5x  and  8t  represent  such  infinitely 
small  amounts  that  they  can  not  be  measured.  By  methods  of  integration,  however,  it  can  be  shown 
that  the  above  equation  may  be  written: 

K=-r^r">*- nat-  -§-' 

thus  permitting  us  to  find  the  value  of  K  (Cj.  Cz  being  the  concentrations  of  cane  sugar  at  the 
times  T!  T2). 

Any  two  determinations  during  the  course  of  the  reaction  can  be  used  for  calculating  K.  These 
equations  apply  only  to  cases  in  which  but  one  substance  5s  changing  (monomolecular  reaction). 
When  two  substances  are  involved,  the  equation  is  more  complicated. 


76  PHYSICOCHEMICAL   BASIS   OF   PHYSIOLOGICAL   PROCESSES 

solution  is  0.002,  this  means  that  when  volume,  concentration  of  acid  and 
temperature  are  constant  in  a  gram-molecular  solution  of  sugar,  0.002 
gram-molecule  of  sugar  would  be  inverted  the  first  minute  and  0.002 
gram  each  succeeding  minute,  provided  we  could  keep  the  solution  con- 
stantly a  gram-molecular  one,  that  is,  provided  we  could  add  sugar  just 
as  quickly  as  it  becomes  inverted. 

At  first  sight  it  may  appear  of  little  practical  importance  to  determine 
K.  In  our  present  discussion  concerning  the  nature  of  enzyme  action, 
it  is  however  of  great  value  for,  whereas  with  inorganic  catalysis  K  is 
really  of  constant  value,  with  enzyme  action  it  is  not  so.  Thus,  when 
cane  sugar  is  inverted  by  sucrase — an  enzyme  present  in  the  intestine 
and  in  yeast — the  constant  gradually  rises;  for  most  other  unimolecular 
reactions  mediated  by  enzymes  it  gradually  falls ;  for  example,  the  action 
of  trypsin  on  proteins. 

Where  there  is  a  great  excess  of  substance  to  be  acted  on,  in  compari- 
son with  the  amount  of  enzyme  present,  it  will  be  found  that  a  more 
constant  value  than  K  is  obtained  when  we  compute  the  absolute  amount 
of  substance  decomposed  in  a  given  time.  In  such  a  case,  too,  the 
amount  of  change  in  a  given  time  will  be  proportional  to  the  amount  of 
enzyme  present,  indicating  that  some  sort  of  combination  between  en- 
zyme and  substrate  must  be  the  first  step  in  the  fermentative  process. 
This  fact  has  been  noticed  by  us  in  connection  with  the  hydrolysis  of 
glycogen  in  the  liver.  When  there  is  an  excess  of  glycogen  present,  the 
amounts  which  disappear  in  equal  intervals  of  time  after  death  are  the 
same;  when,  on  the  contrary,  there  is  not  much  glycogen,  the  amount 
which  disappears  gradually  declines,  but,  if  K  be  computed  by  the  above 
equation,  it  is  constant. 

To  make  these  facts  clear  it  may  be  well  to  pause  for  a  moment  to 
consider  an  illustration.  The  conditions  obtaining  when  there  is  a  large 
excess  of  substrate  over  enzyme  may  be  compared  to  those  governing 
the  removal  of  a  pile  of  bricks  from  one  place  to  another  by  a  number  of 
men.  The  pile  of  bricks  represents  the  substrate ;  the  men,  the  enzyme. 
If  each  man  works  up  to  his  capacity,  it  is  plain  that  the  number  of 
bricks  transferred  in  a  given  time  will  not  depend  at  all  on  the  size  of 
the  pile  to  be  transferred.  When,  however,  the  pile  of  bricks  gets  small, 
though  the  same  number  of  men  continue  to  work  the  number  of  bricks 
transferred  in  a  given  time  falls  off,  because  the  men  interfere  with  one 
another's  activities  in  securing  their  loads  from  the  pile.  When  a  similar 
stage  is  arrived  at  in  enzyme  processes,  we  have  to  use  the  velocity  con- 
stant to  show  how  much  work  could  be  done  by  the  enzyme  if  the  amount 
of  substrate  were  maintained  of  constant  amount. 

In  the  large  volume  of  recent  work  which  has  been  done  with  the 


FERMENTS,   OR  ENZYMES  77 

object  of  discovering  the  cause  of  these  variations  in  the  velocity  con- 
stant in  the  case  of  enzymes,  four  important  conditions  have  been  recog- 
nized: (1)  reversibility;  (2)  gradual  destruction  of  the  enzyme;  (3)  com- 
bination of  the  enzyme  with  products  of  the  reaction;  (4)  autocatalysis. 

Of  these  four  influences  the  only  one  which  could  be  held  accountable 
for  an  increase  in  the  activity  of  the  enzyme  is  autocatalysis;  in  this 
process  the  enzyme  by  its  action  produces  substances  which  intensify 
its  own  activity.  In  some  cases  at  least — for  example,  the  action  of 
invertase  on  cane  sugar — these  are  acid  bodies,  a  moderate  increase  in 
acidity  favoring  the  action  of  this  enzyme. 

The  other  influences  all  tend  to  retard  the  reaction  and  progressively 
lower  the  value  of  K.  Negative  autocatalysis  occurs  when  the  enzyme 
produces  products  which  interfere  with  its  activity.  Gradual  destruc- 
tion of  the  enzyme  and  its  union  with  the  products  of  its  activity  will 
manifestly  also  decrease  its  power.  There  is  plenty  of  evidence  that 
both  of  these  processes  may  occur. 

Reversibility  of  Enzyme  Action 

But  the  most  important  of  all  the  causes  of  retardation  of  enzyme 
activity  is  undoubtedly  reversibility  of  action,  which  is  an  application  of 
the  law  of  mass  action  (page  25).  If  we  take  the  saponification  of  an 
ester,  the  equation  is: 

CH3CH2CH2COOC2H5  +  H2O  ±=>  CH3CH2CH2COOH  +  C2H5OH. 
(ethyl  butyrate)  (butyric  acid)      (ethyl  alcohol) 

The  equilibrium  point  is  not  so  near  the  position  of  complete  hydrol- 
ysis as  in  the  case  of  the  inversion  of  cane  sugar;  in  other  words,  the 
tendency  for  the  bodies  produced  by  the  hydrolysis  to  reunite  and  form 
the  original  substances  is  quite  marked,  so  that  the  reaction  comes  to  an 
end  before  all  the  ethyl  butyrate  has  been  decomposed.  For  some  time 
before  the  equilibrium  point  is  reached,  there  will  have  existed  a  progres- 
sively increasing  opposition  to  the  breakdown  of  the  ester,  as  a  conse- 
quence of  which,  when  enzymes  are  used  to  accelerate  the  reaction,  the 
velocity  constant,  as  determined  by  the  above  equation,  will  gradually 
fall  as  the  reaction  proceeds.  Conversely,  in  a  mixture  of  ethyl  alcohol 
and  butyric  acid  there  is  very  slow  synthesis  to  ethyl  butyrate,  and  here 
again  lipase  accelerates  the  process;  it  induces  a  recognizable  synthesis 
within  a  short  time.  Ethyl  butyrate  is  usually  employed  for  these  ex- 
periments because,  on  account  of  its  odor,  the  ester  is  readily  recognized. 
Thus,  if  the  alcohol  and  acid  be  mixed  alone,  no  ester  will  be  detectable, 
but  if  some  lipase  be  added,  it  will  soon  become  so.  Similar  synthetic 
action  of  lipase  has  also  been  demonstrated  for  mono-  and  tri-olein. 


78  PHYSICOCHEMICAL   BASIS    OF   PHYSIOLOGICAL   PROCESSES 

It  should  be  clearly  understood  that  pure  catalysts,  such  as  the  hydro- 
gen ion,  in  accelerating  a  reaction  like  the  above,  do  so  equally  in  both 
directions,  so  that  the  position  of  equilibrium  remains  unchanged.  En- 
zymes may,  however,  cause  this  position  to  change  because  of  their  form- 
ing intermediate  combinations. 

The  reverse  phase  of  certain  reactions  is  probably  the  cause  of  at  least 
some  of  the  synthetic  processes  which  occur  in  the  animal  body.  A  great 
difficulty  in  accepting  such  a  view,  however,  is  the  fact  that  the  equilib- 
rium point  of  all  hydrolytic  reactions,  in  the  presence  of  an  excess  of 
water,  is  so  near  complete  hydrolysis  that  very  little  synthesis  can  be 
possible.  That  is  true  so  long  as  the  substance  synthesized  is  soluble, 
but  if  it  is  nearly  insoluble  in  water,  or  if  it  is  immediately  removed 
from  the  site  of  the  reaction  by  diffusion,  or  in  any  other  way,  then  it  is 
obvious  that  it  will  go  on  being  synthesized  by  the  reaction.  Thus,  in  the 
intestine  neutral  fat  is  hydrolyzed  by  pancreatic  lipase  into  fatty  acid 
and  glycerol,  which  are  absorbed  into  the  epithelium,  where  they  again 
come  under  the  influence  of  intracellular  lipase.  This  latter  will  tend  to 
accelerate  the  synthesis  of  neutral  fat  from  the  fatty  acid  and  glycerol 
until  the  equilibrium  point  of  the  system  (fat  acid  +  glycerol  +±  neutral 
fat  +  H20)  is  again  reached;  but  this  point,  although  it  is  near  the  right 
hand  of  the  equation,  will  really  never  be  reached  for  the  reason  that  the 
neutral  fat,  as  quickly  as  it  is  formed,  will  become  deposited  in  insoluble 
globules  in  the  protoplasm  and  thus  be  removed  from  the  equation.  In 
support  of  this  view  it  has  been  found  that  lipase  is  present  in  intestinal 
mucosa  after  all  traces  of  adherent  pancreatic  juice  have  been  washed 
away.  By  similar  reactions  the  fat  of  the  tissues  becomes  decomposed  to 
fatty  acid  and  glycerol  and  passes  out  of  the  blood  when  the  concentra- 
tion of  fat  in  this  fluid  falls  below  a  certain  level.  Provided  one  of  the 
substances  synthesized  is  insoluble  or  can  in  some  other  way  be  removed 
from  the  reaction,  it  is  plain  that,  even  though  the  equilibrium  point  is 
very  near  to  that  of  complete  hydrolysis,  yet  the  reversion  will  be  suf- 
ficient to  do  all  that  is  required  of  it. 

Results  such  as  the  above  have  prompted  many  to  conclude  that  it  is 
by  such  reversible  action  that  all  synthetic  processes  occur  in  the  living 
organism.  But  the  demonstrable  synthesis  of  an  ester  must  not  be  taken 
as  evidence  that  all  other  syntheses  are  explainable  on  the  same  basis. 
For  example,  we  have  seen  above  that  in  the  case  of  cane  sugar  the  equi- 
librium point  in  the  equation  is  so  near  that  of  complete  hydrolysis,  that  no 
measurable  amount  of  cane  sugar  is  formed  when  dextrose  and  levulose  are 
allowed  to  act  on  each  other,  and  that  cane  sugar  does  not  appear 
when  sucrase  is  added  to  the  mixture.  If  instead  of  sucrase  we  take 
another  of  the  sugar  enzymes — namely,  maltase,  which  accelerates  the 


FERMENTS,   OR   ENZYMES  79 

decomposition  of  maltose  into  two  molecules  of  glucose  —  there  is,  how- 
ever, evidence  of  synthesis  as  a  result  of  the  acceleration  of  a  reversible 
reaction.  To  understand  these  results  we  must  remember  that  ordinary 
dextrose  is  a  mixture  of  two  stereoisomers  designated  a  and  j8.  "When 
two  molecules  of  a  dextrose  condense  (that  is,  fuse  togther  with  the 
loss  of  a  molecule  of  water)  maltose  is  formed,  but  when  two  molecules 
of  /3  dextrose  condense  isomaltose  results.  There  is  some  controversy 
as  to  whether  maltase  is  really  responsible  for  the  synthesis  of  a  dextrose 
molecules  to  maltose,  it  being  claimed  by  some  that  this  is  accomplished 
by  another  enzyme,  emulsine.  If  this  were  true  it  would  materially 
minimize  the  importance  of  reversible  action  as  a  factor  in  cellular  syn- 
thesis. The  latest  evidence  goes  to  show,  however,  that  it  is  maltase 
and  not  emulsine  that  is  responsible  in  the  above  case  (cf.  Bayliss). 

Evidence,  both  direct  and  indirect,  is  also  steadily  accumulating  to 
show  that  enzymes  may  accelerate  the  synthesis  of  proteins.  As  pieces 
of  indirect  evidence  we  have:  (1)  the  retardation  of  the  digestive  action 
of  trypsin,  etc.,  which  sets  in  after  the  process  has  gone  on  for  a  time, 
and  (2)  the  recommencement  of  a  digestive  process  apparently  at  an 
end,  if  the  products  of  the  digestion  are  removed  by  dialysis  or  other 
means.  As  direct  evidence  may  be  cited  the  formation  of  synthetic 
products  when  pepsin  is  added  to  concentrated  solutions  of  peptone, 
and  the  diminution  in  the  number  of  small  molecules,  as  judged  by  meas- 
urements of  electrical  conductivity,  when  trypsin  is  added  to  the  prod- 
ucts of  tryptic  digestion  of  caseinogen.  Protamine  —  a  simple  form  of  pro- 
tein —  has  also  been  found  to  be  produced  when  trypsin  —  obtained  from 
a  mollusc—  was  added  to  a  tryptic  digest  of  the  same  protamine.  The 
significance  of  these  facts  in  connection  with  the  metabolism  of  the 
amino  acids  will  be  evident  when  we  -come  to  study  this  subject  (page 
634).* 

Specificity  of  Enzyme  Action 

Although  in  all  of  the  above  features  of  enzyme  action  there  is  nothing 
to  contradict  the  view  that  they  are  catalytic  agents,  there  remains  one 
peculiarity  which  at  first  sight  seems  uninterpretable  on  such  a  basis. 
This  is  with  regard  to  their  often  remarkable  specificity  of  action.  Thus, 
as  we  have  seen,  maltase  can  hydrolyze  maltose  alone  (which  is  com- 
posed of  two  a-dextrose  molecules),  but  not  isomaltose  (composed  of 
^-dextrose).  This  means  that  mere  difference  in  the  configuration  of 
molecules  is  sufficient  to  alter  the  influence  of  enzymes  on  them.  Since 
such  differences  could  not  influence  that  of  inorganic  catalysts  we  must 


•We   have  been   unable   in   this  laboratory  to   demonstrate  any   synthesis  of 
cogenase  is  added  to  a  hydrolysis  mixture  of  dextrine,  maltose  and  glucose  produced  by  the 
action  of  glycogenase  on  pure  glycogen. 


80  PHYSICOCHEMICAL   BASIS   OF   PHYSIOLOGICAL   PROCESSES 

explain  the  cause  of  the  difference.  This  has  been  done  on  the  basis 
either  that  enzymes  are  colloids  or  that  the  active  (catalytic)  group  of 
the  enzyme  is  attached  to  a  colloid  molecule.  Before  a  substance  can 
be  acted  on,  it  must  combine  with  the  colloid,  which  it  does  by  the  proc- 
ess of  adsorption  (see  page  66).  This  can  occur,  however,  only  when 
there  is  a  harmony  between  the  adsorbing  substance  and  the  substance 
adsorbed.  Instances  of  the  specificity  of  adsorption  have  already  been 
given. 

In  support  of  this  view  it  has  been  found  that  of  the  two  proteases, 
a  and  /?,  in  the  spleen,  one  is  adsorbed  but  not  the  other  when  a  solu- 
tion containing  them  is  shaken  with  Kieselguhr.  Furthermore,  when 
solutions  of  invertase  are  shaken  with  certain  inert  powders,  the  in- 
vertase  is  adsorbed  by  some  of  them  but  not  by  others.  In  strong  sup- 
port of  the  adsorption  hypothesis  is  also  the  fact  that  the  same  mathe- 
matical laws  as  apply  in  the  process  of  adsorption  are  obeyed  in  the 
ratio  which  exists  between  the  activity  of  an  enzyme  and  its  concen- 
tration in  the  solution. 

To  sum  up,  then,  catalysis  as  exhibited  by  enzymes  involves  three 
processes:  (1)  contact  between  the  enzyme  and  the  substrate,  which  will  be 
dependent  on  their  rates  of  diffusion;  (2)  adsorption  between  them,  which 
will  depend  on  their  configurations  (cf.  the  lock  and  key  simile)  ;  and 
(3)  the  chemical  change  which  itself  probably  takes  place  in  two  stages. 
In  connection  with  the  third  process,  it  is  probable  that  an  initial  com- 
pound of  a  definite  chemical  nature  is  first  formed,  followed  by  the 
hydrolytic  or  other  chemical  change,  after  which  the  enzyme  group 
becomes  free. 

It  is  very  significant  in  this  connection  to  note  that  in  their  solubil- 
ities there  exists  a  distinct  relationship  between  the  ferments  and  the 
substrates  on  which  they  react.  Thus,  trypsin  is  very  soluble  in  water 
and  acts  on  water-soluble  proteins;  lipase  is  soluble  in  fat  solvents. 

Certain  Peculiarities  of  Enzymes 

Notwithstanding  the  very  strong  case  that  is  made  out  for  the  cata- 
lytic hypothesis,  there  are  certain  facts  which  many  find  it  difficult  to 
make  conform  with  such  a  view.  One  of  these  is  that  dextrose  can 
undergo  three  distinct  and  separate  types  of  decomposition  according 
to  the  enzyme  allowed  to  act  on  it.  These  are  alcoholic  fermentation, 
butyric  acid  fermentation  and  lactic  acid  fermentation.  It  is  difficult 
to  see  how  simple  catalytic  action  can  be  responsible  for  all  three  results. 
The  enzyme  must  not  only  initiate  the  changes  but  also  direct  their 
course. 

Another  peculiarity  is  that  when  certain  enzymes — e.  g.,  rennin,  pep- 


FERMENTS,   OB  ENZYMES  81 

sin,  etc. — are  inoculated  in  animals,  they  cause  specific  antienzymes  to 
appear  in  the  blood  of  the  inoculated  animal.  Thus,  when  antirennin 
serum  is  added  to  milk  it  greatly  hinders  clotting  on  the  subsequent 
addition  of  rennin.  It  is  probable  that  powerful  antienzymes  are  pro- 
duced in  the  animal  body  for  the  purpose  of  protecting  the  tissues  from 
attack  by  enzymes.  It  is  on  account  of  the  presence  of  antienzymes 
that  intestinal  parasites  can  exist  in  the  intestine,  and  the  immunity 
from  digestion  which  the  mucosa  of  the  gastrointestinal  tract  enjoys, 
is  believed  to  be  due  to  the  same  cause.  But  there  is  considerable  doubt 
regarding  this  claim.  Fresh  pancreatic  juice  when  injected  into  the 
empty  intestine  digests  its  walls.  When  food  is  present  in  the  intes- 
tine it  evidently  prevents  digestion  of  the  walls  by  diverting  the  enzyme 
to  itself. 

Types  of  Enzymes 

Having  learned  something  about  the  general  nature  of  enzyme  action, 
we  may  now  turn  our  attention  to  certain  details  that  have  a  practical 
importance.  In  the  first  place,  with  regard  to  nomenclature,  in  the 
earlier  work  each  newly  discovered  enzyme  received  a  name  which  was 
often  quite  inappropriate.  Many  of  these  names  are  retained,  such  as 
pepsin,  trypsin,  ptyalin,  etc.,  but  it  is  now  customary  to  name  the 
enzyme  according  to  the  substance  on  which  it  acts.  This  is  done  either 
by  replacing  the  last  part  of  the  name  of  the  substance  acted  on  by  the 
termination  -ase  (for  example,  the  enzyme  which  inverts  maltose  is  called 
maltase),  or  by  merely  adding  -ase  to  the  name  of  the  substance  acted 
upon  (thus,  the  enzyme  which  hydrolyzes  glycogen  is  called  glycogenase). 

Most  of  the  enzymes  in  the  animal  body  accelerate  hydrolytic  proc- 
esses and  are  classified  according  to  the  chemical  nature  of  the  sub- 
strate on  which  they  work.  Thus,  we  have: 

1.  The  amylases — accelerating  the  hydrolysis  of  polysaccharides,  e.  g., 
ptyalin   (in  saliva),   amylopsin   (in  pancreatic  juice),    glycogenase    (in 
liver),  diastase  (in  malt). 

2.  The  invertases — accelerating  hydrolysis  of  disaccharides,  e.  g.,  malt- 
ase, lactase  and  sucrase  (in  succus  entericus). 

3.  The  proteinases — accelerating  hydrolysis  .of  proteins,  e.  g.,  pepsin 
(in  gastric  juice),  trypsin   (in  pancreatic  juice),   erepsin,  intracellular 
proteinases. 

4.  The  Upases — accelerating  disruption  of  neutral  fats,  e.  g.,  steapsin 
(in 'pancreatic  juice),  intracellular  lipases. 

5.  Arginase — accelerating   hydrolysis   of   arginin    into    urea   and    or- 
nithin,  (intracellular). 


82  PHYSICOCHEMICAL   BASIS   OF   PHYSIOLOGICAL   PROCESSES 

6.  Urease — accelerating  hydrolysis   of  urea  to   ammonium   carbonate 
(in  many  microorganisms  and  in  the  soy  bean). 

7.  Glyoxylase — converting  glyoxals  into  lactic  acid   (page  698). 
Other  enzymes  accelerate  oxidative  processes  and  are  called  oxidases 

and  per  oxidases.  Others  bring  about  the  displacement  of  an  amino 
group  by  hydroxyl  (desamidases) .  Others  cause  coagulation  (coagula- 
tive  ferments),  e.g.,  thrombin,  rennin.  One  of  the  enzymes  present  in 
succus  entericus  acts  by  converting  the  zymogen  (trypsinogen)  into  the 
enzyme  (trypsin). 

Enzyme  Preparations 

So  far  it  has  been  impossible  to  prepare  enzymes  in  a  pure  state  al- 
though, being  colloidal  in  nature,  they  are  readily  precipitated  or  ad- 
sorbed along  with  other  colloids. 

Since  most  enzymes  exist  in  cells,  it  is  necessary  to  break  up  the  cells 
in  order  to  isolate  the  enzyme.  This  is  done  in  various  ways.  By  one 
method  the  cells  are  ground  in  a  mortar  with  fine  sand,  then  made  into 
a  paste  with  infusorial  earth  (Kieselguhr),  the  paste  enclosed  in  stout 
canvas  and  placed  under  an  hydraulic  press  at  about  300  atmospheres 
pressure;  a  clear  fluid  separates  and  this  contains  the  enzymes.  An- 
other way  is  to  freeze  the  tissue  with  liquid  air  and  grind  it  in  a  steel 
mortar  by  means  of  a  machine.  Still  another  and  less  expensive  method, 
and  one  which  we  have  found  most  useful  for  organs  and  tissues,  con- 
sists in  reducing  the  tissue  to  a  pulp  and,  after  sieving  it  to  get  rid  of 
connective  tissue,  etc.,  spreading  the  pulp  on  glass  plates  and  drying 
in  a  slightly  warmed,  dry  air  current.  The  scales  of  dried  material  are 
then  ground  in  a  paint  mill  with  toluene,  and  the  resulting  suspension 
filtered ;  the  powder  which  remains  on  the  filter,  after  thorough  washing 
with  toluene,  is  dried  and  kept  for  future  use.  The  toluene  removes  all 
the  fatty  substances,  so  that  when  shaken  with  water,  etc.,  the  enzymes 
dissolve. 

Conditions  for  Enzymic  Activity 

Reactions  brought  about  by  intracellular  enzymes  are  very  readily 
inhibited  when  there  comes  to  be  a  certain  accumulation  of  their  prod- 
ucts of  action.  Thus,  yeast  ceases  to  ferment  sugar  when  the  alcohol 
has  accumulated  to  a  certain  percentage.  This  action  is  partially  due 
to  a  toxic  action  of  the  alcohol  on  the  cell,  which  paralyzes  its  power  of 
absorbing  the  substance  to  be  acted  on  by  the  intracellular  enzyme.  If 
these  products  be  not  in  some  way  removed,  they  will  ultimately  kill 
the  cell  and  stop  the  fermentation.  We  have  seen  above  how  the  ac- 
cumulation of  products  may  interfere  with  the  activities  of  enzymes  in 


FERMENTS,    OR   ENZYMES  83 

other  ways  in  which  the  enzyme  does  not  suffer  destruction,  as  is  shown 
by  the  fact  that  it  resumes  its  original  activities  on  removal  of  the 
products. 

Enzymes,  both  intracellular  and  extracellular,  are  very  sensitive  to- 
wards the  inorganic  composition  of  the  medium  in  which  they  are  act- 
ing. For  the  intracellular  enzymes  this  is  what  we  should  expect  when 
we  bear  in  mind  the  profound  influence  of  inorganic  salts  on  the  heart 
beat  and  on  cell  growth  and  division.  This  influence  of  salts  and  of 
reaction  (acidity,  etc.)  on  the  life  of  the  cell  is  so  pronounced  as  to  lead 
some  observers  to  believe  that  abnormal  cell  multiplication  in  the  body, 
as  in  the  case  of  tumor  formation,  is  due  to  changes  in  the  inorganic 
composition  of  the  tissue  fluids.  Extracellular  enzymes  are  also  very 
susceptible  to  the  influence  of  inorganic  salts  but  more  especially  so 
towards  the  reaction  of  the  solution.  In  terms  of  modern  chemistry 
we  may  say  that  the  concentration  of  H-  and  OH'  ions  has  a  profound 
influence  on  the  activities  of  enzymes.  Most  of  the  enzymes  of  the  an- 
imal body  perform  their  action  normally  in  the  presence  of  a  slight  ex- 
cess of  OH'  ions,  that  is,  in  faintly  alkaline  reaction.  Indeed  the  only 
exception  of  importance  to  this  is  the  pepsin  of  gastric  juice,  which  nor- 
mally acts  in  an  acid  medium.  An  excess  of  either  OH'  or  H-  ions 
inhibits  the  activity  of  the  enzyme  and  usually  destroys  it  permanently. 
The  activities  of  enzymes  are  also  influenced  by  light,  many  of  them 
being  destroyed  by  sunlight;  cells  such  as  microorganisms  are  similarly 
affected. 

Before  being  secreted  the  digestive  enzymes  exist  in  the  cells  which 
produce  them  as  inactive  precursors  called  zymogens.  The  granules  seen 
in  resting  gland  cells  are  of  this  nature.  The  activation  of  the  zymogen, 
or  its  conversion  into  the  enzyme,  occurs  after  it  has  left  the  cell,  and 
this  has  been  considered  as  another  safeguard  to  digestion  of  the  cell. 
Sometimes  the  activation  does  not  occur  until  the  zymogen  has  travelled 
some  distance  along  the  gland  duct,  as  in  the  case  of  the  proteolytic 
enzyme  of  pancreatic  juice.  Till  it  reaches  the  intestine,  this  exists  as 
trypsinogen  (the  zymogen),  but  it  is  here  acted  on  by  another  enzyme- 
like  body  produced  by  the  intestinal  epithelium  and  called  enterokinase 

PHYSICOCHEMICAL  REFERENCES 

(Monographs  and  Original  Papers) 

3Bayliss,  W.  M.:     Principles  of  General  Physiology,  Longmans,  Green  &  Co.,  1915. 
2Philip,  J.  C.:     Physical  Chemistry,  Its  Bearing  on  Biology  and  Medicine,  Arnold, 

ed.  2,  1914. 
3McClendon,  J.  S.:     Physical  Chemistry  of  Vital  Phenomena,  Princeton  University 

Press,  1917. 
4Starling,  E.  H.:     Principles  of  Human  Physiology,  ed.  2,  1915,  Lea  and  Febiger. 


84  PHYSICOCHEMICAL   BASIS   OF   PHYSIOLOGICAL   PROCESSES 

sKahlenberg,  L.:     Jour.  Physical  Chem.,  1906,  x,  141. 

eReid,  E.,  Weymouth:    Jour.  Physiol.,  1898,  xxii,  Ivi.  . 

^Wilson,  T.  M.:     Am.  Jour.  Physiol,  1905,  xiii,  150. 

sHaldane,  J.  S.,  and  Priestley,  J.  G.:     Jour.  Physiol.,  1916,  1,  296;  Priestley,  J.  G.: 

Ibid.,  p.  304. 

sQlark,  W.  M.,  and  Lubs,  H.  A.:     Jour.  Bacteriology,  1917,  ii,  1  and  109. 
i°Henderson,  L.  J.:     The  Excretion  of  Acid  in  Health  and  Disease,  Harvey  Lectures, 

J.  B.  Lippincott  Co.,  1915,  x,  132. 

nHenderson,  L.  J.:     The  Fitness  of  the  Environment,  Macmillan,  N.  Y.,  1913. 
i^Van  Slyke,  D.  D. :     Jour.  Biol.  Chem.,  1917,  xxx,  289,  347,  363. 
isLevy,  R.  L.,  and  Kowntree,  L.  G.:     Arch.  Int.  Med.,  1916,  xvii,  525. 
i4Cullen,  G.  E.:     Jour.  Biol.  Chem.,  1917,  xxx,  369. 
ispalmer,  W.  W.,  and  Henderson,  L.  J.:     Arch.  Int.  Med.,  1913,  xii,  153;   and  Jour. 

Biol.  Chem.,  1912,  xiii,  393;  xix,  81;  xvii,  305;  xxi,  37. 
isSellards,  A.  W.:     The  Principles  of  Acidosis  and  Clinical  Methods  for  Its  Study, 

Harvard  University  Press,  Cambridge,  1917. 
I'Lloyd,  F.  H.:     Private  communication. 
isMacallum,  A.  B, :     Surface  Tension  and  Vital  Phenomena.     University  of  Toronto 

Studies,  No.  8,  1912;  also  Ergebnisse  der  Physiologic,  1911,  ii,  598. 
i»Bayliss,  W.  M.:     Enzymic  Action,  ed.  2.     Monographs  in  Biochemistry,  Longmans, 

Green  &  Co. 

2oBayliss,  W.  M. :     Neutralisation,  etc. 
siHaggard,  and  Henderson,  Y. :     Jour.  Biol.  Chem.,  1919. 
22Christiansen,  Douglas,  and  Haldane,  J. :     Jour.  Physiol.,  1914,  xlviii,  246. 
2^Morawitz,  P.,  and  Walker,  J.  C.:     Biochem.  Ztschr.,  1914,  Ix,  395. 
2>*Macleod,  J.  J.  K.:     Jour.  Lab.  and  Clin.  Med.,  1919,  iv,  1. 
25Bradford,  S.  C. :     Biochem.  Jour.,  1918,  xii,  351. 
26Dale,  H.  H.,  and  Evans,  E.  L.:     Jour.  Physiol.,  1920,  liv,  167. 
27Evans,  E.  L. :     Jour.  Physiol.,  1921,  Iv,  159. 
2«Van  Slyke,  D.  D.:     Physiol.  Rev.,  1921,  i,  141. 
sojoffe,  J.,  and  Poulton,  E.  P.:     Jour.  Physiol.,  1920,  liv,  129. 
soMatthews,  A.  P.:     Physiol.  Rev.,  1921,  i,  553. 


PART  II 
THE  BLOOD  AND  THE  LYMPH 


CHAPTER  X 

BLOOD:  ITS  GENERAL  PROPERTIES 
(Partly  Contributed  by  R.  G.  PEARCE) 

The  blood,  being  the  carrier  of  the  nutritive  and  waste  substances  of 
the  body's  metabolism,  must  at  one  time  or  another  contain  all  the  ma- 
terials which  compose  the  tissues  in  addition  to  those  which  are  peculiar 
to  the  blood  itself.  It  is  a  very  complex  fluid,  and  all  of  its  constituents 
are  not  fully  known.  Structurally  it  is  composed  of  water  in  which  are 
dissolved  various  gases  and  organic  and  inorganic  bodies,  the  corpuscles 
and  platelets. 

THE  QUANTITY  OF  BLOOD  IN  THE  BODY 

The  volume  of  blood  in  the  body  may  be  measured  by  bleeding  and 
subsequently  washing  out  the  blood  from  the  vessels  and  then  estimating 
the  amount  of  hemoglobin  in  the  total  fluid  (Welcher's  method).  This 
method  employed  in  the  case  of  two  criminals  who  had  been  decapitated 
gave  the  weight  of  the  blood  as  7.7  and  7.2  per  cent  of  the  body  weight. 
Bloodless  methods  for  determining  the  total  volume  of  blood  are  based 
upon  the  principle  of  adding  a  definite  quantity  of  a  known  substance  to 
the  circulation  and  then  estimating  its  concentration  in  a  sample  of  blood 
withdrawn  from  the  body  shortly  afterward.  If  the  substance  can  not 
leave  the  blood  vessels  and  does  not  cause  fluid  to  be  withdrawn  from  the 
tissues,  the  total  quantity  of  blood  in  the  body  can  be  calculated  from  the 
concentration  of  the  injected  substance  in  the  blood.  The  most  accurate 
methods  based  on  this  principle  are  Haldane  and  Smith's,  in  which  car- 
bon monoxide  gas  is  inhaled  in  a  given  amount  and  the  carbon  monoxide 
hemoglobin  subsequently  determined  colorimetrically ;  and  Keith,18  Rown- 
tree  and  Geraghty's,20  which  employs  vital  red,  a  dye  of  low  diffusibility. 
The  dye  remains  long  enough  in  the  body  to  be  thoroughly  mixed  with  the 
blood,  and  its  concentration  in  the  plasma  is  determined  colorimetrically 
by  comparing  with  a  suitable  standard  mixture  of  dye  and  serum.  These 

85 


86  THE    BLOOD    AND    THE   LYMPH 


methods  give  the  total  amount  of  blood  in  the  body  as  from  5  to  8.8  per 
cent  of  its  weight.  Meek  has  recently  developed  a  method  in  which  gum 
acacia  is  used.  After  mixing  with  the  blood,  the  concentration  of  this 
substance  is  determined  from  the  calcium  content.  Being  colloid,  none 
of  the  gum  leaves  the  blood  vessels.  Further  details  on  methods  will  be 
found  in  the  papers  of  Hooper,  Whipple,  etc.22 

The  vital  red  method  is  employed  as  follows:  A  1.5  per  cent  solution  of  vital  red  is 
preserved  in  sterile  condition  in  15-20  c.c.  quantities.  A  needle  is  inserted  in  the 
basilic  vein  and  6-8  c.c.  of  blood  withdrawn  into  a  dry  syringe  containing  finely  pow- 
dered pot.  oxalate.  The  syringe  is  removed  from  the  needle,  and  another  syringe  con- 
taining an  amount  of  the  vital  red  solution  corresponding  to  3  mg.  vital  red  per  kilo  body 
weight,  is  connected  with  the  needle  and  the  dye  slowly  injected.  The  blood  removed 
in  the  first  syringe  is  now  transferred  to  a  paraffined  centrifuge  tube,  and  in  about 
10  minutes  a  third  syringe  is  connected  with  the  needle  and  8-10  c.c.  of  blood  removed 
and  transferred  to  two  paraffined  tubes.  From  one  of  these  a  specimen  is  taken  for 
the  hematocrit.  The  tubes  are  then  centrifuged  rapidly  for  some  time.  The  dilution 
of  dye  in  the  plasma  is  now  determined  colorimetrically,  using  as  a  standard  the  fol- 
lowing: 1  c.c.  diluted  dye  (0.5  c.c.  of  the  original  dye  solution  to  100  c.c.  0.8  per  cent 
NaCl  sol.). 

1  c.  c.  plasma  before  injection 

2  c.  c.  0.8  per  cent  NaCl. 
and  using  as  test  solution 

1  c.  c.  plasma  after  dye  injection 

3  c.  c.  0.8  per  cent  NaCl. 
The  formula  for  calculation  is 

200 

X  c-  c-  dye  injected   X  100  =  c.  c.  plasma 

E 
Where  R  —  per  cent  reading  of  test  solution. 

By  use  of  the  above  method  Keith,  Rowntree  and  Geraghty  found  that 
in  man  the  plasma  normally  constitutes  5  per  cent  or  %0  the  body  weight, 
i.e.,  50  c.c.  plasma  per  kg. 

To  determine  total  blood  volume  the  hematocrit  must  also  be  used,  and 
it  was  found  that  the  total  volume  =  =  8.8  per  cent  or  l/11.4th  of  body 
weight.  Normal  individuals  therefore  have  85  c.c.  blood  per  kg. 

In  pregnancy,  before  term  the  blood  and  plasma  volumes  are  increased, 
but  within  a  week  or  so  of  delivery  the  volumes  return  to  normal.  In 
obesity  the  plasma  and  blood  volumes  are  relatively  small.  Many  cases 
of  anemia  exhibit  a  relatively  larger  plasma  volume.  Hypertension  may 
be  accompanied  by  a  small  blood  volume,  therefore  this  condition  is  not 
due  to  large  blood  volume. 

The  newer  methods  have  shown  that  the  volume  of  the  circulating 
fluid  is  maintained  fairly  constant  in  spite  of  influences  tending  to  alter 
it.  The  body  accomplishes  this  by  drawing  upon  the  reserve  fluid  in 
the  tissues  and  by  varying  the  rate  of  water  excretion,  particularly 
through  the  kidneys.  Years  ago  the  doctrine  of  an  increased  amount  of 


BLOOD:    ITS   GENERAL   PROPERTIES  87 

blood  in  the  body  (plethora)  gave  rise  to  the  therapeutic  use  of  bleeding. 
Especially  was  this  thought  to  be  useful  in  conditions  which  we  now 
recognize  as  chronic  hypertension,  and  which  show  no  increase  in  blood 
volume.  Indeed  variation  in  blood  volume  is  not  common,  although 
plethora  may  occur  in  polycythemia,  chlorosis,  and  anemias,  and  there 
may  be  a  temporary  reduction  in  the  amount  of  blood  in  diseases  in 
which  there  is  a  great  depletion  of  water,  as  in  Asiatic  cholera,  and  fol- 
lowing very  severe  hemorrhage. 

While  the  total  quantity  of  the  blood  in  the  body  does  not  vary  greatly, 
the  concentration  of  its  various  constituents  is  subject  to  distinct,  change. 
The  volume  percentages  of  the  corpuscles  and  the  plasma  can  be  approx- 
imately determined  by  allowing  oxalated  blood  to  sediment  or  by  cen- 
trifuging  in  a  graduated  cylinder  by  the  use  of  the  hematocrit.  Such 
methods  are  not  very  reliable,  but  may  yield  some  important  information. 
Normally  45  to  50  per  cent  of  the  volume  of  blood  is  composed  of  cor- 
puscles. It  varies  more  or  less  directly  with  the  number  of  red  blood 
cells. 

THE  WATER  CONTENT  OF  THE  BLOOD 

Since  the  blood  plasma  is  essentially  a  watery  solution,  some  idea  of 
its  water  content  can  be  obtained  by  a  determination  of  the  specific 
gravity.  The  most  accurate  method  for  accomplishing  this  is  to  deter- 
mine directly  the  weight  of  a  given  volume  of  blood  and  compare  it 
with  the  weight  of  the  same  volume  of  water.  Since  this  method  re- 
quires a  rather  large  amount  of  blood,  indirect  methods  using  smaller 
amounts  have  been  devised.  One  of  these  (Hammerschlag's)  uses  a 
solution  of  chloroform  and  benzol  of  a  specific  gravity  of  about  1.050, 
in  which  a  drop  of  blood  is  suspended  by  delivering  it  cautiously  from 
a  pipette  bent  at  right  angles  near  its  tip.  If  the  drop  sinks,  chloroform 
is  added;  if  it  rises,  benzol  is  added  until  the  drop  remains  suspended. 
The  specific  gravity  of  the  benzol-chloroform  mixture  is  then  determined, 
and  this  value  is  supposed  to  give  the  specific  gravity  of  the  blood. 

The  specific  gravity  of  the  blood  determined  in  this  way  varies  be- 
tween 1.040  and  1.065.  It  is  somewhat  less  after  eating  and  increases 
after  exercise;  it  is  slightly  lower  during  the  day  than  at  night,  and 
the  variation  in  individuals  is  considerable.  The  changes  which  occur 
in  the  specific  gravity  of  the  blood  in  disease  are  chiefly  due  to  variation 
in  the  percentage  of  protein,  since  the  salt  content  of  the  blood  is  rela- 
tively fixed.  It  is  only  when  great  changes  occur  in  the  concentration 
of  the  noncolloidal  salts  that  they  markedly  affect  the  specific  gravity. 

From  90  to  92  per  cent  of  the  plasma  and  from  59.2  to  68.7  per  cent  of 
the  corpuscles  consist  of  water.  Of  the  whole  blood,  from  60  to  70  per  cent 


88  THE   BLOOD   AND   THE   LYMPH 

by  volume  or  about  55  per  cent  by  weight  consists  of  plasma;  and  from 
40  to  30  per  cent  by  volume  or  45  .per  cent  by  weight  consists  of  cor- 
puscles. 

THE  PROTEINS  OP  THE  BLOOD 

The  plasma  obtained  by  centrifuging  the  blood  rendered  noncoagula* 
ble  by  oxalates,  hirudin  or  other  means  (see  page  100),  contains  5  to  8 
per  cent  of  coagulable  proteins.  These  proteins  are  serum  albumin, 
serum  globulin,  and  fibrinogen.  They  can  be  separated  from  each  other 
by  the  use  of  acids  and  neutral  salts.  Their  proportion  varies  under  dif- 
ferent conditions,  but  is  approximately  as  follows :  Fibrinogen,  0.15-0.6 
per  cent;  serum  globulin,  3.8  per  cent;  serum  albumin,  2.5  per  cent. 

Fibrinogen 

The  least  soluble  of  the  blood  proteins  is  fibrinogen.  The  plasma  is 
almost  freed  of  it  by  half-saturation  with  sodium  chloride,  or  with  a 
small  amount  of  acetic  acid.  It  is  precipitated  as  fibrin  in  the  process 
of  blood  coagulation  (see  page  102),  and  is  estimated  by  weighing  the 
amount  of  fibrin  which  it  produces.  Pibrinogen  disappears  rapidly  and 
the  blood  fails  to  clot  when  the  liver  is  removed  in  Eck  fistula  dogs  (see 
page  651).  It  also  diminishes  in  CHC13  and  P.  poisoning.  If  blood  is 
withdrawn  and  then  defibrinated  and  reinjected  fibrinogen  reappears  in 
twenty-four  hours. 

Serum  Globulin  and  Serum  Albumin 

Globulins  are  ordinarily  defined  as  being  insoluble  in  distilled  water, 
and  albumins  as  being  soluble.  It  is,  however,  impossible  to  separate 
serum  globulin  and  albumin  satisfactorily  in  this  manner.  The  globu- 
lin obtained  by  dialysis  can  be  returned  to  solution  by  the  addition  of 
a  suitable  amount  of  water,  which  makes  the  salt  adherent  to  the  pre- 
cipitate a  weak  saline  solution.  In  neutral  or  acid  solutions  it  is  coag- 
ulated by  heat  at  about  75°  C.  But  it  does  not  act  as  an  individual  pro- 
tein, since  a  portion  of  it  is  precipitated  by  dialysis  or  by  carbon  diox- 
ide. Probably  serum  globulin  really  consists  of  two  or  more  proteins. 

The  serum  albumin  remaining  in  solution  after  saturation  with  am- 
monium sulphate  likewise  does  not  represent  a  chemical  entity.  It  is 
possible  by  carefully  heating  the  solution  of  serum  albumin  to  distin- 
guish three  separate  coagulation  temperatures.  This  fact  has  been  in- 
terpreted as  meaning  that  the  serum  albumin  consists  of  at  least  three 
closely  related  proteins. 

Since  the  refractive  index  of  the  Mood  depends  primarily  upon  the 
amount  of  protein  present,  this  has  been  taken  as  a  means  of  determining 


BLOOD:  ITS  GENERAL  PROPERTIES  89 

variations  in  the  concentration  of  the  proteins.  It  has  been  found  that 
the  concentration  of  the  blood  proteins  varies  somewhat;  during  ex- 
ercise it  is  increased  probably  because  of  the  taking  up  of  water  by 
the  tissues,  and  during  profuse  bleeding  it  is  diminished  because 
large  amounts  of  fluid  are  being  added  to  the  blood  from  the  lymph, 
which  is  relatively  poor  in  proteins.  The  ingestion  of  considerable 
amounts  of  salts  has  been  found  to  reduce  the  concentration  of  the  blood 
proteins  for  a  short  time.  In  pathological  conditions,  as  in  diabetes,  when 
rapid  changes  in  the  body  weight  due  to  alterations  in  the  diet  are  oc- 
curring, changes  in  the  fluid  content  of  the  blood  are  often  observed. 
Likewise  in  edema  caused  by  faulty  renal  function,  there  may  be  a  re- 
tention of  fluid  in  the  blood  before  there  is  any  indication  of  edema.  The 
hydremic  condition  of  the  blood  can  therefore  be  considered  as  a  useful 
diagnostic  aid  in  determining  the  water  metabolism. 

The  relative  concentration  of  the  proteins  of  the  blood  is  also  of  some 
interest,  especially  since  in  certain  diseases  a  considerable  amount  of 
blood  protein  is  lost.  By  refractrometric  methods  it  is  possible  to  sep- 
arate the  globulin  and  albumin  fractions.  Normally  the  total  proteins 
range  between  6.7  and  8.7  per  cent,  of  which  the  albumins  lie  between 
4.95  and  7.7  per  cent,  and  the  globulins  between  1  and  2.54  per  cent.  In 
some  diseases,  as  in  chronic  nephritis,  pneumonia,  and  syphilis,  the 
total  proteins  of  the  blood  are  decreased  and  the  relative  amount  of 
serum  globulin  is  increased  On  the  other  hand,  in  many  mild  infections 
and  chronic  septic  conditions  the  globulin  fraction  may  be  increased 
with  no  change  occurring  in  the  total  protein  content.3 

Serum  Proteins  disappear  from  the  blood  when  the  animal  is  bled  and 
simultaneously  transfused  with  washed  corpuscles  suspended  in  saline. 
If  the  blood  be  removed  in  several  moieties  during  the  day,  it  will  be 
found  that  1  per  cent  of  the  protein  will  have  reappeared  next  day, 
after  which  it  will  reappear  more  slowly  taking  5-7  days  to  return 
to  normal.  If  the  bleeding  be  performed  at  one  period,  however,  there 
will  be  a  very  rapid  return  (within  15  minutes)  of  a  part  of  it,  which 
indicates  the  presence  of  a  reserve  store  of  proteins  somewhere  in  the 
body.  A  slower  regeneration  of  the  remaining  part  then  follows.  This 
regeneration  proceeds  at  about  the  same  rate  as  that  at  which  the  liver 
regenerates  after  being  damaged  by  CHC13  or  P.,  which  suggests  a  rela- 
tionship of  the  liver  to  the  regenerative  process  of  blood  proteins.  This 
is  further  supported  by  the  fact  that  regeneration  of  blood  proteins  is 
decidedly  delayed  after  the  liver  has  been  damaged  by  P.  or  CHC13. 
Further  evidence  of  the  relationship  of  the  liver  to  blood  proteins  is 
obtained  by  the  fact  that  pronounced  damage  to  the  liver  lowers  blood 
protein  somewhat  and  also  that  Eck  fistula  clogs  regenerate  protein  more 


90  THE   BLOOD   AND    THE   LYMPH 

slowly  than  normal  animals.  Regeneration  is  more  rapid  and  complete 
on  a  meat  or  mixed  diet  than  it  is  during  fasting.  Regeneration  is  also 
more  rapid  on  a  meat  diet  than  on  one  of  bread.  Depletion  of  serum 
proteins  below  1  per  cent  is  fatal. 

THE  FERMENTS  AND  ANTIFERMENTS  OF  THE  BLOOD 

The  blood  plasma  contains  many  of  the  ferments  present  in  the  tissues. 
The  nature  of  these  ferments  has  been  the  subject  of  many  investiga- 
tions in  recent  years,  primarily  because  it  has  been  found  that  they  are 
intimately  connected  with  the  problems  of  immunity. 

Among  the  ferments  the  following  have  been  demonstrated  in  the 
blood: 

Proteases  are  probably  present  normally  in  the  human  blood  serum 
in  small  amounts,  but  they  are  found  in  large  amounts  in  the  white 
blood  corpuscles.  A  protein  foreign  to  the  body  if  injected  into  the 
blood  ordinarily  produces  no  untoward  symptoms,  but  a  second  injec- 
tion following  the  first  by  some  days  will  produce  symptoms  of  poison- 
ing known  as  anaphylaxis.  This  fact  has  led  to  the  assumption  that 
the  injection  of  any  foreign  protein  into  the  blood  promptly  leads  to 
the  appearance  therein  of  specific  proteolytic  enzymes  which  will  digest 
the  strange  protein  into  its  derivatives,  which  are  poisonous.  This 
power  of  the  body  to  produce  specific  proteases  has  been  the  subject 
of  much  research  and  debate,  and  Aberhalden  proposed  a  test  for  preg- 
nancy, for  cancer,  and  for  other  conditions  in  which  he  made  use  of  this 
phenomenon.  He  believes  that  the  presence  of  placenta  or  tumor  tissue 
causes  proteins  to  be  formed  which  bring  about  the  production  of  specific 
ferments  whose  duty  it  is  to  rid  the  system  of  these  substances.  Other 
investigators  fail  to  find  the  specificity  in  proteolytic  action  claimed  by 
Abderhalden,  and  believe  that  proteolytic  ferments  which  are  capable 
of  digesting  foreign  proteins  are  absorbed  from  the  alimentary  canal 
from  the  digestive  juices  (Boldyreff ) .  Some  investigators  fail  to  confirm 
the  claim  that  the  proteolytic  activity  of  the  blood  serum  is  increased  under 
the  above  conditions. 

Blood  contains  an  antiferment  known  as  antitrypsin.  This  can  be 
removed  from  the  blood  serum  by  several  substances,  among  which  are 
kaolin,  colloidal  iron  and  starch.  Serum  thus  treated  shows  strong  pro- 
teolytic activity  and  autodigestion  will  occur.  In  this  case  there  can  be 
no  question  of  the  specific  origin  of  proteases.  Abderhalden  believes 
that  the  ferments  of  the  blood  of  the  pregnant  woman  are  able  to  digest 
the  placental  tissue.  Human  placental  tissue  has  the  ability  of  absorb- 
ing antitrypsin  and  it  is  very  questionable  as  to  whether  the  test  pro- 
posed by  Abderhalden  is  due  to  the  new  formation  of  ferments  or  to 


BLOOD:    ITS   GENERAL   PROPERTIES  91 

the  removal  of  the  antitrypsin  and  the  action  of  the  protease  normally 
present  in  the  blood. 

Nuclein  ferments  are  capable  of  decomposing  nucleic  acid  and  purins 
into  the  simpler  bodies. 

Lipases  have  been  demonstrated  in  the  blood. 

Amylase. — The  presence  of  starch-splitting  ferments  in  the  blood  was 
first  shown  by  Magendie  in  1841,  and  later  Bernard  showed  that  gly- 
cogen  or  starch  injected  into  a  vein  produced  glycosuria.  Since  then 
it  has  been  proved  conclusively  that  diastatic  enzymes  are  normally 
present  in  the  blood  and  lymph.  The  source  of  these  enzymes  has  given 
rise  to  much  speculation.  Some  observers  believe  that  they  are  derived 
from  the  amylopsin  of  the  pancreatic  secretion,  while  others  believe  that 
they  are  manufactured  by  the  liver.  Ligature  of  the  pancreatic  ducts 
is  said  to  increase  the  amount  of  amylase,  while  removal  of  the  pan- 
creas may  (Carlson  and  Luckhardt)  or  may  not  (Schlesinger)  increase 
the  amylase  of  the  blood.  In  some  forms  of  experimental  diabetes  the 
amylase  of  the  blood  has  been  found  increased,  and  this  is  the  case  in 
human  diabetes  (Myers  and  Killian).  If  this  is  true,  a  cause  for  the 
inability  of  the  diabetic  to  store  up  glycogen  is  found.  In  impairment 
of  renal  function,  there  is  usually  an  increase  in  the  blood  amylase  and 
a  decrease  in  the  urine  amylase.  This  has  been  suggested  as  being  of 
diagnostic  value. 

The  blood  contains  a  feeble  glycolytic  enzyme  capable  of  destroying 
glucose.  It  is  claimed  that  this  power  is  reduced  in  diabetics  (Lepine). 

Catalase  is  found  in  the  blood  and  tissues  generally.  It  has  the  power 
of  liberating  oxygen  from  hydrogen  peroxide  without  any  accompany- 
ing oxidation  process.  Its  physiological  significance  is  not  known.  It 
is  said  that  the  amount  of  catalase  is  increased  during  excitement  and 
exercise,  and  is  decreased  in  conditions  where  the  body's  activity  is 
lowered.  Its  determination  is  clinically  unimportant  at  present. 


CHAPTER  XI 

BLOOD:  THE  BLOOD  CELL 
(Contributed  by  R.  G.  PEARCE) 

THE  RED  BLOOD  CORPUSCLES,  OR  ERYTHROCYTES 

The  most  prominent  function  of  the  blood  is  to  carry  oxygen  to  the 
tissues.  It  owes  this  property  chiefly  to  the  red  blood  cells  which  are 
present  in  large  numbers  (5,000,000  per  c.mm.  of  blood).  These  cells 
are  biconcave  discs,  having  a  diameter  of  about  7.7  /A.  They  are  con- 
structed out  of  a  framework  composed  largely  of  lipoid  material,  in 
the  meshes  of  which  is  deposited  a  substance  called  hemoglobin,  to 
which  the  remarkable  oxygen-carrying  power  of  the  blood  is  due.  Nei- 
ther the  manner  by  which  the  red  cell  carries  its  hemoglobin  nor  the 
intimate  structure  of  the  cell  itself  is  accurately  known.  It  is  com- 
monly believed  that  the  hemoglobin  is  held  enmeshed  in  a  framework 
or  stroma,  or  encased  in  the  cell  membrane.  One  thing  is  certain,  how- 
ever, that  the  union  of  hemoglobin  with  the  stroma  of  the  red  cell  is 
a  fairly  strong  one,  since  mere  fragmentation  of  the  corpuscle  fails  to 
liberate  the  hemoglobin.  The  fact  that  the  framework  contains  a  large 
amount  of  lipoid  substances  enables  the  corpuscles  to  maintain  their  shape 
and  is  responsible  for  their  characteristic  permeability. 

Hemoglobin  is  a  very  complex  substance  belonging  to  the  group  of 
conjugated  proteins.  By  chemical  means  it  can  be  broken  up  into  a 
simple  globulin  and  a  pigment  hematin,  containing  iron.  When  com- 
pletely saturated,  oxygen  is  present  in  hemoglobin  in  the  proportion 
of  two  atoms  of  oxygen  to  one  atom  of  iron  (Peters) ;  or  401  c.c.  of 
oxygen  can  be  carried  by  hemoglobin  containing  one  gram  of  iron,  the 
molecular  weight  of  the  molecule  being  about  16.669,  or  some  multiple 
thereof  (Barcroft  and  Peters)  (see  also  page  392).  At  this  figure  the 
iron  in  the  molecule  would  represent  0.34  per  cent  of  the  total  weight 
of  the  molecule.  The  corpuscular  surface  area  has  been  estimated  to 
be  3200  square  meters.  There  is  therefore  a  very  large  surface  avail- 
able for  the  absorption  of  oxygen  from  the  alveolar  air,  as  the  blood 
corpuscles  pass  in  single  file  through  the  capillaries  of  the  lungs. 

Since  the  amount  of  oxygen  which  the  blood  can  carry  depends  upon 
its  hemoglobin  content,  it  is  of  some  importance  clinically  to  have 


THE    BLOOD    CELL  93 

methods  of  determining  the  approximate  amount  present.  The  amount 
of  hemoglobin  present  in  a  quantity  of  blood  is  usually  determined 
colorimetrically  by  comparing  the  color  of  the  blood  with  standard  col- 
ors which  correspond  to  known  strengths  of  hemoglobin.  In  normal 
persons  the  amount  of  hemoglobin  varies  greatly  at  different  ages,  and 
in  order  to  determine  whether  or  not  a  given  blood  contains  more  or 
less  hemoglobin  than  normal,  it  is  imperative  to  consider  the  age.  The 
greatest  variations  occur  between  birth  and  the  sixteenth  year.  After 
the  sixteenth  year  the  blood  in  males  usually  contains  a  larger  amount 
than  that  in  females  (Williamson4).  Instruments  used  in  determining 
the  amount  of  hemoglobin  should  be  standardized  to  give  the  value  in 
grams  hemoglobin  per  100  c.c.  of  fluid. 

The  amount  of  hemoglobin  which  is  present  in  each  corpuscle  in 
terms  of  normal  is  therefore  of  some  clinical  interest.  This  relation  of 
the  number  of  red  cells  to  the  amount  of  hemoglobin  is  known  as  the 
color  index  and  is  computed  as  follows:  The  average  red  count  in  man 
is  5,000,000  to  the  c.mm.,  and  the  average  minimal  amount  of  hemo- 
globin is  taken  as  13.88  grams  in  100  c.c.  of  blood  (=80,  Sahli;  =90, 
Miescher;  =86,  Plesch;  and  110,  Tallquist  methods).  These  relative 
values  give  a  color  index  of  one.  The  percentage  of  normal  red  cells 
divided  by  the  percentage  of  normal  hemoglobin  present  gives  the 
color  index. 

The  Origin  of  the  Red  Blood  Cells 

In  fetal  life  the  spleen  and  the  liver  are  generally  believed  to  be  re- 
sponsible for  the  formation  of  the  red  blood  cells.  In  extrauterine  life 
this  function  is  taken  over  by  the  red  bone  marrow.  In  the  primitive 
condition  all  red  blood  cells  are  supposed  to  be  nucleated.  In  extra- 
uterine  life  the  nuclei  of  the  red  cells  are  lost,  and  nonnucleated  forms 
are  alone  present  in  the  blood  stream.  In  fetal  life  and  in  certain  path- 
ologic conditions,  the  rate  of  blood  formation  is  so  rapid  that  some 
nucleated  cells  appear  in  the  blood.  The  normal  response  of  the  body 
to  a  loss  of  red  blood  corpuscles  consists  in  an  increased  activity  of  the 
blood-forming  cells  of  the  red  bone  marrow.  It  is  not  easy  to  follow 
the  course  of  the  regeneration  of  the  red  corpuscles  or  to  discover  the 
mechanism  of  their  formation  in  the  bone  marrow,  since  this  tissue  pre- 
sents a  mixture  of  cells  which  are  precursors  of  the  varied  corpuscles 
found  in  the  blood  and  the  identity  of  which  can  not  be  determined. 

Recently  new  methods  of  staining  blood  for  microscopic  examina- 
tion have  allowed  more  detailed  study  to  be  made  on  the  site  and 
method  of  blood  cell  formation.  When  fresh  unfixed  blood  is  treated 
with  solutions  of  various  dyes,  such  as  brilliant  cresyl  blue,  polychrome 


94  THE   BLOOD   AND   THE   LYMPH 

methylene  blue  or  neutral  red,  an  otherwise  invisible  structure  appears 
in  some  cells  in  the  form  of  coarse  granular  particles  or  threads,  which 
give  a  reticulated  appearance  to  the  corpuscles.  These  reticulated  cells 
are  more  abundant  in  infants'  blood  and  in  patients  suffering  with  se- 
vere anemia  or  hemolytic  jaundice  than  in  normal  blood,  and  may  be 
taken  as  evidence  of  the  youth  of  the  red  cell  and  not  as  a  degenera- 
tive process.  Since  the  number  of  the  reticulated  cells  that  are  present 
in  the  blood  is  more  or  less  directly  proportional  to  the  hemopoietic 
activities  of  the  bone  marrow,  enumeration  of  the  reticulated  cells  is 
of  clinical  importance  in  anemias.  In  conditions  in  which  animals  have 
been  made  plethoric  by  the  transfusion  of  blood,  it  has  been  found  that 
the  number  of  reticulated  cells  is  decreased;  the  bone  marrow  of  these 
animals  also  shows  a  marked  reduction  in  reticulated  erythroblasts. 
The  diminished  rate  of  blood  cell  formation  sometimes  noted  after  blood 
transfusions  may  be  explained  by  assuming  that  the  stimulus  which 
awakens  the  formation  of  red  cells  in  the  bone  marrow  is  absent  or 
made  subnormal  on  the  injection  of  red  cells  into  the  blood,  and  thus 
the  formation  of  red  cells  is  depressed.  Small  transfusions  are  there- 
fore preferable  to  large  ones  in  cases  in  which  the  rate  of  blood  forma- 
tion is  greatly  impaired.  By  means  of  living  cultures  of  red  bone  mar- 
row the  different  stages  of  the  development  of  the  normoblasts  into 
true  red  corpuscles  may  be  studied  (Tower  and  Herm5).  Some  evidence 
has  been  gathered  from  such  studies  which  points  to  the  conclusion  that 
in  place  of  the  red  cells  being  cells  which  have  lost  their  nucleus,  as  is 
the  current  teaching,  they  are  rather  cells  which  develop  as  a  nuclear 
bud  and  escape  into  the  circulation  as  true  red  cells.  The  nucleated 
red  cell  and  the  red  nucleated  corpuscle  of  the  bird  are  the  product  of 
intranuclear  activity  and  are  morphologically  identical. 

Rates  of  Regeneration  of  Erythrocytes 

Microscopic  examination  of  the  blood  during  rapid  regeneration  of 
red  cells  shows  the  presence  of  nucleated  forms.  Nucleated  red  cells 
in  the  blood  have  therefore  been  taken  as  an  inevitable  feature  of  rapid 
blood  regeneration.  The  evidence  upon  which  this  belief  depends, 
however,  is  hardly  complete,  since  changes  in  the  manner  of  red  blood 
cell  formation  may  be  responsible  for  the  nucleated  forms.  The  red 
bone  marrow  is  considered  the  seat  of  red  cell  formation,  and  it  is  true 
that  an  abnormal  increase  in  the  red  bone  marrow  usually  accompanies 
increased  red  cell  formation.  The  nature  of  the  stimulus  which  brings 
about  the  new  formation  of  red  cells  is  not  understood.  Oxygen  want 
may  be  an  important  factor,  since  we  find  the  presence  of  an  abnormally 
large  number  of  red  cells  in  conditions  where  there  is  a  scarcity  of 


THE  BLOOD  CELL  95 

oxygen  in  the- inspired  air,  as  in  life  at  high  altitudes,  or  a  difficulty  in 
its  absorption  through  the  lungs,  as  in  congenital  heart  disease. 

The  red  cells  produced  following  hemorrhage  and  in  simple  anemia 
contain  less  than  the  normal  amount  of  hemoglobin,  but  their  shape  and 
size  are  approximately  normal,  and  few  nucleated  cells  are  present.  In 
the  regeneration  of  red  cells  which  is  found  in  pernicious  anemia,  we 
find  the  cells  containing  an  unusually  large  amount  of  hemoglobin. 
The  red  cells  in  this  disease  have  abnormal  forms,  many  being  large, 
with  or  without  a  nucleus,  and  containing  basic  staining  granules. 
This  type  of  blood  cell  formation  is  due  to  degenerative  changes. 

The  Fate  of  the  Erythrocytes 

The  length  of  life  of  the  red  blood  cell  is  unknown.  Estimates  based 
upon  the  daily  excretion  of  bile  pigments  are  not  reliable,  since  Hooper 
and  Whipple  have  shown  that  the  pigments,  in  part  at  least,  arise  from 
pigments  which  the  liver  has  made  in  excess  of  its  needs  for  the  manu- 
facture of  hemoglobin,  and  which,  not  being  needed,  are  excreted.15 
There  is  no  question  however  that  every  erythrocyte  sooner  or  later 
undergoes  disintegration,  a  process  formerly  thought  to  be  ushered  in 
by  the  ingestion  of  the  red  blood  cell  by  a  phagocyte  in  the  spleen  or 
in  a  hemolymph  gland,  the  hemoglobin  of  the  disintegrated  cell  being  set 
free  and  carried  to  the  liver,  where  it  is  broken  up  into  hematin,  which 
the  body  stores  for  future  use,  and  into-  bile  pigments,  which  are  ex- 
creted. Rous  and  Robertson6  fail  to  find  evidence  that  this  process 
occurs  in  man  to  an  extent  sufficient  to  account  for  the  normal  destruc- 
tion of  the  blood  cells.  However  they  have  recently  found  another  and 
unsuspected  method  for  blood  destruction  in  all  animals  thus  far 
studied — namely,  the  disintegration  of  the  blood  cells  by  fragmentation 
while  they  are  circulating,  without  loss  of  their  hemoglobin.  These 
fragmented  cells  are  found  most  frequently  in  the  spleen.  They  believe 
that  the  small  ill-formed  cells,  known  as  microcytes  and  poikilocytes, 
observed  in  severe  experimental  anemias,  are  due  not  to  the  fact  that 
they  are  produced  by  the  bone  marrow,  but  rather  to  the  fact  that  the 
marrow  in  its  anemic  condition  is  not  able  to  produce  a  resistant  ery- 
throcyte, and  fragmentation  therefore  takes  place  too  readily.  A  sim- 
ilar condition  may  exist  in  the  severe  anemias  of  man  and  account  for 
the  general  high  resistance  of  the  red  cells  found  in  the  blood  of  these 
patients,  inasmuch  as  the  weak  cells  are  generally  fragmented  very  soon 
after  they  are  formed.  Long  ago  Ehrlich  stated  that  the  microcytes 
and  poikilocytes  of  anemia  are  the  result  of  fragmentation  of  the  cells 
in  the  circulating  blood,  but  he  believed  that  this  fragmentation  was  a 


96  THE    BLOOD    AND    THE   LYMPH 

purposeful  division  in  order  to  increase  the  total  surface  of  the  red 
cells.  The  ultimate  fate  of  the  red  cell  fragments  is  not  known.  It  is 
reasonable  to  suppose  that  the  fragmented  bits  containing  hemoglobin 
are  carried  to  the  liver,  where  the  hemoglobin  is  transformed  into 
hematin  and  bile  pigments. 

Hemolysis 

Another  method  of  red  blood  cell  destruction,  which,  however,  does 
not  take  place  normally,  is  by  hemolysis.  The  nature  of  the  combina- 
tion of  the  hemoglobin  with  the  stroma  of  the  red  cell,  as  already  re- 
marked, is  not  definitely  known.  That  it  is  not  merely  contained  in  a 
sac  is  shown  by  the  fact  that  the  cell  may  be  cut  into  bits  without  the 
hemoglobin  being  set  free.  In  some  manner  the  hemoglobin  is  chem- 
ically bound  with  the  stroma  of  the  red  cell,  from  which  it  can  be 
freed  by  a  number  of  physicochemical  and  chemical  agents.  This  proc- 
ess is  known  as  hemolysis,  and  the  substances  which  bring  it  about  are 
known  as  hemolytic  agents.  The  manner  in  which  these  agents  effect 
the  release  of  hemoglobin  from  the  blood  is  quite  varied. 

If  the  osmotic  pressure  of  the  plasma  is  lowered  by  dilution,  the  pres- 
sure within  the  corpuscle  remains  high,  and  water  is  absorbed  by  the 
cell.  If  this  absorption  is  sufficient,  the  cell  ruptures  and  the  hemoglobin 
is  discharged.  For  this  reason  it  is  necessary  in  diluting  the  blood  to 
use  solutions  of  salt  having  an  osmotic  pressure  equal  to  that  of  the 
blood  to  protect  the  red  cell  from  hemolysis.  This  is  obtained  by  using 
a  0.9  per  cent  solution  of  sodium  chloride.  Better  results  are  had, 
however,  by  using  either  Ringer's  solution  (0.9  per  cent  NaCl,  0.026 
per  cent  CaCl2,  and  0.03  per  cent  KC1)  or  Locke's  solution  (0.9  per  cent 
NaCl,  0.024  per  cent  CaCl2,  0.042  per  cent  KC1,  0.01-0.03  per  cent 
NaHC02  and  0.1  per  cent  glucose). 

In  normal  corpuscles  hemolysis  occurs  to  a  small  extent  in  solu- 
tions containing  about  0.42  per  cent  of  sodium  chloride.  In  certain 
diseases  the  fragility  of  the  corpuscles  may  be  increased  (Butler7). 

The  membrane  and  stroma  of  the  erythrocyte  contain  lipoidal  ma- 
terial which  is  soluble  in  alcohol,  ether,  fatty  acids,  and  bile  salts. 
Addition  of  these  agents  to  the  blood  brings  about  hemolysis,  presum- 
ably by  dissolving  the  lipoidal  material  present.  The  hemolysis  which 
occurs  with  saponin  is  similar  in  type,  since  saponins  combine  with 
lipoids,  the  compound  being  soluble  in  water. 

The  hemolytic  properties  of  serum,  whether  they  are  found  to  be 
normally  present  when  the  bloods  of  certain  animals  are  mixed  or  to 
be  produced  artificially  by  the  injection  of  foreign  red  cells,  furnish  a 
subject  of  great  interest  from  the  standpoint  both  of  immunology  and 


THE   BLOOD    CELL  97 

of  clinical  medicine.  The  hemolytic  serum  produced  by  the  injection 
of  foreign  corpuscles  owes  its  activity  to  two  substances.  The  one 
called  the  amboceptor,  or  immune  body,  is  specific  against  the  type 
of  cell  injected  and  is  increased  during  immunization.  The  second 
body  is  the  complement;  it  is  nonspecific,  and  is  not  increased  dur- 
ing immunization.  Complement  is  destroyed  by  heating  the  serum  for 
one  hour  at  55°  C.,  leaving  the  amboceptor  alone  present.  Corpuscles 
placed  in  such  serum  are  not  hemolyzed  until  complement  either  from 
fresh  immune  or  from  nonimmune  serum  is  added. 

The  serum  of  animals  possessing  natural  hemolytic  properties  towards 
the  corpuscles  of  other  animals  likewise  owes  its  effect  to  the  joint  action 
of  amboceptors  and  complement. 

Ordinarily  the  serum  from  animals  of  one  species  does  not  exhibit 
hemolytic  properties  to  blood  from  another  animal  of  the  same  species. 
In  unusual  cases,  however,  the  serum  of  an  animal  will  produce  hemol- 
ysis  of  the  corpuscles  of  an  animal  of  the  same  species.  Such  sera  are 
said  to  possess  isohemolysins.  The  fact  is  of  great  importance  in  the 
transfusion  of  blood  from  one  individual  to  another. 

The  cause  of  the  acute  hemolysis  which  occurs  in  the  disease  parox- 
ysmal hemoglobinuria  is  not  known.  It  is  probably  due  to  the  presence 
of  a  hemolytic  substance  which  unites  with  the  blood  corpuscles  at 
temperatures  below  the  normal  body  temperature,  since  the  attack  fol- 
lows exposure  to  cold,  and  blood  from  patients  subject  to  the  condition 
may  be  hemolyzed  in  vitro  by  cooling  and  subsequently  heating  it. 

LEUCOCYTES 

There  are  a  number  of  varieties  of  white  cells  in  the  blood.  These  are 
differentiated  from  one  another  by  their  shape,  staining  properties,  and 
the  granules  in  their  protoplasm.  We  may  divide  them  into  two  main 
groups — nongranular  mononuclear  cells  and  granular  polynuclear  cells. 

The  nongranular  mononuclear  cells  are  termed  lymphocytes.  Two  va- 
rieties are  differentiated,  the  small  and  the  large. 

The  small  mononuclear  leucocyte  makes  up  from  23  to  28  per  cent 
of  the  total  leucocytes  and  the  large  mononuclear,  from  2  to  4  per  cent. 

The  polynuclear  leucocytes  are  divided  into  three  groups  according 
to  whether  their  granules  stain  with  basic,  neutral  or  acid  stains.  The 
leucocytes  that  stain  with  basic  dyes,  or  the  basophile  cells,  are  very 
few,  making  up  less  than  one  per  cent  of  the  total  count.  Likewise  the 
acid-staining  granular  cells,  acidophile,  are  few,  comprising  from  2  to 
4  per  cent  of  the  total  count.  The  most  numerous  are  the  neutrophiles, 


98  THE    BLOOD    AND    THE    LYMPH 

or  the  polynuclear  leucocytes,  with  neutral-staining  granules.  These 
comprise  from  65  to  75  per  cent  of  the  total  count. 

Another  type  of  white  cell  is  known  as  the  transitional  cell,  because 
it  was  supposed  to  represent  an  intermediate  form  between  the  mono- 
and  polynuclear  cells.  Probably  such  transitions  do  not  occur,  and  the 
transitional  leucocyte  is  related  to  the  mononuclear  cells. 

The  polynuclear  cells  originate  in  the  bone  marrow,  and  for  this 
reason  have  been  termed  myeloid  cells.  They  develop  from  cells  in 
the  bone  marrow  termed  myeloblasts,  which  are  nongranular  and  con- 
tain a  large  nucleus.  In  the  course  of  development  the  characteristic 
granules  appear,  and  the  nucleus  remains  round  and  later  becomes 
lobulated.  These  intermediate  forms  are  called  myelocytes.  The  mono- 
nuclear  cells  originate  in  the  lymphatic  tissues  of  the  body. 

The  leucocytes  possess  the  ability  to  make  ameboid  movement  and 
to  ingest  foreign  particles  which  may  be  presented  to  them.  On  ac- 
count of  this  latter  ability  they  are  commonly  called  phagocytes.  In 
the  process  of  inflammation  the  leucocytes  assemble  at  the  spot  which 
is  the  seat  of  the  injury  or  infection,  and  remove  the  foreign  organism 
or  necrotic  tissue  by  ingesting  and  digesting  it. 

It  is  not  definitely  known  whether  or  not  the  lymphocytes  func- 
tion as  phagocytes.  Other  functions  besides  those  as  phagocytes  have 
been  ascribed  to  the  white  cells,  but  they  are  not  universally  ac- 
cepted. The  number  of  leucocytes  in  the  blood  is  subject  to  con- 
siderable variation.  They  normally  number  between  6,000  and  8,000 
per  c.mm.  At  the  height  of  digestion  and  after  strenuous  exercise 
there  is  usually  a  small  increase,  and  under  pathological  conditions, 
especially  in  infectious  diseases,  this  becomes  quite  marke'd.  Some 
infections  increase  the  polymorphonuclear  cells,  while  others  add  to 
the  lymphocytes.  The  factors  governing  the  type  of  increase  are  not 
fully  known,  nor  are  the  functions  of  the  various  forms  differentiated. 

The  Blood  Platelets 

These  are  small  oval  particles  about  3  /x  in  diameter,  which  are  found 
in  large  numbers  (250,000  to  the  c.mm.)  in  the  blood.  They  are  sup- 
posed to  be  formed  from  particles  of  protoplasm  which  are  pinched 
off  from  the  large  blood  cells  in  the  bone  marrow.  Their  biological 
and  chemical  properties  are  not  understood.  They  probably  play  a 
very  important  role  in  the  coagulation  of  the  blood  (see  page  104). 


CHAPTER  XII 
BLOOD:   BLOOD   CLOTTING 

On  leaving  the  blood  vessels,  the  blood  clots  so  as  to  form  a  plug, 
which  assists  in  preventing  further  hemorrhage.  The  clotting  must 
therefore  be  considered  as  a  protective  mechanism  against  excessive 
draining  of  blood  out  of  the  organism.  When  the  wounded  vessels 
are  small,  the  clotting,  along  with  constriction  of  the  damaged  vessels 
and  the  formation  in  them  of  thrombi  containing  large  numbers  of 
platelets,  serves  to  effect  complete  stoppage  of  the  hemorrhage  even 
though  the  blood  pressure  may  not  have  become  materially  reduced. 
The  greater  loss  of  blood  from  larger  vessels  causes  the  arterial  pressure 
to  fall,  and  this  enables  the  clot  to  stiffen  and  seal  the  wound  before 
the  pressure  again  rises.  When  the  clotting  power  of  the  blood  is 
subnormal,  life  is  endangered  by  even  trivial  wounds;  under  these 
conditions  the  smallest  surface  scratch  may  continue  to  bleed  exces- 
sively in  spite  of  whatever  local  treatment  is  applied.  The  most  ex- 
treme degree  of  this  condition  occurs  in  hemophilia,  a  disease  which 
is  characterized  by  a  most  interesting  family  history — namely,  that 
although  it  affects  as  a  rule  only  certain  of  the  male  members  of  a  family, 
yet  it  is  transmitted  from  generation  to  generation  by  the  female  side 
alone.  The  disease  has  existed  in  certain  of  the  royal  families  of 
Europe  for  many  generations,  which  has  made  it  possible  by  con- 
sulting the  genealogical  trees  to  demonstrate  the  infallibility  of  this 
law  of  inheritance. 

The  clotting  of  the  blood  is  also  either  depressed  or  increased  in  a 
variety  of  physiological  and  pathological  conditions.  We  shall,  however, 
defer  further  consideration  of  these  until  we  have  learned  something 
of  the  nature  of  the  factors  which  are  responsible  for  the  process  itself. 

The  Visible  Changes  in  the  Blood  During  Clotting 

In  a  few  minutes  after  it  leaves  the  blood  vessels,  the  blood  forms  a 
jelly-like  clot,  which  adheres  to  the  walls  of  the  container  in  which  the 
blood  is  collected  and  soon  becomes  so  solid  that  the  vessel  may  be 
inverted  without  spilling  any  of  the  blood.  Clotting  is  now  said  to  be 
complete.  The  clot  soon  begins  to  contract,  and  as  it  does  so,  drops  of 
clear  fluid  or  serum  become  expressed  and  float  on  the  surface  of  the 

99 


100  THE   BLOOD    AND    THE   LYMPH 

clot  or  collect  between  it  and  the  walls  of  the  container,  so  that  after 
some  time  the  clot  breaks  away  from  the  container  and  comes  to  float 
in  the  serum.  The  latter  may  be  perfectly  clear,  but  usually  is  more  or 
less  opalescent,  partly  because  of  the  presence  of  fat,  and  partly  be- 
cause of  leucocytes  which  have  migrated  out  of  the  clot  on  account  of 
their  power  of  diapedesis. 

If  a  drop  of  freshly  shed  blood  is  examined  under  the  microscope,  it 
will  be  observed  that  the  first  step  in  clotting  consists  in  the  formation 
of  fine  threads  radiating  from  foci,  which  are  undoubtedly  the  blood 
platelets.  The  fine  threads  are  called  fibrin.  They  multiply  rapidly, 
so  as  to  form  an  interlacing  meshwork  which  entangles  the  red  blood 
corpuscles  and  leucocytes.  By  the  use  of  the  ultramicros,cope  (page  52), 
Howell1  and  others  have  observed  that  the  fibrin  (produced  by  adding 
thrombin  to  oxalated  plasma)  is  really  deposited  in  the  form  of  fine 
crystalline  needles — "fibrin  needles" — which  become  packed  together 
as  they  increase  rapidly  in  numbers.  Although  the  process  of  clotting 
consists  therefore  in  the  conversion  of  a  hydrosol  into  a  hydrogel  (see 
page  61),  it  is  a  unique  process;  a  solution  of  the  blood  protein  which 
is  responsible  for  the  formation  of  the  fibrin  (fibrinogen)  may,  like  other 
colloidal  solutions,  be  precipitated  in  a  variety  of  ways,  but  it  is  only 
when  the  conditions  are  favorable  for  blood  clotting  that  fibrin  needles, 
and  therefore  fibrin  threads,  are  formed.  The  blood  of  invertebrates 
forms  a  structureless  gel  when  it  clots  (Howell). 

Methods  of  Retarding  Clotting  of  Drawn  Blood 

To  understand  the  nature  of  the  clotting  process  and  the  factors  that 
are  responsible  for  its  occurrence,  it  is  advantageous  to  simplify  the 
conditions  somewhat  by  getting  rid  of  the  red  corpuscles  and  most  of 
the  other  formed  elements  of  the  blood  and  then  using  the  fluid  in 
which  these  are  suspended  in  living  blood — namely,  the  plasma.  This 
separation  of  blood  into  corpuscles  and  plasma  is  readily  effected  either 
by  sedimentation  or  by  centrifuging  after  measures  have  been  taken  to 
inhibit  or  greatly  delay  the  clotting  process.  The  methods  used  for  this 
purpose  are  numerous.  A  few  of  the  most  important  are  as  follows: 
(1)  Keeping  the  blood  at  a  temperature  very  slightly  above  freezing 
point.  This  method  is,  however,  not  very  effective  unless  the  blood  is 
immediately  received  into  narrow  vessels  placed  in  ice  and  the  tempera- 
ture kept  most  strictly  at  the  low  level.  In  the  case  of  horses'  blood  and 
other  slowly  clotting  bloods,  the  method  succeeds  without  these  precau- 
tions. (2)  Receiving  the  blood  through  a  strictly  clean  and  smooth  can- 
nula,  coated  with  a  layer  of  paraffin  or  vaseline,  into  a  vessel  similarly 
coated.  This  method  is  of  practical  importance  when  it  is  necessary  to 


BLOOD    CLOTTING  101 

transfuse  blood  without  making  a  vessel-to-vessel  anastomosis.  (3)  Mix- 
ing the  blood  with  chemicals  that  are  capable  of  removing  the  calcium 
from  solution.  Such  reagents  are  potassium  or  sodium  oxalate  (in  a  con- 
centration of  0.1  per  cent  after  mixing),  and  sodium  fluoride  and  sodium 
citrate  (2  per  cent  solution,  with  one  part  of  the  solution  to  four  parts 
of  blood).  (4)  Mixing  the  blood  with  certain  neutral  salts,  particularly 
the  sulphates  of  sodium  and  magnesium  (one  part  of  27  per  cent  solution 
of  magnesium  sulphate  mixed  with  four  parts  of  blood).  Blood  thus 
treated  is  known  as  " salted  blood,"  and  the  plasma  separated  by  centri- 
fuging,  as  "salted  plasma/'  Clotting  is  readily  induced  by  adding  water 
to  the  salted  blood  or  plasma,  and  in  this  way  diminishing  the  concen- 
tration of  the  salts.  (5)  The  addition  to  blood  of  one  of  a  class  of  sub- 
stances known  as  antithrombins.  Leech  extract  or  the  purified  substance 
separated  from  it,  known  under  the  trade  name  of  "hirudin,"  and  sub- 
stances present  in  blood  removed  from  animals  after  they  have  been 
injected  with  peptone  solutions,  are  examples. 

The  methods  which  have  just  been  described  are  those  applied  to  blood 
after  it  has  left  the  blood  vessels.  Another  interesting  group  of  anti- 
coagulants prevent  clotting  only  when  injected  Mo  the  blood  vessels  of 
the  living  animal.  The  most  powerful  example  of  this  group  is  snake 
venom,  certain  varieties  of  which  can  prevent  clotting  in  the  dosage  of 
%oo  of  a  milligram  for  each  kilogram  of  body  weight.  Similar  but  much 
less  potent  effects  are  produced  by  the  injection  of  several  proteolytic 
enzymes,  but  most  attention  has  been  paid  to  the  effect  of  commercial 
peptone  injected  in  solution  intravenously  in  the  proportion  of  0.3  gram 
to  each  kilogram  of  body  weight.  Blood  subsequently  removed  up  to  about 
half  an  hour  or  more  does  not  clot,  and  as  we  have  already  seen,  if  added 
to  blood  from  another  animal,  materially  retards  clotting.  This  group  of 
intra  vitam  anticoagulants  is  particularly  interesting,  since  none  of  the 
substances  belonging  to  it  is  capable  of  preventing  clotting  of  blood 
when  mixed  with  this  after  it  has  been  shed.  Their  action  therefore 
obviously  depends  on  the  production  of  some  substance  in  the  body, 
probably,  as  we  shall  see  later,  in  the  liver,  since  they  fail  to  act  after 
the  removal  of  this  organ  from  the  circulation  (see  page  111). 

The  time  of  clotting  varies  greatly  according  to  the  conditions  under 
which  the  blood  is  collected  and  the  animal  from  which  it  is  derived. 
Human  blood,  for  example,  received  into  a  test  tube  from  a  puncture 
through  the  skin  may  clot  at  any  time  within  three  or  ten  minutes,  five 
minutes  being  taken  as  an  average  time  for  blood  kept  at  a  temperature 
of  about  20°  C.  This  time  may  be  considerably  shortened  by  increasing 
the  extent  of  foreign  material  with  which  the  blood  comes  into  contact, 
and  more  particularly  by  whipping  the  blood  with  a  bunch  of  twigs  or 


102  THE   BLOOD   AND    THE   LYMPH 

wires.  In  this  latter  case,  however,  the  clot  does  not  form  in  the  usual 
manner,  but  the  fine  threads  of  fibrin  collect  on  the  twigs  or  wires,  leav- 
ing behind  the  blood  serum  with  the  corpuscles  still  suspended  in  it. 
The  fibrin  removed  in  this  way  may  then  be  washed  free  of  adherent 
serum.  The  serum  and  corpuscles  now  form  defibrinated  blood,  which 
is  used  for  many  physiological  purposes.  Clotting  is  also  greatly  acceler- 
ated by  allowing  the  blood  to  flow  over  exposed  tissues.  Something  is 
evidently  added  to  it  from  the  tissues  which  accelerates  the  clotting 
process,  this  influence  being  particularly  marked  in  the  case  of  blood 
of  the  lower  vertebrates.  When  the  blood  of  the  bird,  for  example,  is 
received  through  a  cannula  inserted  directly  into  a  vessel  with  as  little 
injury  to  the  walls  as  possible,  it  very  slowly  clots  if  at  all,  but  soon 
does  so  if  the  blood  is  allowed  to  come  into  contact  with  excoriated 
tissues,  or  if  it  is  mixed  with  tissue  extract,  such  as  that  of  muscle. 
Clotting  is  considerably  accelerated  by  warming  the  blood.  The  ap- 
plication of  a  cloth  or  tampon  well  wrung  out  with  hot  physiological' 
saline  to  a  wounded  surface  is  a  most  efficient  means  of  allaying  hem- 
orrhage from  vessels  too  small  to  ligate. 

The  Nature  of  the  Clotting  Process 

Plasma  obtained  by  centrifuging  blood  that  has  been  prevented  from 
clotting  by  one  of  the  foregoing  methods  can  be  made  to  clot  by  removing 
the  inhibiting  influence;  for  example,  in  cooled  plasma  by  warming  the 
blood  to  room  temperature,  in  salted  plasma  by  diluting  it  with  at  least 
an  equal  volume  of  water,  and  in  decalcified  plasma  by  adding  a  suffi- 
cient amount  of  soluble  calcium  salts  to  combine  with  all  the  added 
oxalate  and  leave  a  small  trace  of  calcium  salts  in  excess. 

The  first  question  concerns  the  source  of  the  fibrin,  and  the  answer  to 
it  is  furnished  by  comparing  the  composition  of  bood  plasma  with  that 
of  serum.  Though  both  of  these  fluids  contain  the  proteins,  albumin 
and  globulin,  in  approximately  the  same  concentrations,  the  plasma  also 
contains  another  protein  not  unlike  globulin  in  most  of  its  reactions, 
but  distinguished  from  typical  globulin  in  that  it  is  precipitated  by 
half-saturation  with  sodium  chloride,  in  which  typical  globulin  is  solu- 
ble, and  is  more  readily  coagulated  by  heat.  To  produce  half-saturation 
of  the  plasma  with  sodium  chloride,  equal  volumes  of  plasma  and  satu- 
rated sodium-chloride  solution  are  mixed  together.  The  precipitate  of 
fibrinogen,  as  the  substance  is  called,  is  then  collected  at  the  bottom  of 
the  tube  by  centrifuging  and  is  washed  several  times  by  decantation  with 
half-saturated  sodium-chloride  solution.  The  washed  precipitate,  dis- 
solved in  weak  saline  solution  (preferably  containing  a  trace  of  bicar- 
bonate), will  then  be  found  to  clot  under  certain  conditions. 


BLOOD    CLOTTING  103 

The  next  question  concerns  the  nature  of  the  conditions  that  cause  the 
fibrinogen  to  clot.  When  a  fibrinogen  solution  is  mixed  with  a  few  drops 
of  blood  serum,  a  clot  usually  forms,  which  however  is  not  the  case  when 
plasma  is  added  or  when  the  serum  is  heated  before  adding  it.  Because 
a  small  quantity  of  serum  is  capable  of  causing  the  clotting  of  a  large 
quantity  of  fibrinogen  solution  or  plasma,  it  is  supposed  that  the  active 
substance  present  in  it  is  of  the  nature  of  a  ferment — fibrin  ferment  or 
tKrombin.  It  must  be  pointed  out,  however,  that  there  is  considerable 
doubt  whether  this  active  body  is  really  of  the  nature  of  a  ferment  or 
enzyme.  For  example,  although  heated  serum  does  not  cause  clotting, 
thrombin,  prepared  from  serum  by  the  method  about  to  be  described,  in 
the  absence  of  inorganic  salts  can  withstand  even  a  boiling  temperature. 
Moreover,  true  enzymes  are  characterized  by  the  fact  that,  like  other 
catalytic  agents,  a  very  minute  quantity  can  effect  a  change  in  an  indef- 
inite amount  of  substance  without  the  enzyme  becoming  used  up  in  the 
process  (page  72).  When  thrombin  is  allowed  to  act  upon  a  fibrinogen 
solution,  on  the  other  hand,  it  is  said  that  only  a  fixed  amount  of  fibrin 
can  be  formed  when  a  small  amount  of  thrombin  is  added.  Neither  does 
this  amount  increase  when  the  time  of  reaction  is  prolonged. 

Whatever  may  be  the  significance  of  the  foregoing  facts,  it  is  impor- 
tant to  know  that  the  clotting  substance,  thrombin,  can  be  isolated  from 
blood  serum  in  a  tolerably  pure  condition.  For  this  purpose  blood 
serum  is  allowed  to  stand  under  a  large  volume  of  alcohol  for  a  week  or 
two ;  the  precipitate  is  then  collected  and  rubbed  up  with  water,  which 
extracts  the  thrombin  from  it,  leaving  the  serum  protein  in  a  coagulated 
state.  The  resulting  watery  solution  of  thrombin  may  be  further  pre- 
cipitated by  alcohol,  the  precipitate  washed  in  alcohol  and  redissolved 
in  water,  yielding  ultimately  a  solution  which  exhibits  very  marked  co- 
agulating powers  when  added  to  plasma  or  fibrinogen  solution.  Throm- 
bin shows  most  of  the  protein  reactions  but  it  is  not  coagulated  by  heat. 
As  would  be  expected,  a  considerable  quantity  of  thrombin  remains 
adherent  to  the  fibrin  formed  in  the  process  of  clotting,  and  Howell8 
describes  a  very  useful  method  by  which  it  can  be  separated  from  fibrin 
and  preserved  in  a  dry  condition.  Briefly  stated,  this  method  consists 
in  allowing  washed  fibrin  to  stand  overnight  under  eight  per  cent 
sodium-chloride  solution,  which  dissolves  the  thrombin.  The  resulting 
extract  is  then  mixed  with  an  equal  volume  of  acetone,  which  throws 
down  a  precipitate  containing  the  thrombin.  To  preserve  it,  the  precip- 
itate is  collected  on  a  number  of  small  filter  papers,  which  are  subse- 
quently opened  out  and  dried  by  exposure  to  a  current  of  cold  air  before 
an  electric  fan.  When  the  thrombin  solutions  are  desired,  the  dried  pre- 
cipitates are  extracted  with  a  little  water. 


104  THE    BLOOD    AND    THE    LYMPH 

Thrombin  does  not  exist  in  blood  plasma,  for  if  a  clean  and  paraffined 
glass  tube  is  inserted  into  an  artery  and  the  blood  collected  under  al- 
cohol, the  precipitate  after  standing  a  few  weeks  will  yield  no  thrombin 
when  triturated  with  water.  Quite  clearly,  therefore,  the  thrombin  is 
produced  at  the  time  the  blood  clots,  and  the  question  arises,  What  is 
it  produced. from?  It  will  be  remembered  that,  when  the  blood  is  ex- 
amined under  the  microscope  during  the  clotting  process,  the  fibrin 
threads  are  seen  to  start  from  foci  which  correspond  to  the  blood  plate- 
lets. It  would  appear  therefore  that  the  thrombin  must  be  derived  from 
some  substance  that  is  shed  forth  from  the  'platelets  during  the  disin- 
tegration which  they  undergo  shortly  after  the  blood  is  shed.  The  sub- 
stance is  called  prothrombin.  The  platelets  or  their  precursors,  the 
megacaryocytes  of  red  bone  marrow,  are  probably  not  its  only  source, 
for  clotting  may  occur  in  the  complete  absence  of  platelets,  when  it 
appears  to  come  from  the  leucocytes.  Prothrombin  appears  plentifully 
in  the  fluid  used  to  perfuse  red  bone  marrow  outside  the  body  (Drinker 
and  Drinker9). 

To  sum  up  what  we  have  so  far  learned,  it  may  be  stated  that  the 
process  of  clotting  starts  with  the  disintegration  of  blood  platelets  and 
probably  of  leucocytes,  as  a  result  of  which  there  is  shed  forth  into  the 
plasma  a  substance  called  prothrombin,  which  immediately  afterward 
becomes  activated  or  converted  into  thrombin.  The  thrombin  then  at- 
tacks a  protein  present  in  plasma  called  fibrinogen,  producing  from  it  in 
thread-like  form  the  insoluble  protein,  fibrin.  But  this  does  not  com- 
plete the  history,  for  at  least  two  other  important  factors  come  into 
play ;  the  one  is  the  presence  of  soluble  calcium  salts,  and  the  other  that 
of  peculiar  substances  derived  from  the  tissues  outside  the  blood  vessels 
and  called  thromboplastic  substances  or  thromboplastin  (Howell).  We 
must  now  consider  the  action  of  these  two  factors. 

The  Influence  of  Calcium  Salts. — As  already  explained,  the  proof  that 
soluble  calcium  salts  are  necessary  for  clotting  is  furnished  by  the  ob- 
servation that  the  process  is  entirely  prevented  when  the  freshly  drawn 
blood  is  mixed  with  soluble  oxalate.  To  this  proof,  however,  objection 
might  be  made  on  the  score  that  the  oxalate  per  se  inhibited  the  clotting. 
That  such  is  not  the  case  is  indicated  by  the  fact  that,  if  the  oxalated 
blood  or  plasma  is  dialyzed  against  physiological  saline  solution  till  all 
the  soluble  oxalate  has  been  removed  from  it,  clotting  is  still  absent  but 
immediately  supervenes  if  some  soluble  calcium  salts  are  added.  The 
question  arises  as  to  how  the  calcium  ion  acts.  Two  possibilities  exist: 

(1)  that  it  is  concerned  in  the  conversion  of  fibrinogen  to  fibrin,  and 

(2)  that  it  is  necessary  for  converting  prothrombin  into  thrombin.     It 
can  quite  readily  be  shown  that  it  is  by  the  second  of  these  processes 


BLOOD    CLOTTING  105 

that  the  calcium  acts ;  for  example,  clotting  occurs  when  purified  throm- 
bin  is  added  to  dialyzed  oxalate  blood  or  plasma  or  to  a  pure  solution  of 
fibrinogen.  Citrates  prevent  clotting  by  forming  calcium  citrate,  which 
although  soluble  does  not  ionize  in  solution.  It  is  the  free  calcium  ions 
that  are  important.  The  action  of  the  fluoride  is  somewhat  mysterious, 
for  it  has  been  found  that  to  produce  clotting  in  fluoride  plasma  the  sim- 
ple addition  of  calcium  chloride  will  not  suffice;  thrombin  itself  must  be 
added  as  well.  Some  authors  assert,  however,  that  if  the  calcium  chlo- 
ride is  added  cautiously  to  " fluoride"  blood,  it  will  induce  clotting 
(Rettger).  In  any  case  it  appears  that  the  fluoride  does  something  more 
than  precipitate  the  calcium;  possibly  it  prevents  the  breaking  up  of 
platelets  and  leucocytes. 

The  Influence  of  the  Tissues. — As  already  stated,  when  slowly  clotting 
blood,  like  that  of  a  bird,  is  collected  through  a  sterile  glass  tube  into  a 
thoroughly  clean  vessel  and  immediately  centrifuged,  the  plasma  will 
often  remain  indefinitely  unclotted.  If  an  extract  of  some  tissue,  such 
as  muscle,  is  added,  however,  the  plasma  immediately  clots.  To  a  much 
less  degree,  the  same  phenomenon  is  exhibited  by  mammalian  plasma 
when  it  is  collected  in  a  similar  manner.  From  these  observations  the 
conclusions  may  be  drawn  that  the  tissues  furnish  some  substance  as- 
sisting in  the  clotting  process,  and  that  this  substance  is  also  formed 
from  certain  elements  present  in  mammalian  but  not  present  in  avian 
blood.  The  absence  of  platelets  from  the  latter  blood  suggests  that 
these  must  be  the  source  of  the  activating  substance  in  mammalian  blood. 
It  is  plain  that  this  tissue  factor  in  clotting  is  of  importance  in  hasten- 
ing the  process  when  an  animal  is  wounded. 

Before  attempting  to  formulate  an  hypothesis  that  will  explain  the 
process  of  clotting,  it  is  necessary  to  call  attention  to  one  other  impor- 
tant fact.  This  refers  to  the  presence  in  blood  of  a  substance  that  pre- 
vents clotting  and  is  hence  called  antithrombin.  Antithrombin  is  pres- 
ent in  normal  blood,  for  a  given  specimen  of  pure  fibrinogen  will  clot 
less  rapidly  when  mixed  with  serum  to  which  some  oxalated  plasma  has 
been  added  than  with  an  equal  amount  of  the  same  serum  correspond- 
ingly diluted  with  a  solution  of  soluble  oxalate.  A  striking  increase 
in  the  concentration  of  antithrombin  in  blood  can  be  brought  about  by 
rapidly  injecting  a  solution  of  commercial  peptone  into  the  blood  ves- 
sels fifteen  to  thirty  minutes  before  bleeding.  The  peptonized  blood  or 
plasma  will  remain  fluid  for  many  hours,  if  not  indefinitely.  That  the 
failure  of  this  blood  to  clot  depends  on  the  presence  of  some  anticlotting 
substance,  and  not  upon  the  absence  of  one  of  the  necessary  clotting  sub- 
stances (fibrinogen,  thrombin,  etc.),  is  evidenced  by  the  fact  that  the 
addition  of  some  of  it  to  a  mixture  of  thrombin  and  fibrinogen  inhibits 


106  THE    BLOOD    AND    THE   LYMPH 

the  coagulation,  which  it  does  not  do,  however,  if  it  is  first  of  all  heated 
to  80°  C.  and  filtered  free  of  the  coagulated  protein.  Moreover,  the 
antagonistic  action  is  quantitative  in  the  sense  that  a  fixed  amount  of 
the  peptone-plasma  inhibits  the  action  of  a  fixed  amount  of  thrombin. 
The  source  of  antithrombin  in  the  body  appears  to  be  mainly  at  least 
the  liver,  for  it  has  been  found:  (1)  that  peptone  injection  into  an  animal 
from  which  the  liver  has  been  removed  does  not  cause  antithrombin  to 
be  formed  (Denney  and  Minot)  ;10  (2)  that  peptone  injections  into  the 
portal  vein  cause  antithrombin  to  appear  in  the  blood  much  more  rap- 
idly than  when  the  injection  is  made  into  a  systemic  vessel;  and  (3)  that, 
when  the  liver  is  perfused  outside  the  body  with  a  perfusion  fluid  con- 
taining peptone,  antithrombin  accumulates  in  the  perfusion  fluid. 

A  fluid  containing  a  high  concentration  of  antithrombin  is  secreted 
by  the  so-called  salivary  gland  at  the  head  end  of  the  leech.  The  func- 
tion of  the  fluid  is  to  prevent  clotting  of  the  blood,  so  that  the  animal 
may  continue  to  suck  it  without  interference  by  clotting.  After  apply- 
ing leeches  for  medicinal  purposes  it  is  therefore  necessary  to  wash  the 
wound  thoroughly  with  water  so  that  all  traces  of  the  antithrombin  may 
be  removed ;  otherwise  the  bleeding  may  continue  for  a  considerable  time. 
Practical  use  is  made  of  this  effect  of  the  leech  to  prevent  clotting  of  blood 
outside  the  body,  or  it  may  be  used  to  inhibit  coagulation  intra  vitam  in 
experiments  where  clotting  would  otherwise  interfere  with  their  prog- 
ress; for  example,  in  crossed  circulation  experiments  (page  384)  and  in 
experiments  in  vivid  diffusion  (page  641).  For  such  purposes  the  leech 
head  is  cut  off  and  extracted  either  with  saline  or  by  treatment  with 
chloroform,  which  removes  other  proteins  from  the  saline  solution  leav- 
ing a.  strong  antithrombin,  known  under  the  trade  name  of  "hirudin." 
At  temperatures  about  that  of  the  body  the  action  of  antithrombin  is 
greatly  augmented.  In  animals  like  the  mammals  in  which  the  content 
of  antithrombin  is  small,  this  may  be  important  in  maintaining  the  flu- 
idity of  the  blood  (Howell).  Blood  containing  antithrombin  can  be 
made  to  clot  by  the  addition  of  thrombin,  and  therefore  of  blood  serum. 


CHAPTER  XIII 
BLOOD:  BLOOD  CLOTTING  (Cont'd) 

THEORIES  OF  BLOOD  CLOTTING 

Attempts  to  link  all  the  foregoing  facts  together  in  the  form  of  a 
simple  theory  have  not  so  far  been  entirely  successful.  All  agree  that 
the  fibrin  is  derived  from  fibrinogen  by  the  action  of  thrombin,  the  points 
in  dispute  being  those  which  concern  the  origin  of  the  thrombin  and 
the  mode  of  action  of  the  calcium  and  thromboplastic  substances.  The 
theory  most  widely  accepted  in  Europe  is  that  of  Morawitz,  according 
to  which  the  thrombin  exists  in  living  blood  in  an  inactive  state1  called 
thrombogen  (prothrombin),  which  becomes  converted  into  thrombin  by 
the  simultaneous  action  on  it  of  soluble  calcium  salts  and  of  thrombo- 
plastic substances  furnished  by  the  tissue  cells  in  general  and  by  the 
cellular  elements  of  the  blood  platelets  and  leucocytes.  According  to 
this  view  the  thromboplastic  substance,  aided  by  the  presence  of  calcium 
ions,  converts  thrombogen  (prothrombin)  to  thrombin.  It  acts  there- 
fore as  a  kinase  and  is  called  thrombokinase.  The  fundamental  fact  of 
this  theory,  then,  is  that  kinase  is  necessary  for  the  union  of  the  cal- 
cium with  prothrombin — a  fact,  however,  which  is  challenged  by  Howell, 
who  states  that  prothrombin  may  be  converted  to  thrombin  by  the  action 
of  calcium  ions  alone.  This  investigator  believes  that  the  thrombo- 
plastic substance  acts  not  as  a  kinase  but  because  it  neutralizes  anti- 
thrombin,  which  is  constantly  present  in  the  blood,  and  the  function  of 
which  is  to  prevent  the  calcium  from  uniting  with  the  prothrombin  to 
form  thrombin.  HowelPs  theory  in  his  own  words  is  as  follows:  "In 
the  circulating  blood  we  find  as  constant  constituents  fibrinogen,  pro- 
thrombin, calcium  salts  and  antithrombin.  The  last  named  substance 
holds  the  prothrombin  in  combination  and  thus  prevents  its  conversion 
or  activation  to  thrombin.  When  the  blood  is  shed,  the  disintegration 
of  the  corpuscles  (platelets)  furnishes  material  (thromboplastin)  which 
combines  with  the  antithrombin  and"  at  the  same  time  liberates  more 
"prothrombin;  the  latter  is  then  activated  by  the  calcium  and  acts  on 
the  fibrinogen."  Antithrombin  can  also  prevent  the  action  of  thrombin 
on  fibrinogen.  As  already  pointed  out,  the  thromboplastin  can  be  de 
rived  from  the  blood  itself  in  the  mammals,  but  only  from  the  tissues 
in  the  lower  vertebrates.  It  is  interesting  to  note  that  the  thromboplastin 

107 


108  THE    BLOOD    AND    THE   LYMPH 

can  be  extracted  from  the  tissues  by  fat-solvents,  and  that  it  appears  to 
belong  to  the  class  of  phosphatids,  being  indeed  closely  related  to,  if 
not  identical  with,  kephalin  (Howell). 

Intravascular  Clotting 

The  practical  application  of  the  theory  of  blood  clotting  concerns  the 
manner  in  which  the  blood  is  maintained  in  a  fluid  condition  in  the  blood 
vessels,  and  the  disturbance  of  this  function  causing  intravascular  clot- 
ting. According  to  the  one  theory,  the  blood  is  maintained  fluid  by  the 
absence  from  it  of  any  considerable  quantity  of  kinase,  and  according 
to  the  other,  by  the  presence  in  it  of  an  amount  of  antithrombin  suffi- 
cient to  prevent  the  union  of  calcium  with  prothrombin.  The  fluidity 
is  maintained  even  when  large  amounts  of  thrombin  or  of  blood  serum, 
which  contains  this  substance,  are  injected  into  the  living  animal.  We 
can  best  explain  the  immunity  of  the  blood  to  the  action  of  thrombin  un- 
der these  circumstances  as  being  due  to  the  instantaneous  appearance  in  it 
of  antithrombin  in  amounts  sufficient  to  prevent  the  action  of  thrombin 
on  fibrinogen,  for,  as  stated  above,  it  is  claimed  by  Howell  that  anti- 
thrombin has  this  influence  as  well  as  that  of  preventing  the  conversion 
of  prothrombin  into  thrombin. 

Intravascular  clotting  may  be  brought  about  by  a  variety  of  means: 
(1)  Mechanical  damage  to  the  lining  of  the  blood  vessels;  after  the  ap- 
plication of  a  ligature,  for  example,  the  damaged  endothelium  is  soon 
covered  by  a  clot,  which  gradually  becomes  firmer  and  firmer,  and  may 
spread  up  the  vessel  to  the  next  branch.  (2)  The  presence  of  foreign 
substances  in  the  blood.  Emboli,  for  example,  are  apt  to  cause  clots 
to  form  at  the  places  where  they  stick,  namely,  in  the  smaller  vessels. 
Clotting  is  also  a  frequent  occurrence  when  there  are  local  dilatations  of 
the  cardiovascular  tube,  and  it  may  occur  under  imperfectly  understood 
conditions  causing  the  condition  known  as  thrombosis.  (3)  An  inter- 
esting variety  of  intravascular  clotting  is  that  caused  by  the  intrave- 
nous injection  of  saline  extracts  of  cell-rich  tissues,  such  as  the  thymus, 
lymph  glands  or  testes  (Wooldridge).  By  precipitation  with  acetic 
acid  and  digestion  with  peptone,  a  residue'  can  be  obtained  from  these 
extracts  which,  when  dissol'/ed  in  alkali,  has  a  very  pronounced  intra- 
vascular clotting  effect.  Since  these  precipitates  are  very  rich  in  phos- 
phorus, it  is  probable  that  they  are  of  the  nature  of  phosphoprotein 
(nucleoalbumin) .  Their  action  must  depend  on  neutralization  of  anti- 
thrombin, according  to  Howell's  theory,  or  because  they  serve  as  throm- 
bokinases  (according  to  Morawitz'  theory). 

As  a  matter  of  fact,  however,  the  foregoing  observation  is  not  com- 
pletely explained  by  either  theory.  If  in  place  of  making  one  injection 


BLOOD    CLOTTING  109 

frequent  injections  of  small  amounts  of  the  above  material  are  made, 
instead  of  intravascular  clotting,  a  delay  in  the  coagulation  time  is 
likely  to  occur.  Indeed,  repeated  injections  of  small  amounts  may  en- 
tirely remove  the  clotting  power  of  the  blood.  The  readiness  with  which 
this  so-called  "negative  phase"  appears,  seems  to  depend  on  the  nutri- 
tive condition  of  the  animal  at  the  time  of  injection.  If  a  large  dose  is 
injected  into  a  fasting  dog,  for  example,  thrombosis  is  confined  to  the 
portal  area,  whereas  if  it  is  injected  into  a  recently  fed  animal,  the 
thrombosis  is  universal  throughout  the  vascular  system.  The  develop- 
ment of  the  negative  phase  is  undoubtedly  dependent  upon  some  reac- 
tion on  the  part  of  the  living  cells  of  the  organism,  since  it  does  not  occur 
on  the  addition  of  similar  substances  to  blood  outside  the  body.  The 
reaction  is,  indeed,  akin  to  that  by  which  immune  bodies  in  general  are 
produced.  For  example,  a  toxin  injected  in  large  amount  has  a  cer- 
tain toxic  effect,  but  in  repeated  small  doses  with  intervening  intervals 
it  leads  to  the  production  of  an  antitoxin.  So  with  the  substance  in 
question;  a  large  dose  injected  at  one  time  causes  a  positive  effect — clot- 
ting— but  smaller  doses  frequently  injected,  the  opposite  effect — want  of 
clotting.  It  is  probable,  as  suggested  by  Starling,  that  more  intensive 
study  of  the  conditions  causing  intravascular  clotting  will  throw  con- 
siderable light  on  the  general  question  of  the  production  of  immunity. 

Measurement  of  the  Clotting  Time 

To  measiire  the  clotting  ti/me  of  drawn  samples  of  blood,  several  conditions  must 
be  observed.     These  have  been  tabulated  by  Addis1*  as  follows: 

1.  The  specimens  of  blood  must  always  be  obtained  by  exactly  the  same  technic.     It 
would  introduce  serious  errors  to  compare  the  clotting  time  of  one  specimen  of  blood 
received  from  an  incision  of  the  skin   (ear  lobe)   with  that  of  another  collected  in  a 
syringe  by  venipuncture. 

2.  The  temperature  conditions  must  always  be  the  same.     Probably  25  °C.  is  the  best 
temperature  to  use.     Higher   temperatures  are  unsuitable   for   two  reasons:    first,   be- 
cause during  its  collection  the  blood  will  have  become  cooled  to  about  or  below  this 
point,  and  time  would  be  consumed  in  raising  it  higher;  and  second,  because  the  time 
of  coagulation  is  more  and  more  shortened  for  each  degree  that  the  temperature  is 
raised,  this  acceleration  becoming  especially  pronounced  for  temperatures  above  25 °C. 
Quite   apart   from   the  liability   to   incur   errors  incident   to   measurement   of   shorter 
periods  of  time,  observations  at  higher  temperatures  necessitate  most  rigorous  adher- 
ence to  a  fixed  temperature  of  the  water-bath.     Temperatures  much  below  25  °C.  are 
unsuitable,  because  the  clotting  sets  in  gradually  and  it  is  difficult  to  tell  precisely 
when  it  occurs. 

3.  The  blood  must  always  be  collected  in  the  same  sort  of  vessel  and  come  in  con- 
tact with  the  same  kind  and  amount  of  foreign  material.     To  this  it  may  be  added 
that  the  receiving  vessel  must  be  scrupulously  clean;  any  trace  of  old  blood  clot  or  of 
serum  is  especially  to  be  guarded  against. 

4.  The  end  point  must  be  sharp.     It  is  here  that  the  greatest  technical  difficulties 
are   met  with  in  making  precise   measurements,   and  it   is   greatly  to  be   desired  that 


110 


THE    BLOOD    AND    THE   LYMPH 


different  investigators  should  adopt  some  uniform  method.  For  experimental  pur- 
poses the  method  of  Cannon  and  Mendenhallis  is  no  doubt  the  best,  and  it  has  the 
added  advantage  of  giving  a  graphic  record  of  the  observations.  The  accompanying 
figure  (Fig.  19)  shows  the  principle  of  the  method.  The  blood  is  received  through  a 
standard  cannula  (C)  into  a  tube  (T)  5  cm.  long  and  of  5  mm.  internal  diameter; 
and  a  loop  (of  2  mm.  diameter)  at  the  end  of  a  copper  wire  (D),  which  is  8  cm.  long 
and  0.6  mm.  in  diameter,  is  allowed  to  fall  gently  into  the  blood  at  regular  intervals. 
The  upper  end  of  the  wire  is  articulated  with  the  short  arm  of  a  light  lever  so  counter- 
poised that  when  the  stop  (.K),  which  ordinarily  holds  it  in  a  horizontal  position,  is 
released,  the  wire,  now  having  a  net  weight  of  30  mg.,  falls  on  the  blood  in  the  tube. 


Fig.  19. — Diagram  of  the  graphic  coagulometer.  The  cannula  at  the  right  rested  in  a  water 
bath  not  shown  in  this  diagram.  For  further  description  see  text.  (From  Cannon  and  Men- 
denhall.)* 

The  long  arm  of  the  lever  is  provided  with  a  writing  point,  which  is  made  to  inscribe 
its  movements  on  a  drum.  So  long  as  the  blood  is  unclotted  the  loop  sinks  into  it  when 
the  lever  is  released  and  a  vertical  line  is  traced,  but  whenever  clotting  occurs  the 
loop  sticks  on  the  blood  and  the  writing  point  does  not  rise. 

For  clinical  purposes  where  blood  collected  in  a  syringe  by  venipuncture  is  used,  the 
method  of  Howell13  is  most  accurate.  It  consists  in  placing  2  or  4  c.c.  of  the  blood  in 
a  wide  tube  (of  21  mm.  diameter)  that  has  been  cleaned  by  a  bichromate- acid  mixture. 
The  period  that  elapses  between  the  moment  of  the  entry  of  fluid  into  the  syringe  and 


Fig.  20. — Coagulometer.  The  drop  of  blood  is  placed  on  the  upper  end  of  the  glass  cone  and 
the  air  stream  is  directed  against  it  from  the  side  tube  shown  by  the  black  dot.  The  apparatus 
is  placed  on  the  stage  of  the  microscope  and  the  drop  observed  by  the  low  power. 

that  at  which  the  clot  has  become  firm  enough  so  that  the  tube  can  be  inverted  without 
spilling  any  blood,  is  taken  as  the  clotting  time.  Since  the  blood  does  not  come  in 
contact  with  exposed  tissues,  it  takes  from  20  to  60  minutes  to  clot  by  this  method. 

For  routine  clinical  examination  of  blood  taken  from  a  skin  wound  Brodie  and 
Kussel's  method**  is  most  satisfactory.  This  consists,  in  principle,  in  observing  a  drop 
of  blood,  under  the  low  power  of  the  microscope,  while  a  fine  current  of  air  is  gently 
blown  against  it  at  regular  intervals  in  a  tangential  direction.  Until  clotting  sets  in, 


*Am.    Jour.    Physiol.,    May    1,    1914,    xxxiv,    No.    2. 


BLOOD    CLOTTING  111 

the  individual  corpuscles  move  freely  in  a  circular  direction,  but  as  soon  as  clotting 
begins  they  move  in  masses  which  soon  tend  to  become  fixed  so  that,  although  they 
move  somewhat  when  the  air  impinges  on  them,  they  immediately  return  to  their 
original  position  when  the  current  is  discontinued.  When  clotting  is  complete,  the  air 
current  merely  presses  on  the  corpuscles  at  one  point.  By  this  method  the  clotting 
time  averages  five  minutes.  A  convenient  apparatus  for  this  method  is  that  of  Boggs, 
which  is  shown  in  Fig.  20.  It  consists  of  a  truncated  cone  of  glass,  projecting  into  a 
moist  chamber  provided  with  a  tube  on  the  side  so  arranged  that  when  air  is  blown  into 
the  chamber,  it  strikes  the  drop  of  blood  placed  on  the  end  of  the  cone  tangentially. 

Blood  Clotting  in  Certain  Physiological  Conditions 

Besides  the  experimental  conditions  already  enumerated  as  changing 
the  clotting  time  in  the  blood  of  laboratory  animals,  special  mention 
must  be  made  of  the  influence  of  epinephrine  injections,  of  conditions 
supposed  to  cause  a  hypersecretion  of  this  hormone,  of  the  emotions, 
and  of  hemorrhage. 

Epinephrine  added  to  drawn  blood  does  not  affect  the  clotting  time, 
but  if  small  amounts  are  injected  intravenously  or  even  subcutaneously, 
a  marked  decrease  occurs  (Cannon  and  Gray;  cf.  Cannon,  loc.  cit.). 
Larger  injections  may  have  the  opposite  effect,  and  intermediate  amounts 
may  cause  at  first  a  prolongation  and  later  a  shortening  of  the  time. 
These  results  with  larger  doses  are  related  to  Howell's  observation  that 
repeated  doses  of  relatively  large  amounts  of  epinephrine  in  dogs  may 
so  greatly  retard  coagulation  as  to  make  the  animals  practically  hemo- 
philic.  It  was  further  found  by  Cannon  and  his  co-workers  that  epineph- 
rine does  not  influence  the  clotting  time  when  injected  into  animals 
from  which  the  abdominal  viscera  have  been  removed  from  the  circulation 
by  ligation  of  the  inferior  vena  cava  and  the  abdominal  aorta.  In  the  light 
of  the  influence  which  destruction  of  liver  cells  (by  phosphorus,  chloro- 
form, etc.)  is  known  to  have  in  lengthening  clotting  time,  it  would  seem 
reasonable  to  conclude  that  it  must  be  through  this  organ  that  epineph- 
rine develops  its  clotting  effects. 

Stimulation  of  the  splanchnic  nerves  also  shortens  the  clotting  time, 
and  it  would  appear  that  this  action  depends  on  the  resulting  hyperse- 
cretion of  epinephrine  (page  787),  for  it  is  not  observed  following  stimula- 
tion of  the  nerves  in  animals  from  which  the  adrenal  glands  have  been 
excised  (Cannon  and  Mendenhall).  The  interesting  suggestion  is  made 
by  Cannon  that  the  shorter  clotting  time  observed  in  animals  showing 
strong  emotions  of  fright  or  fear  may  also  be  due  to  the  hypersecretion 
of  epinephrine  which  this  worker  believes  accompanies  such  states. 

Blood  Clotting  in  Disease 

With  the  factors  concerned  in  the  process  so  wrapped  in  mystery,  it  is 
not  surprising  that  the  underlying  causes  responsible  for  delayed  or  de- 


112  THE   BLOOD    AND    THE   LYMPH 

ficient  clotting  of  blood  in  diseased  conditions  or  for  the  formation  of 
intravascular  clots  (thrombi)  are  little  understood.  According  to  How- 
ell's  theory  of  the  nature  of  the  process,  which  is  the  most  satisfactory  at 
the  present  time,  abnormal  clotting  might  be  due  to  the  following 
causes:  (1)  A  diminished  amount  of  fibrinogen.  This  occurs  when  the 
hepatic  cells  are  greatly  damaged,  as  in  poisoning  by  chloroform  or 
phosphorus  and  in  such  diseases  as  acute  yellow  atrophy  and  yellow 
fever.  In  many  cases  of  chronic  cirrhosis  of  the  liver,  as  Whipple,  etc.,15 
have  shown,  the  blood  also  clots  feebly  because  of  deficient  fibrinogen. 
It  should  be  pointed  out  that  it  is  not  so  much  the  clotting  time  that  is 
increased  in  such  cases,  as  the  firmness  or  consistency  of  the  clot  that 
is  affected. 

2.  A  deficiency  in  prothrombin.     In  the  condition  known  as  "melena 
neonatorum,"  undoubted  benefit  is  derived  from  intravenous  injections 
of  blood  serum  or  by  direct  blood  transfusions,  probably  because  throm- 
bin  or  prothrombin  is  thus  furnished. 

3.  A  deficiency  of  thromboplastin.    Since  this  substance  is  derived  from 
both  blood  cells  and  tissue  cells,  it  does  not  seem  likely  that  a  deficiency 
could  ever  occur.    Certain  observers,  however — Morawitz,  for  example — 
lay  great  stress  on  this  as  an  important  factor  in  hemorrhagic  diseases. 

4.  An  excess  of  antithrombin.    The  undoubted  increase  in  this  substance 
that  can  be  brought  about  experimentally  by  injecting  hirudin  or  pep- 
tone into  animals,  has  stimulated  careful  search  for  a  similar  increase  in 
the  blood  in  clinical  conditions  in  which  abnormal  blood  clotting  is  one 
of  the  symptoms  (Whipple16).    Antithrombin  is  said  to  be  increased  in 
septicemia,  pneumonia,  miliary  tuberculosis,  etc. 

5.  A  deficiency  of  calcium  ions.    Although  at  one  time  it  was  supposed 
that  this  might  be  responsible  for  the  feeble  clotting  in  hemophilia,  it 
has  not  been  found,  after  very  extensive  trials,  that  the  exhibition  of 
Ca  salts  in  any  way  relieves  the  condition.    It  is  said,  however,  that  the 
slow  coagulation  seen  in  obstructive  jaundice  is  decidedly  shortened  by 
treatment  with  calcium  salts. 

One  thing  stands  out  prominently  in  connection  with  the  whole  problem, 
and  that  is  the  close  relationship  of  the  blood  platelets  to  the  clotting 
process.  From  these  cells  are  derived,  according  to  Howell,  not  only  the 
prothrombin  but  also,  as  from  other  cells,  thromboplastin.  It  is  not  sur- 
prising therefore  to  find  that  decided  alterations  in  the  platelet  count 
occur  in  cases  of  faulty  blood  clotting,  and  that  local  accumulations  of 
these  elements  within  the  blood  vessels,  produced  by  their  clumping  to- 
gether or  agglutinating,  is  followed  by  a  formation  of  local  clots,  as  in 
thrombosis. 


BLOOD   CLOTTING  113 

Hemorrhagic  Diseases 

In  many  of  the  so-called  hemorrhagic  diseases  (acute  leucemia  and 
aplastic  anemia)  and  in  the  hemorrhagic  varieties  of  diphtheria  and 
smallpox,  the  platelet  count  drops  from  its  normal  of  between  200,000 
and  800,000  per  cubic  millimeter  to  well  below  100,000,  and  indeed  in 
these  conditions  it  is  frequently  difficult  to  find  any  platelets.  Samples  of 
blood  clot  outside  the  body  within  the  normal  time,  but  the  clot  is  soft 
and  usually  fails  to  retract  in  the  normal  manner.  It  is  on  account  of 
this,  rather  than  slow  clotting  that  the  hemorrhage  continues,  so  that  in 
appraising  the  gravity  of  the  symptom  it  is  best  to  measure  not  the  clot- 
ting time  but  the  time  that  it  takes  for  bleeding  to  cease  from  a  small 
skin  wound,  as  in  the  lobe  of  the  ear.  This  can  be  very  accurately  done 
by  applying  blotting  paper  at  regular  intervals  to  the  puncture  (Duke17). 

The  most  interesting  and  at  the  same  time  the  most  mysterious  of  all 
conditions  in  which  blood  clotting  is  interfered  with  is  hemophilia.  The 
clotting  time  is  longer  than  normal,  but  even  after  the  clot  forms,  bleed- 
ing is  likely  to  continue  because  the  clots  are  very  readily  displaced.  Both 
clotting  time  and  bleeding  time  are  increased.  So  far  no  change  in  the 
clotting  factors  of  the  blood  has  been  demonstrated  in  this  disease ;  the 
corpuscles  and  the  platelets  are  normal  in  numbers,  fibrinogen  and  cal- 
cium salts  are  normal,  and,  as  Howell  has  shown,  there  is  no  excess  of 
antithrombin.  One  significant  fact,  however,  is  that  the  addition  of 
thromboplastin  or  of  its  active  ingredient,  kephalin,  greatly  shortens  the 
clotting  time  of  the  blood  when  it  is  removed  by  venipuncture.  In  agree- 
ment with  this  observation  it  has  been  found  that  hemophilic  blood  clots 
much  more  rapidly,  indeed  sometimes  in  the  usual  time,  if  it  is  allowed  to 
flow  over  cut  or  damaged  tissue  and  so  become  mixed  with  thromboplas- 
tin. These  facts  taken  together  would  seem  to  indicate  that  the  fault 
must  lie  in  a  deficiency  in  prothrombin,  and  since  this  is  derived  mainly 
from  the  platelets,  which  however  are  not  decreased  in  number,  we  must 
further  assume  that  these  elements  have  undergone  some  qualitative 
change  preventing  their  disintegration.  An  accompanying  defect  in 
their  agglutinating  properties  would  at  the  same  time  explain  their  fail- 
ure in  hemophilia  to  clump  together  at  the  site  of  the  hemorrhage  so  as 
to  block  the  smaller  vessels  with  thrombi;  hence  the  prolonged  bleeding 
time  even  after  clotting  has  occurred. 

Thrombus  Formation 

The  first  formed  portion  of  a  thrombus  is  paler  than  those  formed  later, 
because  it  contains  excessive  numbers  of  platelets;  and  it  seems  clear 
that  it  is  by  agglutination  of  these  into  masses,  which  then  stick  in  the 


114  THE   BLOOD   AND    THE   LYMPH 

blood  vessels  and  by  disintegrating  shed  forth  prothrombin  and  thrombo- 
plastin,  that  the  clotting  starts.  This  platelet  agglutination  may  result 
from  stagnation  in  the  bloodflow,  or  from  roughening  and  damage  to  the 
vessel  walls.  Stagnation  may  be  due  either  to  failure  of  the  circulation 
as  a  whole  as  in  heart  disease,  or  to  local  physical  alterations  in  the  vas- 
cular tube,  setting  up  conditions  in  which  eddy  currents  with  stagnant 
pools  of  blood  are  formed,  such  as  will  occur  at  places  where  the  vessels 
suddenly  become  wider,  as  in  varicose  veins,  in  aneurisms  and  at  the 
sudden  bend  of  large  veins.  The  first  formed  (platelet)  thrombus  is  fol- 
lowed by  one  of  a  darker  color,  which  fills  the  vessel  up  to  the  next 
anastomotic  branch.  Similar  stagnation  may  also  follow  the  obstruc- 
tion caused  by  lodgment  of  emboli  in  the  smaller  vessels  (air,  foreign 
bodies  in  fine  suspension,  bacteria,  etc.).  The  thrombi  in  such  cases  are 
very  small  and  occur  particularly  in  the  capillaries  of  the  liver,  spleen, 
and  lungs.  The  small  thrombi  often  serve  as  foci  from  which  clotting 
spreads  into  the  larger  vessels,  this  being  often  encouraged  by  an  increase 
in  the  coagulability  of  the  blood.  When  the  intima  is  inflamed,  it  is  pos- 
sible that  excessive  amounts  of  thromboplastin  are  produced  and  that 
this  neutralizes  the  antithrombin  in  blood  moving  so  slowly  that  it  is  not 
replaced  by  fresh  blood  before  clotting  ensues,  or  it  may  be  that  sub- 
stances derived  from  the  inflamed  tissue  cause  the  platelets  to  aggluti- 
nate. The  increased  clotting  often  observed  after  the  injection  of  hemo- 
lytic  agencies  (foreign  sera,  snake  venom,  etc.)  may  also  be  due  to 
platelet  agglutination.  Like  the  thrombosis  following  embolism,  the 
clotting  occurs  at  first  in  the  capillaries,  the  initial  thrombi  containing 
masses  of  platelets  along  with  skeletons  of  blood  corpuscles  and  cells 
from  the  blood-forming  organs. 


CHAPTER  XIV 

LYMPH     FORMATION     AND     CIRCULATION— CEREBROSPINAL 

FLUID 

GENERAL  CONSIDERATIONS 

Lymphatics  are  modified  veins.  They  grow  from  the  veins  in  embry- 
onic life  as  buds  of  endothelium,  which  are  rirsi  visible  in  the  human 
embryo  in  the  sixth  week  of  development.  The  earliest  outgrowth  oc- 
curs from  the  internal  jugular  vein,  and  the  endothelial  buds  soon  be- 
come hollow  and  join  together,  forming  first  a  plexus  and  subsequently 
a  sac,  from  which  again  lymphatic  vessels  made  of  endothelium  grow 
out  to  invade  the  skin  of  the  head,  neck,  thorax  and  arm,  and  partly 
the  deep  structures  of  the  head.  The  sac  is  ultimately  transformed  into 
groups  of  lymph  glands.  At  a  later  stage  similar  nodes  develop  from 
certain  of  the  abdominal  veins,  forming  a  retroperitoneal  sac,  from  which 
grow  out  the  lymphatics  of  the  abdominal  and,  to  a  certain  extent,  of 
the  thoracic  viscera.  A  similar  pair  of  sacs  also  develops  from  the  iliac 
veins  supplying  the  lymphatics  for  the  skin  of  the  legs  and  abdominal 
walls.  The  retroperitoneal  and  iliac  sacs  then  become  connected  with 
the  jugular  sac  by  means  of  the  thoracic  duct.  In  the  embryo  there  are 
no  valves  in  the  lymphatic  vessels,  so  that  the  whole  system  can  be  in- 
jected either  from  the  thoracic  duct  or  from  the  skin,  showing  clearly 
that  the  superficial  and  deep  lymphatics  are  parts  of  one  closed  system 
of  vessels. 

Anatomists  have  succeeded  in  tracing  the  course  of  the  lymphatics  in 
many  parts  of  the  body.  This  knowledge  is  of  great  importance  in 
connection  with  the  spread  of  infections,  etc.  Lymphatics  are  abun- 
dant in  the  skin,  the  intestine,  and  connective  tissues,  but  are  absent 
from  the  muscle  bundles,  from  the  hepatic  lobules  (though  present  in 
the  connective  tissue  between  them),  from  the  substance  of  the  spleen, 
and  from  the  central  nervous  system. 

The  lymphatics  have  the  same  functions  as  blood  capillaries,  namely, 
to  absorb  substances  from  the  tissue  spaces.  There  is  some  evidence  to 
show  that  this  absorption  may  be  selective.  When  injections  are  made 
into  the  peritoneal  cavity,  the  pathway  of  absorption  may  be  either  the 
blood  vessels  or  the  lymphatics,  according  to  the  nature  of  the  sub- 

115 


116  THE   BLOOD   AND   THE   LYMPH 

stance  injected.  True  solutions  are  absorbed  by  the  blood,  but  granules 
are  taken  up  by  special  large  cells  showing  phagocytic  powers,  and  trans- 
ferred to  the  lymphatics — for  example,  those  of  the  diaphragm.  A  sim- 
ilar selective  absorption  is  well  known  in  the  case  of  the  villi  of  the  in- 
testine, where  fat  passes  into  the  lacteals  and  carbohydrates  into  the 
blood.  It  appears  as  if  lymphatic  adsorption,  both  of  solid  materials 
and  of  solutions,  requires  the  cooperation  of  phagocytic  cells. 

The  newer  conception  of  the  lymphatics  as  a  closed  system  is  at  vari- 
ance with  the  older  one,  in  which  they  were  supposed  to  get  smaller  and 
smaller,  and  their  walls  less  and  less  complete  until  ultimately  they 
faded  off  into  the  tissue  spaces.  These,  however,  bear  no  closer  relation- 
ship to  lymphatics  than  they  do  to  blood  capillaries.  The  tissue  spaces 
include  all  the  minute  spaces  between  the  fibers  and  cells  of  the  con- 
nective tissues  and  between  the  parenchyma  of  the  organs  and  the  great 
serous  cavities  of  the  body  (pleural,  peritoneal),  as  well  as  specially 
developed  tissue  spaces,  forming  the  subarachnoid  spaces  of  the  brain, 
the  scala  vestibuli  and  tympani  of  the  cochlea  and  the  anterior  chamber 
of  the  eye.  The  fluids  in  these  spaces — the  tissue  fluids — are  quite  dif- 
ferent from  the  lymph  in  the  lymphatics  both  in  composition  and  in 
function.  Indeed,  the  tissue  fluids  are  among  the  most  varied  of  all 
the  fluids  of  the  body.  The  spaces  may  themselves  become  linked  to- 
gether so  as  to  form  a  circulatory  system,  which  is  quite  independent  of 
the  lymphatics.  This  is  particularly  the  case  in  the  brain,  where  the  tis- 
sue spaces  surrounding  every  individual  nerve  cell  extend  into  the  sub- 
arachnoid  area,  where  they  drain  into  the  cerebral  sinuses  through  the 
arachnoidal  villi,  which  exist  as  lace-like  projections  of  the  arachnoid 
into  the  dural  sinuses,  being  covered  by  a  layer  of  mesothelial  cells  spe- 
cially abundant  at  the  tips  of  the  villi,  where  they  form  cell  nests.  Ob- 
servations of  the  passage  of  substances  in  solution  by  these  pathways 
have  been  made  by  injecting  potassium  ferrocyanide  and  citrate  of  iron 
into  the  subarachnoid  and  subdural  spaces  and  afterwards  detecting 
the  presence  of  the  salts  by  mounting  sections  in  acid  media,  so  as  to 
permit  prussian  blue  to  develop.  Ordinarily  the  precipitate  is  found  in 
or  near  the  villi,  but  after  cerebral  anemia  it  forms  in  the  tissue  spaces 
that  surround  the  nerve  cells. 

There  are  therefore  three  fluids  concerned  in  the  transference  of  food 
materials  and  gases  between  the  gastrointestinal  apparatus  and  lungs 
and  the  tissue  cells — namely,  the  blood  plasma,  the  tissue  fluids,  and  the 
lymph.  The  tissue  fluid,  being  in  contact  with  the  tissue  elements,  serves 
as  their  immediate  nutritive  fluid,  and  it  is  the  function  of  the  blood  and 
lymph  to  maintain  it  of  proper  composition.  Everything  must  be  trans- 
ferred to  and  from  the  tissue  cells  through  the  tissue  fluid,  making  it 


LYMPH   FORMATION   AND   CIRCULATION  117 

therefore  in  many  ways  the  most  important  of  the  fluids  of  the  body. 
In  the  tissue  cells  themselves  there  is  also  the  fluid  in  which  the  various 
colloids  and  crystalloids  that  enter  into  the  composition  of  protoplasm 
are  dissolved.  This  can  be  removed  from  cells  only  by  mechanical  means, 
such  as  grinding  with  fine  sand  in  a  mortar  and  subjecting  the  mass 
to  a  pressure  of  several  thousand  atmospheres  in  a  hydraulic  (Buchner) 
press.  This  is  known  as  the  tissue  juice.  The  ultimate  exchange  of 
foodstuffs  occurs  between  the  tissue  fluids  and  the  tissue  juices  across 
the  cell  membrane.  The  extent  and  character  of  this  exchange  depend 
on  many  circumstances,  some  affecting  the  cell  wall,  others,  the  osmotic 
and  other  properties  of  the  two  fluids.  Obviously,  the  function  of  the 
circulation  is  to  maintain  the  tissue  fluids  of  correct  composition,  the 
blood  plasma  serving  to  carry  food  materials  and  dissolved  oxygen  to 
them  (see  page  393),  but  being  assisted  in  the  opposite  function  of  re- 
moval of  effete  products  by  the  lymph.  The  lymph  is  purely  a  scavenger ; 
the  blood  is  both  purveyor  and  scavenger. 

The  above  description  of  the  lymphatics  is  not  universally  accepted 
by  anatomists,  certain  of  whom  believe  that  the  lymphatics  are  developed 
from  tissue  spaces  and  are  consequently  much  more  extensive  than  they 
appear  to  be  from  injected  specimens.  The  above  conclusions  are  based  on 
reconstruction  models,  made  from  serial  sections  of  embryonic  tissues, 
in  which  the  lymphatics  frequently  appear  as  isolated  vesicles  without 
visible  connections.  The  failure  of  injections  to  penetrate  into  the  re- 
moter parts  of  such  a  lymphatic  system  in  the  embryo  is  attributed  to 
the  discontinuity  of  spaces,  which  is,  however,  removed  at  later  stages 
of  development. 

The  manner  of  absorption  of  injected  fluids  does  not,  however,  sup- 
port the  view  that  the  lymphatics  are  directly  connected  with  the  tis- 
sue spaces.  When  all  the  structures  of  a  part  are  ligated  except  the 
main  artery  or  vein,  injected  poisons  which  affect  central  structures, 
such  as  the  nerve  centers,  develop  their  action  as  quickly  as  in  the  in- 
tact animal  (e.g.,  strychnine).  Similarly,  when  pigments  such  as  meth- 
ylene  blue  are  injected  into  the  pleural  cavity  or  subcutaneously,  they 
appear  in  the  urine  long  before  the  lymph  of  the  thoracic  duct.  Such 
results  indicate  the  pathway  of  absorption  to  be  the  blood  rather  than 
the  lymph  vessels.  Through  this  latter  channel  absorption  proceeds 
more  slowly,  but  can  be  greatly  assisted  by  massaging  the  site  of  injec- 
tion. When  colored  solutions,  such  as  India  ink  or  carmine,  are  injected 
subcutaneously,  however,  a  very  perfect  injection  of  the  neighboring 
lymphatics  may  ultimately  occur,  and  through  the  same  pathways  mi- 
croorganisms spread  from  an  infected  area. 


118  THE    BLOOD    AND    THE   LYMPH 

EXPERIMENTAL  INVESTIGATIONS 

It  has  proved  a  most  difficult  problem  to  gain  any  exact  knowledge 
of  the  production  of  lymph  by  experimental  means.  Starling,  some  years 
ago,  in  repeating  many  of  the  experiments  of  older  physiologists  in  the 
light  of  the  newer  facts  of  physical  chemistry,  added  much  that  is  of 
interest,  and  it  is  chiefly  with  his  work  that  we  will  concern  ourselves 
here. 

The  unequal  lymph  supply  of  different  regions  of  the  body  is  strik- 
ingly demonstrated  by  comparing  the  lymph  flow  from  the  lymphatics 
of  the  leg  with  that  from  the  thoracic  duct.  No  lymph  flows  from  the 
former  unless  the  muscles  are  thrown  into  activity  or  the  blood  is  pre- 
vented from  leaving  the  limb  by  ligaturing  all  the  veins.  Changes  in  the 
arterial  blood  pressure  do  not  affect  the  flow.  On  the  other  hand,  a  great 
increase  in  the  flow  from  the  thoracic  duct  can  readily  be  induced  by 
disturbances  in  the  blood  supply.  Obstruction  of  the  portal  vein,  for 
example,  immediately  increases  the  lymph  flow  four  or  five  times  because  of 
venous  congestion  in  the  intestinal  capillaries,  whilst  a  still  greater 
increase — perhaps  tenfold — is  induced  by  obstruction  to  the  inferior  vena 
cava,  which  raises  the  capillary  pressure  in  both  the  liver  and  the  intes- 
tines. After  ligation  of  the  hepatic  lymphatics  (at  the  hepatic  pedicle), 
obstruction  of  the  vena  cava  no  longer  causes  the  outflow  of  lymph  to 
increase,  indicating  that  the  lymph  in  the  last  mentioned  experiment 
must  have  come  from  the  hepatic  lymphatics. 

These  results,  so  far  as  they  go,  could  be  satisfactorily  explained  on 
the  basis  that  lymph  formation  is  a  filtration  process,  that  is,  a  process 
dependent  upon  difference  in  mechanical  pressure  between  the  blood 
capillaries  and  the  tissue  spaces.  The  lymphatics  would  then  serve  as 
channels  to  return  this  fluid  to  the  blood  vessels  through  the  thoracic 
duct.  The  difference  in  the  magnitude  of  the  increased  lymph  flow  from 
increase  in  capillary  pressure  in  different  regions  would  be  dependent 
on  the  permeability  of  the  filter,  the  capillaries  of  the  limbs  being  much 
less  permeable  than  those  of  the  intestine,  and  particularly  of  the  liver. 
Another  fact  in  conformity  with  this  view  concerns  the  composition  of 
the  lymph  from  the  two  regions,  that  from  the  limb  lymphatics  being 
poor  in  protein,  whereas  that  from  the  thoracic  duct  does  not  fall  far 
behind  the  blood  plasma  in  this  regard. 

Although  filtration  may  explain  the  considerable  increase  in  lymph 
flow  produced  by  extreme  changes  in  capillary  pressure,  it  by  no  means 
suffices  to  explain  lymph  formation  under  less  abnormal  conditions. 
When  a  muscle  or  a  gland  is  at  rest,  it  produces  practically  no  lymph, 


LYMPH   FORMATION   AND   CIRCULATION  119 

but  during  activity  the  flow  becomes  marked.  This  can  not  be  explained 
by  nitration,  but  may  be  accounted  for  by  a  physico-chemical  process — 
namely,  osmosis.  The  energy  required  for  the  activity  of  the  tissue 
cell  is  produced  by  chemical  changes,  whereby  large  molecules  become 
broken  down  into  numerous  smaller  ones.  These  smaller  molecules  are 
then  discharged  into  the  surrounding  tissue  fluids,  the  osmotic  pressure 
of  which  they  increase,  with  the  consequence  that  water  is  attracted 
by  osmosis  from  the  plasma  in  the  blood  capillaries  (see  page  4).  This 
increases  the  volume  of  tissue  fluid,  which  is  then  drained  away  by  the 
lymphatics.  The  increase  in  molar  concentration  will  also  affect  the 
tissue  juices,  tending  to  make  the  cell  swell  up  by  absorbing  water. 
In  gland  cells  this  extra  water  is  immediately  extruded  to  form  the 
water  of  the  secretion  (see  page  455). 

An  analogous  method  of  lymph  formation  is  not  confined  to  situations 
where  the  capillaries  are  relatively  impermeable,  for  it  also  occurs  in 
the  liver,  the  lymph  flow  from  which  is  greatly  increased  by  the  injec- 
tion of  bile  salts.  A  similar  process  no  doubt  results  from  muscular 
activity,  although  in  this  case  the  tissue  spaces  must  form  a  continuous 
system  of  their  own,  there  being,  according  to  most  authorities,  no 
lymphatics. 

Considerable  interest  has  been  taken  in  the  stimulating  effect  which 
certain  chemical  substances  have  on  the  secretion  of  lymph  from  the 
thoracic  duct.  These  so-called  lymphagogues  belong  to  two  classes — 
crystalline  and  colloidal.  Of  the  former,  glucose,  urea,  and  sodium 
chloride  in  hypertonic  solution,  are  the  best  known.  Starling  explains 
their  action  as  dependent  upon  an  increase  in  the  osmotic  pressure  of 
the  blood.  This  attracts  water  into  the  blood  from  the  tissue  juices, 
and  leads  to  an  hydremic  plethora,  with  a  consequent  increase  in  capil- 
lary pressure.  If  the  blood  pressure  is  lowered  by  hemorrhage  before 
the  hypertonic  solution  is  injected,  very  little  stimulation  of  lymph  flow 
occurs,  because  there  is  no  available  fluid  in  the  tissue  to  produce  the 
plethora.  This  observation  does  not,  however,  very  strongly  support 
the  explanation,  because  so  many  other  disturbances  may  result  from 
hemorrhage. 

The  colloidal  lymphagogues  include  watery  extracts  of  the  dried  tis- 
sues of  leeches,  crayfish,  and  mussels,  as  well  as  commercial  peptone. 
They  probably  act  by  damaging  the  endothelium  of  the  capillaries,  so 
that  filtration  occurs  more  readily.  Although  their  action  is  displayed 
more  particularly  on  the  lymphatics  of  the  liver  and  intestines,  it  is  also 
apparent  on  the  skin  capillaries,  producing  cutaneous  edema  and  the 
formation  of  blisters  (nettle  rash). 


120  THE   BLOOD   AND   THE   LYMPH 

EDEMA 

With  such  an  imperfect  knowledge  concerning  the  physiology  of 
lymph  formation,  it  is  not  surprising  that  the  causes  of  excessive  accu- 
mulation of  fluid  in  and  between  the  tissue  elements  should  be  little  un- 
derstood. All  of  the  conditions  which  have  been  mentioned  as  capable 
of  causing  an  increased  secretion  of  lymph — such  as  increase  in  capillary 
pressure,  hydremic  plethora,  action  of  poisons  on  the  endothelium— are 
likely  to  cause  edema  if  the  lymphatics  of  the  part  are  simultaneously 
obstructed.  To  produce  in  animals  edema  of  the  subcutaneous  tissues 
like  that  observed  clinically,  it  is,  however,  necessary  that  the  vascular 
disturbance  be  accompanied  either  by  local  damage  to  the  capillary 
endothelium,  such  as  is  produced  by  arsenic  or  uranium;  or  by  a  gen- 
eral toxemic  condition,  such  as  is  set  up  by  nephritis.  When  large 
amounts  of  saline  solution  are  injected  intravenously,  extensive  ex- 
travasation of  fluid  may  occur  into  the  liver,  peritoneum  and  intestinal 
lumen,  without  any  subcutaneous  edema. 

Clinical  edemas  are  of  at  least  three  types: 

1.  The  inflammatory  edemas,  in  which  the  fluid  permeates  the  cells  of 
the  inflamed  area  and  does  not  shift  to  other  parts  of  the  body  under 
the  influence  of  gravity. 

2.  The  nephritic  edemas,  in  which  the  fluid  is  more  or  less  loose  in  the 
subcutaneous   tissues   and   readily   changes   its   position,    and   which  is 
accompanied  by  excess  of  water  in  the  blood  with  a  corresponding  in- 
crease of  sodium  chloride ;  the  percentage  concentration  of  sodium  chlo- 
ride in  the  blood  remains  unchanged,  but  that  the  other  constituents 
diminished. 

3.  Cardiac  edemas,  which  are  also  hypostatic,  but  are  unaccompanied 
by  changes  in  the  relative  amount  of  water  and  sodium  chloride  in  the 
blood. 

The  second  and  third  varieties  of  edema  may  of  course  be  more  or 
less  present  together,  for  the  kidneys  are  likely  to  become  secondarily 
affected  during  venous  stasis. 

The  salt  retention  in  nephritic  edema  is  very  significant.  As  ex- 
plained elsewhere,  it  is  revealed  by  comparing  the  daily  output  of  so- 
dium chloride  by  the  urine  with  the  concentration  of  this  salt  in  the 
blood.  Less  salt  is  eliminated  than  would  be  the  case  in  a  normal  in- 
dividual with  the  same  percentage  of  salt  in  the  blood.  In  many  cases 
also  edema  can  be  diminished  by  withholding  salt  from  the  food.  Widal 
and  Javal  have  conclusively  shown  the  relationship  of  retention  of  water 
in  the  body,  as  judged  by  variations  in  body  weight,  to  the  hydremic 
condition,  as  judged  by  the  refractive  index  of  the  blood  serum,  and 


LYMPH   FORMATION   AND   CIRCULATION  121 

to  the  amount  of  salt  in  the  diet.  A  very  considerable  retention  of 
water  usually  occurs  before  there  is  any  evidence  of  edema;  indeed,  as 
a  result  of  giving  salt,  the  body  weight  may  increase  from  five  to  seven 
kilograms  (10  to  15  pounds)  within  a  day  or  two  without  the  appear- 
ance of  puffiness. 

The  cause  of  the  edema  during  salt  retention  is  no  doubt  closely  re- 
lated to  the  action  of  lymphagogues.  In  a  normal  person  excessive  in- 
gestion  of  salt  is  immediately  followed  by  excretion  of  the  excess  through 
the  kidney.  Where  the  kidneys  are  diseased,  this  excess  of  salt  is  re- 
tained in  the  blood,  raising  its  osmotic  pressure  and  attracting  water 
from  the  tissue  fluids.  This  leads  to  excessive  thirst,  the  imbibed  water 
being  used  to  replace  that  lost  from  the  tissues.  But  all  the  crystalline 
lymphagogues  do  not,  when  present  in  excess  in  the  blood  of  nephritic 
patients,  necessarily  cause  edema;  urea,  for  example,  may  accumulate 
considerably  without  any  such  effect.  The  different  action  is  usually 
attributed  to  inequality  in  the  diffusibility  of  the  two  crystalloids  through 
animal  membranes,  sodium  chloride  diffusing  much  less  readily  than 
urea. 

It  is  most  important  to  note  that  the  fluid  in  edema  is  loose  in  the 
tissues  and  can  be  drained  away  by  the  insertion  of  tubes.  There  is 
absolutely  no  evidence  in  support  of  the  claim  of  Martin  Fischer  that 
edema  is  due  to  imbibition  of  water  by  the  colloids  of  the  tissues.  This 
question  has  been  fully  discussed  elsewhere  (page  63). 

THE  CEREBROSPINAL  FLUID 

Considerable  attention  is  now  paid  to  the  cerebrospinal  fluid  which  is 
present  in  the  subarachnoid  spaces  of  the  spinal  cord  and  brain.  This  is 
because  the  fluid  is  readily  collected  by  the  method  of  lumbar  puncture, 
which  is  performed  for  the  purpose  either  of  relieving  increased  inter- 
cranial  pressure  as  in  hydrocephalus,  delirium  tremens,  eclampsia,  enceph- 
alitis, etc.,  or  of  collecting  some  of  the  fluid  for  diagnostic  purposes. 
The  rationale  of  the  removal  for  the  relief  of  pressure  in  the  brain  case 
is  somewhat  difficult  to  understand,  as  will  be  evident  from  a  perusal  of 
the  chapter  on  the  circulation  of  blood  in  the  brain  (page  254) .  There  is  no 
doubt,  however,  that  the  procedure  gives  relief.  It  is  more  particularly 
with  the  biochemical  characteristics  of  the  fluid  that  we  are  concerned  here 
(of  Levinson19).  The  normal  fluid  (i.e.,  obtained  from  patients  not  suf- 
fering from  inflammatory  processes  of  the  cerebrospinal  membranes)  is 
colorless,  it  contains  only  from  4-6  cells  per  cubic  mm.,  its  specific  gravity 
varies  between  1,000  and  1,008  and  it  does  not  clot.  The  H-ion  concentra- 
tion of  perfectly  fresh  fluid,  removed  during  life,  can  be  accurately  meas- 
ured by  the  colorimetric  method  without  dialysis  (page  32)  and  has  been 


122  THE   BLOOD   AND    THE   LYMPH 

found  by  Levinson  to  vary  between  PH  7.4  and  7.6,  being  therefore  practi- 
cally that  of  blood.  On  standing  in  unstoppered  vessels  the  alkalinity 
gradually  increases  so  that  PH  of  8  may  be  reached  in  two  hours.  If  the 
vessel  be  tightly  stoppered,  however,  PH  may  remain  almost  stationary. 
The  reason  for  this  change  is  that  there  is  as  large  a  percentage  of  bicar- 
bonate in  the  cerebrospinal  fluid  as  in  the  blood  plasma.  The  so-called 
alkaline  reserve,  as  determined  by  the  Van  Slyke  method  is  therefore  the 
same  as  in  blood  plasma  (viz.,  about  60).  With  regard  to  organic  constit- 
uents, there  is  only  a  trace  of  protein  (0.02-0.04  total  N.)  but  the  urea 
and  sugar  are  present  in  about  the  same  percentage  amounts  as  in  the 
blood  plasma.  There  is  no  certain  evidence  that  any  enzymes  are  con- 
tained in  the  fluid. 

The  pathological  changes  observed  in  the  fluid  are  of  two  types,  systemic 
and  meningitic.  In  connection  with  the  former,  it  may  be  mentioned  that 
in  uremia  the  amount  of  fluid  is  usually  increased  and  there  is  a  high  per- 
centage of  urea;  in  diabetes,  the  sugar  is  increased;  in  the  various  psy- 
choses, in  epilepsy  and  chorea  there  may  or  may  not  be  changes.  In 
hydrocephalus  the  amount  of  fluid  is  increased,  but  it  is  normal  in  its 
properties.  This  is  also,  although  less  markedly,  the  case  in  encephalitis  and 
cerebral  tumor.  Eegarding  conditions  in  which  the  meninges  are  in- 
flamed (tubercular,  meningococcic,  pneumococcic)  the  changes  in  the  fluid 
are  very  marked  and  of  decided  diagnostic  value ;  it  is  somewhat  increased 
in  amount,  turbid,  forms  a  sediment,  shows  many  cells,  contains  excess  of 
protein  (globulin)  and  gives  a  typical  culture  of  the  infecting  organism 
when  examined  by  bacteriological  methods.  Levinson  has  found  that 
there  are  significant  changes  in  PH  in  various  diseases  and  he  considers 
that  several  tests  that  have  been  devised  for  diagnostic  purposes  are  in- 
timately associated  with  the  changes  in  PH.  These  tests  are  known  as  the 
cataphoresis  test,  the  colloidal  gold  reaction  of  Lange  and  the  mastic  reac- 
tion, and  they  all  depend  on  the  manner  in  which  the  protein  colloidal 
particles  aggregate  or  become  precipitated. 


BLOOD  AND  LYMPH  REFERENCES 

(Monographs) 

iHowell,  W.  H.:     The  Harvey  Lectures,  J.  B.  Lippincott  Co.,  xii,  272. 
sStarling,  E.  H.:     Human  Physiology,  Lea  &  Febiger,  1915. 
3Kowe,  A.  H.:     Arch.  Int.  Med.,  1917,  xix,  354,     . 
*  Williamson,  C.  S.:     Arch.  Int.  Med.,  1916,  xviii,  505. 
sTower  and  Herm:     Proc.  Soc.  Biol.  and  Med.,  1916,  xviii,  505. 
6Eous  and  Eobertson:     Jour.  Exp.  Med.,  1916,  xxiii,  219,  239,  549. 
?Butler,  G.  G.:     Quart.  Jour.  Med.,  1912,  vi,  145. 

sHowell,  W.   H.:     cf.  Harvey  Lecture;    also  Am.   Jour.  Physiol.,  1913,  xxxii,  264.. 
»Drinker,  C.  K.,  and  K.  E.:     Am.  Jour.  Physiol.,  1916,  xli,  5. 

loBenny   and  Minot:     Arch.  Int.   Med.,   1916,   xvii,    101;   Am.   Jour.   Physiol.,   1915, 
xxxviii,  233. 


LYMPH   FORMATION   AND   CIRCULATION  123 

"Addis,  T.:    Quart.  Jour.  Med.,  1910,  iv,  14. 

i2Cannon  and  Mendenhall:     Am.  Jour.  Physiol.,  1914,  xxxiv,  225. 

isHowell,  W.  H.:     Arch,.  Int.  Med.,  1914,  xiii,  80. 

J*Brodie,  T.  G.:     Jour.  Physiol.,  1897,  xxi,  403. 

isWhipple,  G.  H.:     Arch.  Int.  Med,  1912,  ix,  365;  Jour.  Exp.  Med.,  1911,  xiii,  136. 

isAVhipple,  G.  H.:    Arch.  Int.  Med.,  1913,  xii,  637. 

"Duke,  W.  W  :     Arch.  Int.  Med.,  1912,  ix,  258. 

isKeith,  N.  M.:     Eeport  27  Medical  Eesearch  Committee,  London,  1919. 

isLevinson,  A.:     Cerebrospinal  Fluid  in  Health  and  in  Disease,  C.  V.  Mosby  Co.,  1919. 

zoKeith,  N.  M.,  Eowntree,  L.  G.,  and  Geraghty.  J.  T. :     Arch.  Int.  Med.,  1915,  xvi,  547. 

2iHooper,  C.  W.,  Whipple,  G.  H.,  etc. :     Am.  Jour.  Physiol.,  1920,  li,  205-257. 

22\Vhipple,  G.  H.,  etc.:     Am.  Jour.  Physiol.,  1918,  xlvii,  356,  370,  379;  and  1920,  lii,  54. 

238abin,  F.  E.:     Physiol.  Eev.,  1922,  ii,  38. 


PART  III 

THE  CIRCULATION  OF  THE  BLOOD 


CHAPTER  XV 

BLOOD  PRESSURE 

The  object  of  the  circulation  is  to  maintain  through  the  tissues  a  sup- 
ply of  blood  that  is  adequate  to  meet  their  demands  for  nutriment  and 
oxygen  and  to  remove  the  effete  products  of  their  metabolism.  The  de- 
mands vary  according  to  the  activities  of  the  tissue,  being  particularly 
variable  in  the  case  of  such  tissues  as  the  muscular  and  the  glandular. 
In  studying  the  physiology  of  the  circulation  we  have  therefore  to  bear 
in  mind  two  aspects  of  the  problem:  (1)  the  cause  for  the  continuous 
bloodflow,  and  (2)  the  mechanism  by  which  alterations  in  this  bloodflow 
are  brought  about. 

If  we  open  an  artery  we  shall  find  that  the  blood  escapes  from  it 
under  such  a  pressure  that  it  is  thrown  to  a  height  of  about  six  feet, 
that  its  outflow  is  proportional  to  the  size  of  the  artery,  and  that  it  pul- 
sates. If,  on  the  other  hand,  we  open  a  vein,  we  shall  find  that  the 
blood  wells  out  without  any  very  evident  pressure,  and  that  it  flows 
in  a  continuous  stream,  its  outflow  being  the  same  in  a  unit  of  time  as 
that  of  the  artery,  provided  the  two  vessels  are  the  only  ones  supplying 
the  particular  area.  The  general  conditions  governing  the  bloodflow 
are  the  same  as  those  governing  the  flow  of  fluid  through  any  system  of 
tubes.  For  example,  in  the  city  water  mains  it  is  known  to  every  one 
that  the  rate  of  outflow  from  any  part  of  the  system  depends  finally  on 
two  factors:  (1)  the  difference  in  pressure  at  the  beginning  and  end  of 
the  system,  and  (2)  the  caliber  of  the  tube  at  the  outlet.  We  may  in- 
crease the  outflow  either  by  raising  the  pressure  at  the  beginning  of  the  sys- 
tem, the  caliber  of  the  outlet  meanwhile  remaining  constant,  or  by  main- 
taining the  pressure  constant  but  increasing  the  caliber  of  the  outlet. 

In  the  circulation  of  the  blood,  the  difference  in  pressure  at  the  be- 
ginning and  end  of  the  circulation  is  furnished  by  the  pumping  action 
of  the  heart,  and  the  alteration  of  the  caliber  of  the  outlet  is  provided 
for  by  the  constriction  or  dilatation  of  the  blood  vessels.  These  simple 
physical  principles  indicate  the  direction  which  a  study  of  the  circulation 

124 


BLOOD   PRESSURE  125 

should  take.  They  indicate  that  our  first  consideration  should  be  of  the 
mean  blood  pressure,  how  it  is  maintained,  and  how  it  can  be  made  to 
vary.  After  we  have  learned  this,  we  may  then  proceed  to  a  more 
particular  examination  of  the  mechanism  of  the  pump — that  is,  of  the 
heartbeat ;  then  finally  .we  may  proceed  to  examine  the  nature  of  the 
processes  by  which  the  caliber  of  the  arteries  is  controlled. 


THE  MEAN  ARTERIAL  BLOOD  PRESSURE 

The  first  prerequisite  to  the  investigation  of  the  blood  pressure,  as  of 
any  other  physical  problem,  is  that  we  should  possess  some  means  by 
which  it  can  be  quantitatively  measured.  The  earliest  attempt  to  accom- 
plish this  was  made  by  the  English  scientist,  the  Rev.  Stephen  Hales,  a 
little  over  a  century  after  Harvey  published  his  account  of  the  circula- 
tion of  the  blood.  Hales  connected  a  glass  tube  nine  feet  in  length  with 
a  severed  artery  of  a  horse,  the  connection  between  the  two  being  made 
by  means  of  a  piece  of  brass  pipe  joined  to  the  windpipe  of  a  goose  as  a 
substitute  for  rubber  tubing.  He  found  on  untying  the  ligature  on  the 
artery  that  the  blood  rose  in  the  tube  to  a  height  of  eight  feet  and  three 
inches  above  the  level  of  the  left  ventricle  of  the  heart,  and  that  when 
at  full  height  it  rose  and  fell  with  each  pulse  through  a  distance  of  two, 
three  or  four  inches. 

Mercury  Manometer  Tracings 

The  somewhat  crude  but  very  significant  experiment  of  Hales  clearly 
established  the  existence  of  the  enormous  pressure  at  which  the  blood  is 
made  to  circulate  through  the  arteries.  To  render  possible  a  further 
investigation  of  the  factors  on  which  this  pressure  depends,  it  became 
necessary  to  invent  some  more  convenient  means  for  its  measurement, 
but  this  was  not  accomplished  until  a  century  later,  when  Poiseuille  ap- 
plied the  mercury  manometer,  which  Ludwig  subsequently  adapted  so 
that  tracings  might  be  taken  (Fig.  21). 

Having  before  us  such  a  tracing  as  shown  in  Fig.  22,  let  us  consider 
how  it  may  be  used  in  the  study  of  blood  pressure.  The  first  thing  we 
must  do  is  to  measure  the  average  height  of  the  tracing  above  the  line  of 
zero  pressure;  the  mean  arterial  blood  pressure  is  then  equal  to  this 
distance  multiplied  by  two,  because  the  distance  through  which  the  mer- 
cury has  moved  up  in  the  limb  of  the  manometer  carrying  the  writ- 
ing point  is  only  one-half  of  its  total  displacement.  Since  mercury 
is  about  13.5  times  heavier  than  an  equal  volume  of  blood,  the  above 
measurement  must  be  multiplied  by  this  figure  if  we  desire  to  express 


126 


THE    CIRCULATION    OF    THE   BLOOD 


our  result  in  terms  of  the  height  to  which  the  blood  pressure  could  raise 
a  column  of  blood. 

In  arteries  of  approximately  the  same  size,  the  mean  arterial  blood 
pressure  does  not  markedly  vary  in  different  mammals.  Thus,  in  the 
carotid  artery  of  the  dog  it  averages  about  110  to  120  mm.  Hg,  in  that 
of  the  cat  about  105  to  115  mm.,  in  the  rabbit  from  90  to  105  mm.,  in 
the  sheep  about  150  mm.,  in  the  horse  about  200  mm.,  and  in  man 


Fig;  21. — Mercury  manometer  and  signal  magnet,  arranged  for  recording  the  mean  arterial 
blood  pressure  in  a  laboratory  experiment.  The  pressure  bottle  (R)  is  filled  with  anticoagulating 
fluid  and  is  connected  by  tubing  with  the  manometer  (M),  the  cannula  for  the  artery  (U)  being 
connected  with  the  T-piece  (J).  By  this  arrangement  it  is  possible  to  flush  out  the  tubing 
when  clotting  interferes  with  the  experiment.  (From  Jackson — Experimental  Pharmacology.) 

where  between  120  and  140  mm.  The  pressure  varies  in  different  parts 
of  the  vascular  system,  being  greatest  in  the  aorta  and  least  in  the  small- 
est arterioles  but  the  fall  in  pressure — the  pressure  gradient — does  not 
become  very  pronounced  until  the  arterioles  have  become  so  small  that 
it  is  no  longer  possible  to  insert  a  cannula  into  them;  thus,  the  mean 


BLOOD   PRESSURE 


127 


blood  pressure  in  the  renal  or  femoral  artery  is  very  little  less  than  that 
in  the  aorta. 

If  we  examine  the  contour  of  the  tracing  which  the  pressure  draws,  we 
shall  find  that  it  exhibits  two  types  of  wave,  small  and  large ;  and  if  we 
observe  the  animal  while  the  tracing  is  being  taken,  we  shall  find  that 


Fig.  22. — The  arterial  blood  pressure  recorded  with  a  mercury  manometer  (lower  tracing), 
along  with  a  tracing  of  the.  respiratory  movements  of  the  thorax.  Note  that  the  beginning  of 
respiration  occurs  distinctly  before  the  rise  in  blood  pressure. 

the  former  are  caused  by  the  heartbeats  and  the  latter  by  the  respira- 
tions— an  observation  which  immediately  raises  the  question  as  to  the 
trustworthiness  of  the  method,  for  it  will  be  asked,  How  can  it  be  that 
the  heartbeat  produces  an  effect  on  blood  pressure  which  is  less  than 
that  of  the  respirations?  Obviously  the  tracing  must  be  faulty  in  re- 
gard to  the  relative  significance  of  the  waves. 


128  THE    CIRCULATION   OF   THE   BLOOD 

Spring  Manometer  Tracings 

The  cause  of  this  inaccuracy  depends  on  the  inertia  of  the  mercury, 
an  inertia  which  is  so  great  that  the  sudden  changes  of  pressure  produced 
by  each  heartbeat  are  not  able  to  overcome  it,  whereas  the  much  less 
significant  but  more  prolonged  pressure  changes  produced  by  each  respi- 
ration develop  their  full  effect  on  the  mercury.  These  facts  led  investi- 
gators to  seek  for  instruments  in  which  the  inertia  error  is  eliminated, 
with  the  result  that  they  invented  what  are  known  as  spring  manometers. 


Fig.    23. — Hiirthle's   spring    manometer. 

Many  forms  of  this  instrument  have  been  devised,  but  for  our  pur- 
pose it  is  necessary  to  describe  the  principle  of  only  the  simplest  and 
most  efficient — the  Hiirthle  manometer.  As  shown  in  Fig.  23,  it  consists 
of  a  variety  of  tambour,  which  differs  from  the  ordinary  tambour  in  two 
important  particulars:  (1)  the  chamber  is  made  as  small  as  possible,  and 
(2)  it  is  covered  not  with  an  elastic  membrane  but  with  one  of  leather  or  of 
thin  fluted  metal.  These  two  precautions  are  taken  in  order  to  avoid  spuri- 
ous waves  set  up  on  account  of  elastic  recoil.  Such  errors  are  further 
reduced  by  filling  the  tubing  and  chamber  of  the  tambour  with  a  fluid 
so  as  to  eliminate  the  elastic  recoil  of  air. 


Fig.   24. — Normal  curve  of  arterial  blood  pressure  obtained  with  spring  manometer. 
(Burdon-Sanderson.) 

Before  the  tracing  taken  with  the  spring  manometer  can  be  em- 
ployed for  quantitative  measurements,  it  must  obviously  be  graduated 
according  to  some  scale.  This  is  accomplished  immediately  before  or 
after  the  experiment  by  connecting  the  manometer  through  a  T-piece 
with  a  pressure  bottle,  which  can  be  raised  or  lowered  to  a  specified 
height,  and  with  a  mercury  manometer.  The  displacement  of  the  writing 
point  of  the  spring  manometer  corresponding  to  each  10  mm.  Hg  of 
pressure  is  then  written  on  the  tracing. 

The  tracings  taken  with  such  a  manometer,  as  shown  in  Fig.  24,  are 
quite  different  from  those  with  the  mercury  manometer.  It  will  be  seen 


BLOOD   PRESSURE 


129 


that  now  the  cardiac  waves  are  decidedly  the  more  pronounced,  the  respira- 
tory, being  comparatively  inconspicuous.  The  pressure  in  the  arteries, 
instead  of  being  fairly  steady,  undergoes  very  considerable  alteration 
tion  during  each  heartbeat. 

Examination  of  this  tracing  gives  us  accurate  information  regarding 
the  blood  pressure  both  between  the  heartbeats — diastolic,  as  it  is  called — 
and  during  them — systolic.  It  gives  us  a  means  of  measuring  the 
dead  load  of  the  circulation — that  is,  the  pressure  that  is  constantly 
present — as  well  as  the  live  load  that  is  superadded  to  this  by  each  heart- 
beat. This  difference  is  often  called  the  pressure  pulse,  and  in  man  it 
amounts  to  somewhere  about  35  mm.  Hg.  If  we  take  tracings  with  a 
spring  manometer  from  different  parts  of  the  arterial  tree,  we  shall  find 


160 


L  ine    of 
SYSTOLIC   PRESS  UPE 


Of 

WEAK    PRESSURE 


Line  of 

DtASTOLIC 

Pressure 


PULSE 

Tfyetf/fference  between 
SYSTOLIC 


D/ASTOL/C  PRESSURE 


Fig.  25. — Diagram  based  on  experiments  on  dogs  to  show  the  magnitude  of  the  systolic, 
diastolic  and  mean  blood  pressures  at  different  parts  of  the  circulatory  system.  O  is  the  line 
of  zero  pressure,  and  the  letters  below  it  indicate  the  parts  of  the  system  to  which  the  curves 
refer.  (From  Brubaker.) 

that,  as  we  travel  towards  the  periphery,  the  pressure  pulse  becomes  less 
and  less  marked,  until  finally  by  the  time  the  capillaries  are  reached  it 
has  almost  entirely  disappeared.  This  decline  in  the  pressure  pulse  can 
moreover  be  seen  to  be  dependent  more  largely  on  a  fall  in  systolic  than 
in  diastolic  pressure.  In  other  words,  the  dead  load  of  the  circulation— 
the  diastolic  pressure — remains  practically  constant  all  along  the  arte- 
rial tree,  whereas  the  systolic  pressure  falls  relatively  quickly  (Fig.  25). 

Clinical  Measurements 

The  methods  of  blood-pressure  measurement  in  man  have  recently 
become  so  perfected  that  the  results  are  almost  as  accurate  as  those  ob- 


130  THE    CIRCULATION    OF    THE    BLOOD 

tained  in  laboratory  animals  by  direct  measurement  through,  the  use  of 
cannulse  inserted  into  the  vessels.  Both  the  systolic  and  the  diastolic 
pressure  can  be  measured  with  equal  facility  and  accuracy.  Since  the 
technic  for  making  the  systolic  measurements  was  described  at  a  much 
earlier  date  than  that  for  the  diastolic,  it  has  until  recently  been  the 
habit  with  a  great  part  of  the  medical  profession  to  be  satisfied  with 
systolic  readings  alone.  This  is  most  unfortunate,  because  the  knowledge 
which  such  information  gives  us  is  incomparably  inferior  to  that  which 
can  be  obtained  by  gauging  the  diastolic  pressure.  Until  we  have  learned 
more  about  the  dynamics  of  circulation,  it  would  be  profitless  to  go 
into  any  details  as  to  the  reasons  for  this  statement,  but  it  will  soon 
become  self-evident.  Suffice  it  for  the  present  to  state  that  the  diastolic 
pressure  is  the  more  important  because  it  gives  us  the  load  ivhich  the  ves- 
sels and  aortic  valves  must  constantly  bear,  and  the  resistance  which  must 
be  overcome  prior  to  the  opening  of  these  valves  at  the  beginning  of 
systole.  Moreover,  it  helps  us  to  gauge  the  peripheral  resistance. 

The  first  step  in  the  technique  of  blood-pressure  measurements  in  man 
is  the  placing  of  an  armlet  or  cuff  around  the  arm  or  leg.  This  armlet 
consists  of  a  rubber  bag  at  least  12  cm.  broad  and  covered  on  its  outer 
surface  by  cloth  or  leather.  The  bag  is  connected  by  tubing  with  a  pres- 
sure gauge  and  a  pump.  The  pressure  gauge  may  be  either  an  ordinary 
mercury  manometer  (Fig.  26)  or  one  of  the  numerous  gauges  built  on 
the  aneroid  principle  that  are  now  on  the  market.  For  measuring  the 
blood  pressure  in  the  vessels  of  the  upper  extremities,  the  armlet  should 
be  applied  around  the  fleshy  part  of  the  upper  arm  and  for  the  lower  limbs 
around  the  thigh.  For  accurate  reading  of  both  pressures  in  the  arm  the 
following  procedure  should  be  followed.  Having  applied  the  armlet,  the 
pulse  is  palpated  at  the  radial  artery,  and  the  pressure  in  the  arm- 
let then  raised  until  the  pulse  can  no  longer  be  felt,  at  which  moment 
the  pressure  in  the  manometer  is  noted.  The  cuff  is  then  slowly 
decompressed  and  the  pressure  noted  at  which  the  pulse  reappears. 
These  two  readings  of  systolic  pressure  should  be  close  together,  but 
they  will  not  usually  agree  exactly  for  reasons  which  will  be  explained 
immediately.  They  give  us  the  palpatory  systolic  index,  as  it  is  called. 
The  pressure  is  now  lowered  about  15  mm.  Hg,  and  a  stethoscope  is 
placed  in  front  of  the  bend  of  the  elbow  over  the  artery  and  as  close  up 
to  the  cuff  as  possible.  With  each  heartbeat  a  distinct  sound  like  a  pistol 
shot  will  be  heard.  The  decompression  is  now  continued  slowly,  and  as 
the  pressure  falls  the  sounds  will  be  heard  to  become  louder  and  prob- 
ably somewhat  murmurish  in  quality.  At  a  certain  pressure  this  loud 
character  of  the  sound  will  suddenly  become  much  less  marked,  and  the 
murmurish  quality  if  present  will  disappear.  This  point  corresponds  to 
the  diastolic  pressure,  which  is  now  read  off  from  the  manometer. 


BLOOD   PRESSURE 


131 


It  must  be  remembered  that  below  this  point,  as  the  pressure  in  the 
cuff  is  further  lowered,  a  sound  is  still  heard  in  the  artery;  indeed  it 
does  not  entirely  disappear  until  the  pressure  has  become  quite  low.  This 
point  of  final  disappearance  is,  however,  of  no  significance.  The  cuff  is 
now  entirely  decompressed,  and  should  be  left  so  for  a  moment  or  more, 
so  that  the  circulation  in  the  part  of  the  arm  below  it  may  return  to  the 
normal. 

The  above  readings  should  then  be  controlled  by  a  second  observa- 


Fig.  26. — Apparatus  for  measuring  the  arterial  blood  pressure  in  man.  The  pressure  in  the 
cuff  is  raised  by  means  of  the  syringe  until  the  pulse  can  no  longer  be  felt  at  the  wrist.  This 
pressure  is  read  off  on  the  mercury  manometer  (systolic  pressure). 

tion,  in  which  the  procedure  is  slightly  modified.  With  the  stetho- 
scope at  the  bend  of  the  elbow  the  pressure  in  the  cuff  is  run  up  to 
a  little  above  the  previously  determined  diastolic  pressure,  so  that  the 
sound  is  clearly  heard.  The  pressure  is  then  further  raised  till  the 
sound  disappears.  This  point  indicates  the  systolic  pressure;  it  is  called 
the  auditory  systolic  index.  It  will  be  found  to  give  a  systolic  pressure 
a  little  higher  than  that  obtained  by  palpation  of  the  artery  at  the  wrist. 
The  sound  being  now  absent,  the  pressure  in  the  cuff  is  lowered  until 
the  sound  reappears,  and  the  point  at  which  this  occurs  should  almost 


132  THE    CIRCULATION    OF    THE   BLOOD 

exactly  correspond  to  that  at  which  the  sound  was  found  to  disappear. 
If  the  palpatory  systolic  index  is  not  below  the  auditory,  it  indicates 
that  some  error  has  been  made  in  the  application  of  the  apparatus,  and 
that  the  reading  of  the  diastolic  pressure  will  be  unreliable.  The  usual 
source  of  error  is  in  the  position  of  the  stethoscope,  if  readjustment  of 
this  does  not  bring  the  two  indices  into  proper  relationship,  the  auscul- 
tatory  method  can  not  be  relied  upon  for  either  systolic  or  diastolic 
readings. 

In  case  of  failure  of  the  auscultatory  method,  we  have  to  fall  back  upon 
the  palpatory  method  for  measurement  of  the  systolic  pressure;  and  for 
measurement  of  diastolic,  we  must  use  the  method  known  as  the  oscillatory, 
which  until  recent  years  was  the  only  one  known  for  gauging  the  dias- 
tolic pressure.  This  consists  in  observing  the  oscillation  of  the  indicator 
of  the  pressure  gauge;  as  the  pressure  in  the  cuff  falls  gradually  from 
below  the  systolic  pressure,  these  oscillations  will  be  observed  to  increase 
in  amplitude,  until  they  reach  a  maximum  beyond  which  with  lower 
pressure  they  rapidly  decline.  The  pressure  in  the  cuff  at  the  moment 
when  the  oscillations  are  at  the  maximum  represents  the  diastolic  pres- 
sure. With  a  mercury  instrument  it  is  obviously  difficult  to  employ  this 
method,  but  with  a  modern  spring  instrument  it  can  with  a  little  practice 
be  used  with  great  accuracy  and  will  serve  as  a  valuable  check  on  the 
diastolic  reading  as  taken  by  the  auscultatory  method. 

The  procedure  may  be  altered  in  various  ways,  there  being  only  one  pre- 
caution to  bear  in  mind ;  namely,  that  the  pressure  in  the  cuff  should  not  be 
applied  continuously  for  more  than  a  few  moments  of  time,  for  if  this 
is  done  for  long  periods,  not  only  will  it  interfere  with  the  accuracy 
of  the  reading,  but  it  may  cause  considerable  discomfort  to  the  patient. 

There  are  several  conditions  affecting  the  accuracy  of  the  readings  by  each  method 
which  it  is  well  to  bear  in  mind.  These  have  been  investigated  by  Mac  William,*  Leon- 
ard Hill,2  and  Erlanger.3  The  most  important  conditions  affecting  the  systolic  pressure 
are  as  follows:  (1)  The  compression  cuff  should  be  a  wide  one  (12  cm.),  and  it 
should  never  be  applied  so  that  there  is  any  chance  of  its  compressing  the  artery 
against  a  bony  surface.  This  precaution  is  necessary,  since  it  has  been  found  that 
much  less  pressure  is  required  to  obliterate  any  perceptible  pulse  below  the  armlet 
when  the  artery  is  flattened  against  some  hard  structure  than  when  it  is  uniformly 
compressed  in  the  tissues  in  which  it  lies.  (2)  Discrepancies  are  often  noted  between 
the  systolic  readings  on  compression  and  decompression  of  the  artery;  that  is,  the 
pulse  may  reappear  on  decompression  at  a  lower  pressure  than  that  at  which  it  dis- 
appeared on  compression,  the  difference  being  most  marked  when  the  decompression 
is  done  quickly.  This  difference  is  owing  to  the  fact  that  the  full  force  of  the  pulse 
does  not  reach  the  forearm  until  all  the  vessels  have  become  distended  with  blood. 
(3)  There  are  often  discrepancies  in  the  systolic  readings  taken  from  different  limbs; 
thus,  it  is  not  uncommon  to  find  that  the  systolic  pressure  in  the  leg  is  higher  than 
that  in  the  arm  even  when  the  observed  person  is  in  the  horizontal  position.  These 
differences  are  most  commonly  observed  in  patients  suffering  from  aortic  regurgita- 


BLOOD   PRESSURE  133 

tion  or  thickened  arteries.  In  aortic  regurgitation  the  pulse  is  of  the  water-hammer 
variety,  and  the  greater  systolic  pressure  observed  in  the  leg  vessels  in  such  cases 
seems  to  depend  on  differences  in  the  physical  conditions  concerned  in  the  transmission 
of  this  exaggerated  pulse  wave  to  the  vessels  of  the  two  extremities. 

The  reason  for  the  discrepancies  in  cases  of  hardened  arteries  is  no  doubt  that  the 
hardening  is  likely  to  be  more  pronounced  in  the  vessels  of  the  thigh  than  in  those  of  the 
arms.  When  a  hardened  vessel  is  compressed  it  does  not  collapse  uniformly — that  is, 
it  does  not  become  completely  closed — but  its  walls  come  together  at  the  middle  part 
while  chinks  still  remain  at  the  sides.  The  blood  continues  to  pass  through  these  chinks, 
and  a  very  considerably  higher  pressure  in  the  cuff  is  required  to  obliterate  them. 
That  this  is  probably  the  correct  explanation  is  supported  by  the  observation  that,  al- 
though in  such  patients  the  pulse  does  not  disappear  in  the  vessels  of  the  foot  at  the 
same  pressure  as  it  does  at  the  wrist,  a  distinct  change  is  nevertheless  perceptible  in 
the  pulse  of  the  foot  at  a  cuff  pressure  equal  to  that  producing  obliteration  in  that  of 
the  wrist.  In  a  patient  showing  a  systolic  pressure  of  115  mm.  for  the  upper  arm  and 
198  mm.  for  the  leg,  at  116  mm.  the  pulse  in  the  leg,  although  not  obliterated,  became 
notably  cut  down  in  volume.  Thereafter  it  persisted  at  a  small  volume  with  little 
alteration  until  the  pressure  became  sufficient  to  obliterate  it.  It  is  said  that  re- 
peated compression  and  decompression  of  the  hardened  arteries  greatly  reduces  the  dis- 
crepancy in  the  systolic  readings.  Differences  in  systolic  readings  are  also  sometimes 
observed  in  normal  individuals,  particularly  after  muscular  exercise,  but  for  these  no 
satisfactory  explanation  can  be  given. 

While  palpating  the  radial  artery,  it  will  often  be  noticed,  as  the  pressure  in  the 
cuff  is  gradually  raised  from  zero,  that  the  force  of  the  pulse  increases  perceptibly 
until  a  pressure  of  about  50  mm.  is  reached.  This  paradoxical  behavior  of  the  pulse 
can  also  be  demonstrated  by  the  sphygmograph  (see  page  202).  Its  cause  is  not  un- 
derstood, but  it  is  of  significance  that  the  greatest  augmentations  occur  at  the  same 
cuff  pressure  as  that  at  which  a  sound  first  comes  to  be  heard  by  listening  over  the 
artery  at  the  elbow. 

With  regard  to  the  diastolio  pressure,  there  has  been  some  controversy  as  to  whether 
it  is  more  accurately  gauged  by  the  oscillatory  or  the  auscultatory  method.  If  both 
methods  are  employed  it  will  usually  be  found  that  the  oscillatory  gives  a  higher  read- 
ing than  the  auscultatory.  The  consensus  of  opinion  seems  to  be  that  the  latter 
method  is  the  more  accurate,  and  certainly  it  is  the  easier  to  apply,  for  with  the 
oscillatory  there  is  often  great  difficulty  in  deciding  just  exactly  when  the  maximum 
oscillation  occurs. 

The  strongest  evidence  supporting  the  conclusion  that  the  auscultatory  readings  are 
more  reliable  than  the  oscillatory  has  been  gained  by  experiments  with  an  artificial 
schema,  consisting  of  a  wide  glass  tube  representing  the  armlet,  filled  with  Ringer's 
solution  and  closed  by  rubber  stoppers  pierced  by  tubes,  which  are  connected  with  a 
fresh  artery,  which  therefore  runs  from  end  to  end  inside  the  tube.  Through  tubing 
connected  with  the  artery  a  pulsatile  flow  of  oxygenated  Ringer's  solution'  is  made 
to  flow  at  varying  pressures,  which  are  indicated  by  valved  manometers  (see  page  152) 
connected  with  the  artery  tubing  just  beyond  the  compression  tube.  The  pressure  in 
the  latter  is  also  measured  by  a  manometer,  and  it  is  caused  to  vary  by  a  suitable 
compressor.  By  comparing  the  behavior  of  the  artery  with  the  pulsating  movement  of 
a  spring  manometer  connected  with  the  compression  chamber,  under  different  degrees 
of  pressure  inside  and  outside  the  artery,  it  has  been  observed  that  the  maximal  oscilla- 
tion occurs  when  the  artery  is  actually  somewhat  flattened  between  the  pulse  beats;  that 
is,  it  occurs  at  an  outside  pressure  above  the  diastolic  pressure,  at  which  of  course  the 
vessel  should  retain  its  circular  shape.  When  a  stethoscope  is  applied  to  the  tube 


134  THE   CIRCULATION   OF   THE   BLOOD 

leading  from  the  artery  just  beyond  the  compression  chamber,  in  the  above  described 
model,  sounds  similar  to  those  in  the  arm  are  heard  with  each  pulsation.  While  the 
pressure  is  being  gradually  lowered  from  above  the  obliteration  point,  these  sounds 
will  be  found  to  become  first  audible  as  soon  as  a  certain  amount  of  fluid  is  forced 
through  the  compressed  area  at  each  pulse  (the  systolic  index),  and  to  become  louder 
and  often  murmurish  in  quality  as  the  decompression  is  proceeded  with,  until  a  pres- 
sure is  reached  at  which  they  suddenly  become  less  intense  and  change  in  character.  At 
this  moment  it  will  be  observed  by'  watching  the  artery  that  the  external  pressure  is 
no  longer  capable  of  producing  any  flattening  of  the  vessel  between  pulses.  Evidently, 
therefore,  the  change  of  sound  corresponds  exactly  to  the  diastolic  pressure. 

With  regard  to  the  cause,  it  should  be  clearly  understood  that  it  is  the 
systolic  wave  that  produces  it,  although  its  occurrence  and  character  are 
dependent  upon  the  intra-arterial  pressure  existing  during  the  diastolic 
phase.  The  cause  of  the  sound  has  been  shown  to  depend  on  the  pro- 
duction of  a  water-hammer  in  the  blood  vessels  below  the  compres- 
sion cuff  (Erlanger3).  By  a  water-hammer  is  meant  the  pressure  changes 
which  are  caused  by  suddenly  stopping  the  flow  of  water  in  a  tube.  These 
changes  in  pressure  cause  the  walls  to  be  thrown  into  vibration  and  so 
produce  a  sound.  In  the  taking  of  blood-pressure  measurements, 
as  above  described,  when  the  pressure  in  the  cuff  is  between  the 
systolic  and  diastolic,  the  volume  of  the  compressed  artery  will  in- 
crease abruptly  with  each  heartbeat  and  thus  permit  a  considerable 
volume  of  swift-flowing  blood  to  enter  the  rest  of  the  artery  underneath 
the  cuff.  When  this  quickly  moving  column  of  blood  comes  into  con- 
tact with  the  stationary  blood  filling  the  uncompressed  artery  below  the 
cuff,  it  will  become  immediately  checked,  and  thus  distend  the  arterial 
wall  with  unusual  violence  and  set  it  into  vibration. 


CHAPTER  XVI 

THE  FACTORS  CONCERNED  IN  MAINTAINING  THE 
BLOOD  PRESSURE 

Having  become  familiar  with  the  principles  of  the  methods  by  which 
blood-pressure  measurements  are  made,  the  next  problem  is  to  examine 
into  the  causes  which  operate  to  maintain  the  pressure.  Two  of  these 
causes  may  be  considered  as  fundamental,  since  without  them  no  such 
pressure  could  exist.  These  are:  jl)  the  pumping  action  of  the  heart, 
and  (2)  the  peripheral  resistance — that  is,  the  resistance  to  outflow  of 
blood  from  the  ends  of  the  arterial  system.  Less  essential  though  im- 
portant factors  are:  (3)  the  volume  of  blood  in  the  blood  vessels,  (4) 
the  viscidity  or  viscosity  of  the  ^blood,  and  ^(5)  the  elasticity  of  the 
walls  of  the  vessels.  We  shall  now  pro.ceed  to  examine  the  experimental 
evidence  which  indicates  the  relative  importance  of  each  of  these  factors. 

1.  The  Pumping1  Action  of  the  Heart 

Changes  produced  in  the  mean  arterial  blood  pressure  by  alteration 
in  the  pumping  action  of  the  heart  are  most  strikingly  demonstrated  by 
observing  this  pressure  after  cutting  or  during  stimulation  of  the  vagus 
nerves.  As  will  be  explained  later  (page  222),  impulses  conveyed 
through  these  nerves  to  the  heart  make  the  beats  slower  and  weaker. 
These  impulses  are  constantly  acting  in  the  heart,  so  that  when  both 
vagus  nerves  are  cut,  the  beats  become  more  frequent  and  stronger, 
with  the  result  that  the  mean  arterial  pressure  rises  considerably.  A 
lesser  degree  of  this  effect  can  usually  be  obtained  by  cutting  the  vagus 
nerve  on  one  side  (Fig.  27).  If  now  the  peripheral  end  of  a  cut  vagus 
nerve  is  stimulated,  as  by  applying  an  electric  current  to  it,  the  heart  will 
either  stop  beating  altogether  or  become  very  much  slowed,  with  the  result 
that  the  mean  arterial  blood  pressure  will  fall,  in  the  former  case  almost  to 
zero  and  in  the  latter,  to  a  level  corresponding  to  the  degree  of  slowing 
of  the  heart  (Fig.  28). 

2.  The  Peripheral  Resistance 

To  demonstrate  the  influence  of  peripheral  .resistance  on  mean  arte- 
rial blood  pressure,  the  most  striking  experiment  is  performed  by  cutting 
or  stimulating  the  great  splanchnic  nerve.  Through  this  nerve,  impulses, 

135 


136 


THE   CIRCULATION   OF   THE   BLOOD 


Fig.    27. — Effect   of   cutting   the   vagus   nerve   on   the   arterial    blood    pressure. 


Fig.    28. — Effect    of    stimulating    the    peripheral    end    of    the    right    vagus    on    the    arterial    blood 

pressure. 


BLOOD   PRESSURE  137 

which  are  called  vasoconstrictor  because  they  constrict  the  lumen  of  the 
blood  vessels,  are  transmitted  to  the  blood  vessels  in  the  abdomen. 
The  vessels  are  under  the  constant  influence  of  these  impulses  so  that, 
when  the  nerves  that  transmit  them  are  severed,  the  vessels  dilate  and 
thus  offer  less  resistance  to  the  movement  of  blood.  The  result 
produced  on  the  mean  arterial  blood  pressure  by  cutting  the  two 
splanchnic  nerves  is  therefore  a  marked  and  sudden  fall,  which  is  im- 


Fig.     29. — Effect    of    stimulation    of    the    left    splanchnic    nerve    on    the    arterial    blood    pressure. 
Note    the    primary    and    secondary    rises. 

mediately  recovered  from  if  the  peripheral  end  of  one  of  the  cut  nerves  is 
stimulated  artificially  (Fig.  29).  In  choosing  this  experiment  to  prove  the 
relationship  between  peripheral  resistance  and  the  mean  arterial  blood 
pressure,  it  must  be  remembered  that  it  is  not  entirely  conclusive,  since 
the  results  observed  on  the  mean  arterial  blood  pressure  from  cutting 
or  stimulating  the  nerve  may  be  in  part  explained  as  due  to  variation 
in  the  total  capacity  of  the  circulation ;  more  room  is  created  by  cutting 
the  nerves,  less  room  by  stimulating  them. 


138  THE    CIRCULATION   OF    1HE   BLOOD 

3.  The  Amount  of  Blood  in  the  Body 

This  can  be  altered  by  hemorrhage  or  transfusion,  and  the  results 
of  such  procedures  are  of  interest  not  only  on  account  of  their  physi- 
ological bearing,  but  also  because  of  their  great  practical  importance. 

To  appreciate  the  significance  of  the  results,  it  is  important  to  bear  in 
mind  that  the  total  volume  of  the  ~blood  constitutes  from  5  to  7  per  cent 
of  the  weight  of  the  animal  (see  page  85). 

The  immediate  effect  of  hemorrhage  on  the  blood  pressure  depends  on 
the  rate  of  bleeding.  If  a  large  artery,  such  as  the  femoral,  is  cut  across, 
the  pressure  will  show  an  immediate  but  moderate  fall,  due  largely  to  the 
fact  that  we  have  suddenly  decreased  the  peripheral  resistance.  If  on 
the  other  hand  only  a  small  artery  or  a  vein  is  opened,  the  bleeding  will 
at  first  produce  no  effect  on  the  blood  pressure,  and  it  is  only  after  some 
considerable  amount  of  blood  has  been  removed  that  it  begins  to  fall. 
To  be  more  exact,  we  may  state  that  the  removal  of  5  c.c.  of  blood  per 
kilogram  of  body  weight  does  not  influence  the  blood  pressure.  The  re- 
moval of  a  second  portion  of  5  c.c.  per  kilogram  causes  the  blood  pres- 
sure to  begin  to  fall,  the  fall  of  pressure  for  each  subsequent  5  c.c.  of 
blood  per  kilogram  removed  averaging  about  6  mm.  Hg,  until  after  20 
to  25  c.c.  of  blood  per  kilogram  have  been  removed,  when  a  more  rapid 
fall  in  pressure  sets  in  (Downs'*).  When  the  pressure  reaches  the  level 
of  from  20  to  30  mm.  Hg,  the  danger  limit  is  reached,  for  there  now 
supervenes  a  train  of  symptoms  known  as  * '  shock, ' '  and  the  chances  for  the 
animal's  recovery  become  uncertain.  That  the  removal  of  the  first  por- 
tion of  blood,  if  this  removal  is  slow  enough,  does  not  influence  the  blood 
pressure,  indicates  that  some  adjustment  has  occurred  in  the  vascular 
system  to  hold  up  the  pressure  in  spite  of  the  loss  of  blood.  This  adjust- 
ment is  believed  to  consist  in  vasoconstriction. 

Recovery  from  hemorrhage  is  remarkably  rapid,  the  original  volume  of 
blood  being  restored  within  a  few  hours.  The  chances  of  recovery  de- 
pend upon  the  amount  of  blood  lost.  A  loss  equal  to  2  or  3  per  cent  of 
the  body  weight  can  almost  always  be  recovered  from  in  laboratory  ani- 
mals, and  in  the  case  of  man  there  is  reason  to  believe  that  recovery 
may  occur  after  as  much  as  3  per  cent  of  the  body  weight  has  been  lost. 
The  recovery  of  blood  pressure  is  brought  about  partly  by  a  transfer 
of  fluid  from  the  tissues  to  the  blood.  This  abstraction  causes  a  drying 
out  of  the  tissues,  which  soon  excites  an  extreme  degree  of  thirst.  The 
dilution  of  blood  by  fluid  derived  from  the  tissues  occurs  very  rapidly, 
as  can  be  shown  by  comparison  of  the  hemoglobin  content,  or  the  number 
of  blood  corpuscles,  in  samples  of  blood  removed  immediately  before 


BLOOD    PRESSURE  139 

and  immediately  after  a  hemorrhage.  The  specific  gravity  of  the  post- 
hemorrhagic  blood  is  also  decidedly  below  normal,  indicating  that  the 
diluting  fluid  contains  a  lower  concentration  of  dissolved  substances  than 
the  blood  plasma.  The  dilution  of  the  blood  is  indeed  often  so  great  that 
hemolysis  occurs,  the  plasma  being  distinctly  tinted  red. 

Hemorrhage  also  slightly  raises  the  hydrogen-ion  concentration  of  the 
blood  plasma,  and  diminishes  the  store  of  reserve  alkali,  so  that  the  ad- 
dition of  a  certain  amount  of  acid  to  the  blood  (e.g.,  carbon  dioxide) 
causes  a  greater  rise  in  the  hydrogen-ion  concentration. 

The  deficiency  in  the  blood  elements  produced  by  the  dilution  is  recti- 
fied by  the  manufacture  of  new  corpuscles  in  the  bone  marrow,  etc.,  but 
this  process  in  a  liberally  fed  animal  takes  several  days  for  accomplish- 
ment, and  while  it  is  going  on  microscopic  examination  of  the  blood  will 
reveal  the  presence  of  immature  corpuscles. 

Careful  studies  of  blood  regeneration  following  the  removal  on  two 
successive  days,  of  25  per  cent  of  the  blood,  have  shown  that  even  in 
starving  animals  the  total  amount  of  hemoglobin  (percentage  of  hemo- 
globin multiplied  by  the  volume  of  blood)  slowly  recovers  (Whipple 
and  Hooper).  Recovery  is  greatly  hastened  by  feeding  with  flesh  or 
even  with  gelatin.  Removal  of  the  spleen  or  the  establishment  of  a  bili- 
ary fistula  does  not  interfere  with  the  recovery. 

Incidentally  it  will  be  advantageous  to  consider  here  the  effects  of 
transfusion,  These  are  very  different  according  to  the  nature  of  the  fluid 
used  for  transfusion.  Three  transfusion  fluids  have  been  investigated: 
(1)  blood  itself,  (2)  physiological  saline  solution  (see  page  96),  and  (3) 
physiological  saline  solution  containing  viscid  substances  such  as  gum  or 
gelatin.  The  effects  are  also  very  different  according  to  whether  the  solu- 
tions are  injected  into  animals  with  normal  blood  pressure  or  into  those 
whose  blood  pressure  has  been  lowered  by  preceding  hemorrhage.  The 
general  effects  are  shown  in  the  curves  of  Fig.  30. 

When  blood  is  injected  into  animals  with  normal  blood  pressure,  it 
will  very  soon  cause  the  pressure  to  rise,  and  as  the  injection  is  main- 
tained the  rise  may  continue  until  the  pressure  is  perhaps  50  per  cent 
or  more  above  its  normal  level.  If  the  injection  is  long  continued,  how- 
ever, a  sudden  fall  of  pressure  occurs,  on  account  of  engorgement  of  the 
right  side  of  the  heart.  If  the  injection  is  not  pushed  so  far,  the  increased 
blood  pressure  after  being  maintained  for  a  short  time  returns  to  its  old 
level. 

Injection  of  saline  into  a  normal  animal,  if  made  slowly,  has  no  effect 
at  all  on  the  blood  pressure;  if  more  rapidly  injected,  the  pressure  will 
rise  slightly,  but  to  a  much  less  extent  than  that  observed  when  blood 
itself  is  injected.  Much  larger  quantities  of  the  saline  than  of  the  blood 


140 


THE    CIRCULATION    OF    THE    BLOOD 


can  be  tolerated  before  cardiac  embarrassment  ensues.  After  the  dis- 
continuance of  the  saline  injection,  the  blood  pressure  returns  very 
rapidly  to  its  old  level.  The  most  striking  result  of  such  experiments  is 
the  enormous  volume  of  saline  solution  which  can  be  slowly  injected 
without  perceptibly  affecting  the  pressure.  The  question  is,  Where  does 
the  fluid  go  ?  If  the  urinary  outflow  is  examined,  a  certain  increase  will 


Fig.  30. — Composite  curves  to  show  effects  on  blood  pressure  of  hemorrhage,  and  transfusion 
with  various  solutions  (N.  M.  Keith,  from  Bayliss).  The  average  pressure  in  the  various  experi- 
ments before  and  after  hemorrhage  is  given  on  the  left  in  a  continuous  line.  The  behavior  of  the 
pressure  after  transfusion  varied  according  to  the  solution  used. 


BLOOD   PRESSURE  141 

usually  be  observed,  but  never  by  any  means  sufficient  to  account  for 
the  disappearance  of  the  injected  saline.  If  we  open  the  abdominal  cav- 
ity, we  shall  find  that  a  considerable  transudation  of  the  saline  into  the 
peritoneal  cavity  has  occurred,  and  that  the  liver  is  conspicuously  edem- 
atous.  A  certain  degree  of  edema  is  also  usually  evident  in  the  tissues 
of  the  extremities. 

Still  more  interesting  and  important,  from  a  practical  standpoint,  are 
the  results  obtained  by  injecting  the  above  solutions  into  animals 
whose  blood  pressure  has  been  lowered  by  a  previous  hemorrhage.  If 
the  blood  removed  during  the  hemorrhage  is  defibrinated  (see  page  102), 
and  then  reinjected  into  the  animal,  it  will  bring  the  blood  pressure  al- 
most but  not  quite  back  to  its  original  level,  which  will  then  be  fairly 
well  maintained.  If,  on  the  other  hand,  saline  solution  instead  of  blood 
is  injected,  the  restoration  of  blood  pressure  (with  an  amount  of  saline 
equal  to  that  of  the  removed  blood)  will  amount  only  to  about  three- 
quarters  of  the  extent  to  which  it  had  fallen.  This  partial  recovery  is, 
moreover,  maintained  for  a  short  time  only,  after  which  the  pressure 
approaches  the  level  to  which  it  was  reduced  by  the  hemorrhage. 

These  observations  raise  two  important  practical  questions:  (1)  Why 
is  saline  relatively  ineffective  in  the  restoration  of  pressure?  and  (2) 
Why  is  the  restored  pressure  not  maintained? 

The  answers  to  these  questions  brings  us  to  a  consideration  of  the  next 
of  the  factors  concerned  in  the  maintenance  of  the  blood  pressure, 
namely,  the  viscosity  of  the  blood. 

4.  The  Viscosity  of  the  Blood 

The  importance  of  this  factor  arises  from  the  fact  that  facility  of  flow 
in  a  tube  is  inversely  proportional  to  the  viscosity  of  the  fluid  and 
directly  proportional  to  the  driving  pressure  to  which  it  is  subjected — 
that  is,  to  the  difference  in  pressure  between  two  points  in  the  tube. 
If  therefore  the  output  of  the  heart  remain  constant,  but  the  viscos- 
ity of  the  blood  be  decreased  by  a  saline  injection,  the  facility  of  flow 
will  be  increased  and  the  pressure  decreased.  This  fact  can  easily 
be  shown  experimentally  in  a  model  by  causing  gum  solutions  of  various 
concentrations  to  be  driven  through  a  glass  tube  by  means  of  a  small 
piston  pump  delivering  a  constant  amount  of  fluid  into  the  tube  with 
each  movement.  Although  the  outflow  from  the  narrow  end  of  the  tube 
must  remain  constant,  the  pressure  in  the  tubing  will  vary  in  proportion 
to  the  viscosity  of  the  gum  solution  (Bayliss5.) 

Transferring  these  results  to  an  animal  whose  blood  pressure  has  been 
lowered  by  hemorrhage,  it  has  been  found  that  if  saline  solutions  con- 


142  THE   CIRCULATION   OF   THE   BLOOD 

taining  a  sufficient  amount  of  gum  acacia  or  gelatin  to  make  the  viscos- 
ity about  equal  to  that  of  blood,  are  injected,  the  original  level  of  blood 
pressure  is  recovered  as  well  as  it  would  have  been  had  blood  itself  been  in- 
jected. A  7  per  cent  solution  of  gum  acacia  almost  fulfills  these  require- 
ments, but  unfortunately  this  solution  contains  a  slightly  greater  amount 
of  calcium  than  it  is  safe  to  inject  into  an  animal.  The  excess  of  calcium 
may,  however,  be  removed  by  exactly  neutralizing  the  gum  solution  with 
sodium  hydroxide,  neutral  red  being  used  as  an  indicator.  Most  of  the 
calcium  becomes  precipitated  as  phosphate.  The  mucilage  of  the  British 
Pharmacopeia,  diluted  five  times  with  water,  makes  a  7  per  cent  solu- 
tion of  gum  acacia.  A  6  per  cent  solution  of  gelatin,  after  being  heated 
to  100°  C.,  gives  a  viscosity  similar  to  that  of  blood,  but  on  account  of 
the  possible  presence  of  tetanus  spores  such  solutions  must  be  very  care- 
fully sterilized  before  injection,  and  the  process  of  sterilization  causes 
a  decrease  in  viscosity.  The  injection  of  a  quantity  of  one  of  the  above 
solutions  equal  to  that  of  blood  lost  by  a  hemorrhage  will  usually  bring 
the  blood  pressure  back  to  its  original  height  and  hold  it  there  for  an 
hour  or  so. 

Viscosity  is,  however,  not  the  only  property  of  such  solutions  upon 
which  their  desirable  effect  depends.  The  osmotic  pressure  of  the  colloids 
also  comes  into  play.  By  injecting  saline  solution  containing  a  sufficient 
amount  of  a  colloid  such  as  soluble  starch,  which  gives  it  the  correct 
viscosity  but  has  no  osmotic  pressure,  the  blood  pressure,  although  it 
temporarily  recovers  after  transfusion,  does  not  maintain  its  recovery  in 
the  same  way  as  with  solutions  containing  gum  or  gelatin.  The  difference 
between  a  starch  solution  and  one  of  gum  or  gelatin  is  that  the  former 
has  no  osmotic  pressure.  This  property  influences  the  rate  at  which  water 
passes  through  the  walls  of  the  capillaries  as  can  be  shown  by  observing 
the  outflow  of  urine  from  the  ureters  during  the  injection  into  animals 
of  saline  alone  or  of  saline  containing  either  starch  or  gelatin  (Knowl- 
ton6).  Diuresis  is  produced  with  either  of  the  first  two,  but  not  with 
the  gelatinous  solution.  The  reason  that  the  osmotic  pressure  of  certain 
colloids  prevents  passage  of  water  from  the  blood  into  the  uriniferous 
tubules  is  that  the  development  of  this  pressure  on  the  blood  side  of 
the  renal  epithelium  tends  to  counteract  the  filtration  pressure  by  which 
the  urine  is  formed  (see  page  547). 

Although  the  urinary  factor  will  not  in  itself  explain  the  efficiency  of 
the  colloids  in  recovering  the  blood  pressure,  the  conditions  controlling 
it  reveal  the  mechanism  by  which  the  passage  of  fluid  from  the  blood 
vessels  into  the  tissues  is  prevented  when  solutions  of  correct  composi- 
tion are  injected.  Normally  the  protein  content  of  the  blood  plasma  is 
higher  than  that  of  the  tissue  lymph,  so  that  there  is  a  continual  attrac- 


BLOOD   PRESSURE  143 

tion  of  water  from  the  tissues  to  the  blood — an  attraction  which  is  nor- 
mally balanced  by  nitration  going  in  the  opposite  direction.  When  the 
nitration  pressure  in  the  blood  vessels  exceeds  the  difference  existing 
between  the  osmotic  pressure  of  their  contents  and  that  of  the  tissue 
fluids,  water  will  pass  into  the  tissue  spaces.  When  the  blood  is  diluted, 
as  by  the  injection  of  saline  solution,  the  osmotic  pressure  of  the  colloids 
in  a  given  volume  becomes  lowered  and,  the  nitration  pressure  remaining 
constant,  fluid  passes  into  the  tissue  spaces.  Of  course  these  explanations 
rest  on  the  assumption  that  the  walls  of  the  blood  vessels  consist  of  a 
membrane  which  is  permeable  to  crystalloids  but  impermeable  or  nearly 
so  to  colloids.  A  further  account  of  the  use  of  the  solutions  for  transfu- 
sion in  cases  of  surgical  shock  will  be  found  on  page  311. 

Another  important  property  of  the  transfused  saline  solution  to  con- 
sider is  its  hydrogen-ion  concentration.  This  value  increases  in  the  blood 
left  in  the  body  after  hemorrhage,  and  injection  of  sodium  chloride  solu- 
tion aggravates  the  acidosis;  addition  of  NaHC03  so  as  to  make  a  0.2 
M  solution  restores  the  correct  PH,  and  at  the  same  time  restores  the 
lost  buffer  influence  (Milroy7.)  These  observations  are  of  interest  in  the 
light  of  the  recent  discovery  of  Cannon  that  a  condition  of  acidosis,  as 
judged  by  the  C02-combining  power  of  the  blood,  is  present  in  shock, 
and  that  the  development  of  this  condition  can  often  be  guarded  against 
by  bicarbonate  injections. 

5.  Elasticity  of  Vessel  Walls 

The  elasticity  of  the  vessel  walls  is  essential  to  the  maintenance  of  the 
diastolic  pressure.  If  the  walls  possessed  no  elasticity  but  were  rigid, 
blood  pressure  would  fall  to  zero  between  the  heartbeats.  This  fact  can 
very  readily  be  shown  by  a  simple  physical  model  consisting  of  a  pump, 
to  represent  the  heart,  connected  through  a  T-piece  with  two  tubes,  one 
of  which  is  elastic,  the  other  rigid.  The  free  end  of  each  tube  is  con- 
tracted to  a  narrow  aperture  representing  the  peripheral  resistance,  and 
either  tube  may  be  shut  off  from  the  pump  by  means  of  a  stopcock  (see 
Fig.  31).  Each  tube  should  also  be  connected  with  a  mercury  manom- 
eter. If  now  the  stopcocks  are  arranged  so  that  the  fluid  passes  into 
the  rigid  tube  while  the  pump  is  in  action,  it  will  be  found  that  with 
each  stroke  of  the  pump  the  pressure  in  the  tube  rises  considerably,  but 
that  it  falls  to  zero  between  the  strokes.  If  now  the  stopcocks  are  turned 
so  that  the  flow  is  through  the  elastic  tube,  the  action  of  the  pump  being 
meanwhile  kept  up,  it  will  be  found  that  the  pressure  between  the  strokes 
is  maintained  at  a  height  which  is  dependent  on:  (1)  the  rate  at  which 
the  pump  is  operating,  and  (2)  the  resistance  to  outflow  from  the  tube. 


144  THE   CIRCULATION   OF   THE   BLOOD 

The  quicker  the  action  of  the  pump  and  the  higher  the  resistance,  the 
lower  the  fall  of  pressure  between  the  beats. 

The  physical  explanation  of  this  result  is  clearly  that  the  fluid  within 
the  elastic  tube  when  the  wave  of  pressure  travels  into  it  from  the  pump 
distends  the  walls  of  the  tube,  so  that  when  the  pressure  from  the  pump 
ceases  to  act,  the  stretched  elastic  walls  recoil  on  the  column  of  fluid 
and  so  maintain  the  pressure.  We  may  say  that  the  elastic  fibers  in  the 
vessel  walls  store  up  some  of  the  systolic  pressure  and  then  transmit  it  to 
the  blood  during  diastole. 


Fig.  31. — Diagram  of  experiment  to  show  that  the  diastolic  pressure  depends  on  the  elasticity 
of  the  vessel  wall.  The  pulse  (produced  by  compressing  the  bulb  B)  disappears  when  fluid 
flows  through  an  elastic  tube  (F)  when  there  is  resistance  (g)  to  the  outflow.  A,  basin  of 
water;  B,  bulb  syringe;  C  and  E,  stopcocks;  D,  rigid  tube;  F,  elastic  tube;  G,  bulb  filled  with 
sponge. 

These  considerations  would  lead  us  to  expect  that  patients  with  hard- 
ened arteries  should  exhibit  a  lower  diastolic  pressure  than  normal  per- 
sons, which,  however,  is  not  usually  the  case,  since  such  patients  also 
suffer  from  an  increase  in  the  resistance  to  the  flow  of  blood  in  the  periph- 
ery. The  pressure  pulse  in  these  patients  is,  however,  very  marked. 
On  the  other  hand,  when  the  vessel  walls  become  more  extensible  and 
elastic,  as  in  certain  cases  of  aneurism,  the  pressure  pulse  in  the  vessels 
below  the  aneurism  is  distinctly  less  than  that  observed  in  normal  ves- 
sels of  the  same  patient. 


CHAPTER  XVII 
THE  ACTION  OF  THE  HEART 

Having  studied  the  methods  for  measurement  and  the  main  factors  con- 
cerned in  the  maintenance  of  the  arterial  blood  pressure,  we  may  now  pro- 
ceed to  study  in  greater  detail  the  two  most  important  of  these ;  namely,  the 
action  of  the  heart,  and  the  peripheral  resistance. 

The  heart  action  has  to  be  studied  from  two  viewpoints,  the  physical 
and  the  physiological.  From  the  physical  viewpoint  we  have  to  study 
the  heart  as  the  pump  of  the  circulation.  We  must  see  how  it  acts  so  as 
to  raise  the  pressure  of  the  blood  within  it,  and  how  the  valves  operate 
so  as  to  direct  the  bloodflow  always  in  one  direction.  We  must  also  ex- 
plain the  causes  of  certain  secondary  physical  phenomena,  such  as  the 
heart  sounds  which  accompany  the  heart  action,  and  of  certain  secondary 
changes  in  pressure  produced  in  the  other  thoracic  viscera  by  each  heart- 
beat. From  the  physiological  viewpoint  we  must  investigate  the  conditions 
responsible  for  the  constant  rhythmic  activity  of  the  heart  and  the  con- 
trol to  which  this  is  subjected  through  the  nervous  system. 

THE  PUMPING  ACTION  OF  THE  HEART 

When  the  heart  is  viewed  in  the  opened  thorax  of  an  animal  kept  alive 
by  artificial  respiration  and  lying  in  the  prone  position,  it  can  be  noted 
that  with  each  contraction  the  ventricles  become  smaller  and  harder,  that 
the  apex  tends  to  rise  up  a  little,  so  that  if  the  thorax  were  intact  it 
would  press  more  firmly  against  the  walls,  and  that  it  rotates  slightly 
from  left  to  right,  but  does  not  move  nearer  the  base  of  the  heart.  If 
the  auriculoventricular  groove  is  carefully  observed,  it  will  often  be 
noted  that  it  moves  slightly  toward  the  apex  with  each  systole,  whereas 
the  base  of  the  heart  itself,  where  it  is  attached  to  the  large  vessels,  re- 
mains fixed.  The  auricles  can  often  be  seen  to  contract  and  relax  before 
the  ventricles. 

The  most  noteworthy  results  of  this  inspection  are  that  during  sys- 
tole the  apex  of  the  heart  does  not  move  toward  the  base,  but  that 
the  auriculoventricular  groove  moves  slightly  toward  the  apex.  That 
these  same  movements  occur  in  the  intact  animal  can  be  shown  by  the 
very  simple  experiment  of  pushing  two  long  steel  knitting  needles 

145 


146  THE   CIRCULATION   OF   THE   BLOOD 

through  the  thoracic  walls  into  the  heart  walls,  one  of  them  so  placed 
that  it  pierces  the  apex  of  the  ventricle,  the  other  so  that  it  pierces  the 
base.  The  needles  then  act  as  levers  with  their  fulcra  at  the  chest  wall, 
and  if  the  movements  of  their  outer  free  ends,  produced  by  the  movements 
of  the  heart,  are  observed,  they  will  be  found  to  confirm  the  observations 
made  on  the  exposed  heart. 

More  particular  investigations  of  the  changes  occurring  in  the  shape  of  the  heart 
cavity  during  systole  and  diastole  have  been  undertaken  by  making  measurements  of  sec- 
tions across  the  heart  in  one  or  other  of  these  conditions.  For  such  purposes  the  heart  in 
diastole  is  easily  obtained,  but  for  the  heart  in  systole  it  is  necessary  to  use  the  some- 
what artificial  means  of  injecting  the  heart  with  hot  chromic  acid  solution  just  be- 
fore the  death  of  the  animal.  The  chromic  acid  causes  the  cardiac  muscle  to  contract 
and  maintains  it  in  this  condition.  The  outcome  of  these  investigations  is,  however, 
not  of  much  practical  importance. 

Although  it  is  now  common  knowledge  that  the  direction  of  the  flow  of  the  blood 
is  from  the  veins  to  the  arteries,  yet  it  may  be  of  interest  to  consider  for  a  moment 
the  general  principle  of  the  methods  by  which  William  Harvey  succeeded  in  making 
this  discovery.  His  evidence  was  partly  anatomic,  partly  experimental.  He  pointed 
out  that  the  walls  of  the  veins,  and  of  the  auricles  to  which  they  lead,  are  very  thin, 
whereas  those  of  the  arteries  and  ventricles  are  very  thick,  and  he  concluded  that 
in  the  veins  the  blood  must  flow  gently  from  the  tissues  toward  the  heart,  to  which  the 
valves  in  the  veins  direct  it,  and  that  in  the  arteries  it  must  be  propelled  by  pulses 
with  each  systole  through  the  arteries  towards  the  tissues  by  the  contraction  of  the 
walls  of  the  ventricles.  The  experimental  support  for  this  hypothesis  he  furnished 
partly  by  clamping  the  large  vessels,  veins  and  arteries  leading  to  or  from  the  heart, 
and  observing  the  resulting  distention  or  collapse  of  the  vessel;  and  partly  by  cal- 
culation of  the  amount  of  blood  which  must  be  expelled  from  the  ventricles  in  a  given 
period  of  time. 

Harvey's  discoveries  concerning  the  events  of  the  cardiac  cycle  were 
not  much  added  to  until  experimental  methods  were  devised  by  which 
the  pressure  changes  occurring  in  the  various  cavities  could  be  measured 
and  compared.  Until  such  measurements  were  elaborated,  it  was  impos- 
sible to  investigate  the  mechanism  by  which  the  various  valves  between 
the  heart  cavities  and  the  vessels  connected  with  them  perform  their 
function,  or  to  describe  with  any  degree  of  accuracy  the  events  occurring 
in  the  heart  chambers  during  the  various  phases  of  the  cardiac  cycle. 
It  is  for  the  purpose  of  ascertaining  the  exact  time  relationship  of  these 
changes  that  intracardiac  pressure  curves  are  studied. 

Intracardiac  Pressure  Curves 

The  earliest  method  for  taking  such  curves  consisted  in  introducing 
into  the  cardiac  chambers  and  the  blood  vessels  of  the  horse,  so-called 
cardiac  sounds.  These  consisted  of  a  more  or  less  rigid  tube  furnished  at 
one  end  with  a  little  elastic  bag  or  ampulla  and  connected  at  the  other 
with  a  tambour,  by  means  of  rubber  tubing.  One  of  these  little  bags 


THE    ACTION    OF    THE   HEART 


147 


was  placed  in  one  of  the  ventricles,  another  in  the  auricle  or  aorta,  the 
tube  being  inserted  in  the  former  case  through  one  of  the  large  veins  at 
the  root  of  the  neck ;  in  the  latter  case  through  the  carotid  artery.  The 
intracardiac  pressure  curves  obtained  in  this  way  marked  a  great  ad- 
vance over  the  methods  that  had  previously  been  used  to  study  the  events 
of  the  cardiac  cycle,  but  they  were  so  faulty  in  comparison  with  tracings 
taken  by  more  modern  methods  that  it  is  not  worth  while  considering 
them  any  further  here. 

The  physical  errors  involved  in  the  use  of  the  older  instruments  were  due  mainly  to 
the  elastic  recoil  of  the  membranes,  etc.,  used  in  their  construction.  A  great  improve- 
ment in  technique  was  afforded  by  the  use  of  the  spring  manometer  of  Hiirthle  (see  page 
128),  which  was  connected  with  one  of  the  heart  cavities  by  a  cannula  filled  before 


Fig.  32. — Diagram  of  Wiggers'  optical  manometer.  The  wide  glass  tube  (A)  (connected 
with  the  ventricle,  etc.)  is  connected  with  a  brass  cylinder  (B)  provided  with  a  stopcock  (C), 
the  lumen  of  which  comes  in  apposition  with  a  plate  (a)  having  a  small  opening  in  it.  The 
freedom  of  communication  between  B  and  a  is  regulated  by  the  position  of  the  tap.  Above  a  is 
a  segment  capsule  (&)  3  mm.  in  diameter  and  covered  by  rubber  darn.  This  carries  a  small 
mirror  (C)  fastened  so  that  it  pivots  on  the  chord  side  of  the  capsule.  Above  the  capsule  is 
arranged  an  inclined  mirror,  from  which  a  strong  beam  of  light  is  reflected  on  to  the  mirror 
(c)  on  the  capsule.  This  beam  then  travels  back  and  the  mirror  (£)  is  adjusted  so  that  it 
impinges  on  a  moving  photographic  plate.  The  slightest  movements  of  the  small  mirror  (C) 
are  thus  greatly  magnified. 

insertion   with   some    anticoagulant    fluid.     The    cavity   of   the   tambour   was   made    as 
small  as  possible,  and  either  left  empty  or  filled  with  the  anticoagulating  fluid. 

A  searching  investigation  into  the  physical  principles  involved  in  taking  records  of 
sudden  changes  in  pressure  by  such  instruments  has,  however,  shown  that  considerable 
errors  are  incurred,  the  inertia  of  the  moving  mass  of  fiuid  in  the  tubing  and  the 
necessity  of  using  levers  in  order  to  secure  records  being  responsible  for  most  of  them 
(cf.  Wiggers).  Their  elimination  has  recently  been  achieved  by  using  a  so-called 
optical  manometer,  one  of  which  (Wiggers')  is  shown  in  the  accompanying  figure.  It 
consists  of  a  wide  glass  tube  A,  connected  above  with  a  hollow  brass  cylinder  B,  pro- 
vided with  a  stopcock  C,  the  lumen  of  which  tapers  from  below  upward  till  it  assumes 
the  same  diameter  as  an  aperture  in  the  segment  capsule  fc,  above  it — that  is,  a  capsule 


148 


THE   CIRCULATION   OF   THE   BLOOD 


cut  away  at  one  end  —  which  is  3  mm.  in  diameter  and  covered  with  rubber  dam.  By 
adjustment  of  this  stopcock  the  pulsations  of  the  fluid  in  A  and  B  can  be  damped  to 
a  greater  or  less  extent  before  they  are  transmitted  into  the  segment  capsule.  A  small 
piece  of  celluloid  carrying  a  tiny  mirror  rests  on  the  rubber  dam,  being  pivoted  on  the 
chord  side  of  the  capsule.  A  mirror  is  attached  to  the  capsule  with  its  plane  so  ad- 
justed that  the  image  of  a  strong  light  placed  at  some  distance  from  it  is  focused  on  the 
little  mirror  carried  by  the  celluloid.  The  ray  reflected  from  the  little  mirror  and 
again  reflected  from  the  larger  mirror  is  adjusted  so  as  to  impinge  upon  a  moving 
photographic  plate  travelling  at  a  uniform  rate  in  a  suitably  constructed  photographic 
apparatus.  By  the  use  of  such  an  apparatus  the  chief  errors  encountered  by  the  use 
of  the  older  instruments  are  eliminated,  because  there  is  no  moving  mass  of  fluid  and 
there  are  no  levers  to  set  up  spurious  vibrations.  Curves  secured  by  the  use  of  this 
instrument  are  shown  in  Fig.  33. 


V 


Fig.  33. — Optical  records  of  intraventricular  pressure;  a-b,  auricular  systole;  b-d,  presphygmic 
period;  d-f,  sphygmic  period;  after  f,  diastole.  Instruments  of  varying  degrees  of  sensitiveness 
were  employed  in  taking  the  curves.  ('From  Wiggers.) 

Two  objects  must  be  kept  in  view  in  analyzing  the  curves:  (1)  Curves 
obtained  from  the  different  cavities  may  be  compared  in  order  to  de- 
termine the  exact  moment  during  the  cardiac  cycle  at  which  such  pres- 
sure changes  occur  as  must  serve  to  produce  opening  or  closing  of  the 
various  valves;  and  (2)  the  contour  of  the  curves  obtained  from  each 
cavity  may  be  examined  in  order  to  find  out  exactly  how  the  pressure 
in  that  particular  cavity  is  behaving. 

Comparison  of  the  Curves 

Before  using  the  curves  for  ascertaining  the  relative  pressure  in  the 
different  cavities,  they  must  be  graduated  according  to  some  scale,  for 
it  is  clear  that  by  the  use  of  instruments  like  those  we  have  been  describ- 
ing, the  absolute  pressure  value  of  each  curve  will  vary  according  to  the 
construction  of  the  instrument  (thickness  of  membrane,  etc.),  and  in- 
deed instruments  of  varying  degrees  of  resistance  must  be  employed  in 
taking  curves  from  places  having  such  different  pressures  as  exist  in 
the  auricles  and  ventricles.  The  graduation  is,  however,  a  very  easy 
matter,  and  consists,  as  already  explained  (page  128),  in  connecting  the 


THE   ACTION    OF    THE   HEART  149 

instrument  by  means  of  a  T-piece  with  a  mercury  manometer  and  a  pres- 
sure bottle  and  then  marking  on  the  tracing,  the  points  corresponding  to 
each  10,  20  or  50  millimeters  of  increase  of  pressure,  as  the  case  may  be. 

To  ascertain  the  time  relationship  between  the  opening  and  the  closing 
of  the  auriculoventricular  valve,  the  tracings  should  be  taken  simultaneously 
from  the  right  auricle  and  the  right  ventricle,  and  to  ascertain  the  same 
with  regard  to  the  semilunar  valve,  from  the  left  ventricle  and  the  aorta.* 

By  comparing  the  curves  it  is  now  an  easy  matter  to  ascertain  the 
exact  moment  at  which  the  pressure  in  the  one  cavity  comes  to  equal 
that  in  the  other.  This  moment,  read  on  the  accompanying  time  tracing, 
will  obviously  indicate  that  at  which  the  particular  valve  is  just  about  to 
open  or  close.  From  the  results  of  such  experiments,  the  curves  may  be 
superimposed  as  in  Pig.  34. 

In  the  first  place  let  us  compare  the  curves  from  the  right  auricle  and 
ventricle.  The  curves  begin  at  the  very  end  of  diastole,  and  they  show 
that  a  distinct  increase  in  pressure  is  occurring  in  both  auricle  and  ven- 
tricle and  lasting  about  0.1  second.  This  is  of  course  caused  by  auric- 
ular systole,  and  since  it  occurs  in  both  cavities,  it  indicates  that  the 
passage  between  them,  the  auriculoventricular  orifice,  must  be  open. 
The  ventricular  curve  then  suddenly  shoots  away  beyond  the  auricular 
because  of  the  onset  of  systole  in  the  ventricle,  and  the  point  at  which 
the  two  curves  begin  to  separate  indicates  the  moment  at  which  the 
auriculoventricular  valves  close.  From  this  time  on  until  ventricular 
systole  has  given  place  to  diastole,  (0.3  second),  the  auricle  is 
therefore  shut  off  from  the  ventricle.  The  exact  moment  in  diastole  at 
which  the  two  cavities  are  again  brought  into  communication — i.e.,  the 
auriculoventricular  valves  open — is  indicated  by  the  curves  coming  to- 
gether. 

Having  thus  determined  the  exact  moments  of  opening  and  closing 
of  the  auriculoventricular  valve,  we  may  now  proceed  to  compare  the 
intraventricular  pressure  curve  with  that  taken  from  the  aorta.  After  the 
necessary  calibration  corrections,  this  curve  has  been  placed  in  Fig.  34 
in  its  true  relationship  to  the  ventricular  curve.  Beginning  again  at  the 
end  of  diastole,  we  find  that  the  aortic  pressure  is  very  considerably 
above  that  of  the  ventricles,  indicating  that  the  semilunar  valves  must 
be  closed,  and  it  will  be  observed  that  the  intraventricular  pressure  at 
the  beginning  of  systole  does  not  rise  sufficiently  to  open  them  until  an 
appreciable  interval  (0.02  to  0.04  second)  after  the  closure  of  the  auric- 
uloventricular valves  (lines  2  and  3)  ;  that  is  to  say,  there  is  a  period  at  the 
beginning  of  ventricular  systole  during  which  the  ventricle  is  a  closed  cavity. 

*The  connections  with  the  heart  may  be  made  by  pushing  long  cannulae  down  the  large  veins  or 
arteries,  or  in  the  case  of  the  ventricles  by  inserting  a  cannula  with  a  sharp  point  directly  through 
the  wall  of  the  ventricle. 


150 


THE    CIRCULATION    OF    THE   BLOOD 


It  is  a  period  during  which  the  ventricle  by  its  contraction  is  getting  up  a 
sufficient  amount  of  pressure  in  the  fluid  contained  in  it  to  force  open 
the  semilunar  valves  against  the  resistance  of  the  pressure  in  the  aorta, 
and  it  has  been  popularly  called  "the  period  of  getting  up  steam,"  or, 
in  physiological  language,  the  isometric,  or  the  presphygmic,  period.  We 
shall  use  the  last-mentioned  term  in  our  further  discussion  here. 

After  the  aortic  valves  have  been  opened,  it  will  be  observed  that  the 
pressure  in  the  ventricles  is  just  a  little  above  that  in  the  aorta,  and  that 


Fig.  34. — Superimposed  pressure  curves  from  aorta,  ventricle  and  auricle,  along  with  electrocar- 
diogram and  phonocardiogram.  A,  aorta.  V,  ventricle.  Aur,  auricle.  EL,  electrocardiogram.  PH, 
phonocardiogram.  Showing  first  and  second  sounds. 

it  continues  so  during  the  whole  of  ventricular  systole.  When  diastole 
sets  in,  the  pressure  in  the  ventricles  quickly  falls,  and  a  point  is  soon 
reached  at  which  equality  of  pressure  in  ventricle  and  aorta  is  again 
attained.  This,  as  we  have  seen,  corresponds  to  the  moment  of  the  closure 
of  the  semilunar  valves.  The  pressure  in  the  ventricle,  although  now 
rapidly  falling,  takes  a  little  time  before  it  has  fallen  low  enough  to  permit 
the  auricular  valves  to  open.  Here  again,  then,  the  ventricle  is  a  closed 
cavity,  and  we  have  what  is  known  as  the  postsphygmic  period  (lines  5 
and  6). 


CHAPTER  XVIII 
THE  PUMPING  ACTION  OF  THE  HEART  (Cont'd) 

THE  CONTOUR  OF  THE  INTRACARDIAC  CURVES 

The  Ventricular  Curve 

From  an  analysis  of  the  contour  of  each  curve,  further  interesting 
points  are  brought  to  light.  The  intraventricular  pressure  curve  recorded 
by  older  methods  was  shown  as  having  a  flat  top  or  plateau.  By  the  use 
of  the  more  modern,  optically  recording,  instruments  it  has  been  shown 
that  this  plateau  becomes  displaced  by  an  arch  if  every  precaution  is 
taken  to  prevent  dulling  down  of  the  pressure  changes  in  the  instrument, 
as  by  opening  wide  the  stopcock  in  the  instrument  (Fig.  33).  We  may 
therefore  describe  the  contour  of  the  ventricular  curve  during  the  sphygmic 
period  as  consisting  of  a  rising  portion,  almost  continuous  with  the  curve 
during  the  presphygmic  period,  a  summit  and  then  a  declining  portion, 
which  is  usually  slower  than  the  ascending.  On  the  rising  portion  there 
is  usually  a  notch  at  the  moment  the  semilunar  valves  open.  The  cause 
for  this  is  not  satisfactorily  explained.  The  practical  value  arising  from 
a  study  of  the  curves  lies  in  the  insight  which  they  give  us  into  the 
nature  of  the  stroke  of  the  cardiac  pump.  They  show  us  that  the  impulse 
which  the  ventricle  gives  to  the  moving  mass  of  blood  in  the  aorta  rises 
quickly,  attains  a  peak  and  then  more  gradually  falls  until  the  aortic 
valves  close  when  the  fall  becomes  much  more  sudden.  The  pressure  is 
maintained  long  enough  to  overcome  the  inertia  of  the  heavy  load  of 
blood  in  the  large  arteries. 

Wiggers  has  shown  that  the  exact  contour  of  the  curve  during  the 
sphygmic  period  depends  partly  on  the  degree  of  sensitiveness  of  the  op- 
tical manometer  used  and  partly  on  the  tension  existing  in  the  ventricle 
just  before  contraction.  When  the  tension  is  low  the  arch  becomes  a 
plateau.  In  the  case  of  the  right  ventricle  the  contour  of  the  curve  also 
depends  on  the  degree  of  resistance  to  the  bloodflow  through  the  pul- 
monary circuit.  The  top  of  the  curve  becomes  broader  when  the  initial 
tension  is  high,  and  more  rounded  when  there  is  a  high  pulmonary 
resistance. 

By  the  use  of  the  older  methods  of  observation  (spring  manometers) 
it  was  believed  that  the  intraventricular  pressure  fell  below  the  zero 
line  in  the  early  stage  of  diastole,  thus  indicating  that  a  negative  or 

151 


152 


THE   CIRCULATION   OF   THE   BLOOD 


suction  pressure  existed.  This  conclusion  seemed  to  be  confirmed  by 
using  a  mercury  manometer  furnished  with  a  valve  so  arranged  that 
only  suction  pressure  could  cause  a  movement  of  the  mercury  (a  minimum 
manometer).  The  more  recent  methods,  in  which  optical  manometers  are 
used,  do  not  indicate  the  presence  of  such  a  suction  pressure  and  there 
can  be  no  doubt  that  the  results  of  the  earlier  methods  were  erroneous : 
those  by  the  spring  manometers  because  of  elastic  recoil,  and  those  of 
the  minimum  manometer  because  of  the  inertia  of  the  mercury, — the 
valve  catching  it,  as  it  were,  on  the  rebound. 


Fig.  35. — Diagram  to  illustrate  optical  method  for  recording  pressure   curves  from  auricles. 
A,    Auricles;    C,    Ventricles:    B,    Aorta;    D,    Photographic    surface.       (From    Wiggers.) 


Fig.  35  is  a  diagram  taken  from  Wiggers  to  demonstrate  the  optical 
method  of  recording  simultaneously  the  pressure  changes  occurring 
within  the  auricle  and  ventricle  and  in  the  aorta.  A,  B,  and  C  are  small 
chambers  filled  with  fluid  and  covered  with  rubber  membranes.  They 
are  inserted  through  the  walls  of  the  auricle  and  ventricle  and  aorta. 
Each  membrane  responds  to  any  change  in  pressure  by  a  minute  move- 
ment which  is  magnified  by  reflecting  a  narrow  beam  of  light  from  a 
mirror  fastened  to  its  surface.  The  light  beams  are  focussed  upon  a 
moving  photographic  film.  The  volume  changes  are  recorded  by  slip- 
ping the  ventricles  as  far  as  their  A-V  junctions  into  a  glass  oncometer 


THE   PUMPING   ACTION   OF    THE   HEART  153 

which  is  covered  by  a  rubber  diaphragm  and  connected  with  a  large 
tambour.  The  absence  of  any  suction  pressure  in  the  heart  shows  that 
its  filling  cannot  depend,  as  does  that  of  a  mechanical  pump,  on  aspira- 
tion between  each  beat.  This  does  not  mean  that  there  may  not  be  a 
slight  suction  pressure  in  the  ventricle,  as  well  as  the  auricle,  during 
the  beginning  of  each  inspiratory  movement  in  the  unopened  thorax, 
but  since  this  pressure  inside  the  ventricle  must  always  be  less  negative 
than  that  in  the  thoracic  cavity  it  can  participate  in  the  filling  of  the 
heart  only  to  the  small  extent  indicated  on  page  324.  The  rate  of  filling 
of  the  ventricle  depends  primarily  on  the  rate  of  flow  in  the  great  veins 
leading  to  the  heart  (page  217). 

The  Auricular  Curve 

Examination  of  the  intraauricular  pressure  curve  is  of  particular  in- 
terest because  of  the  relationship  which  it  has  to  a  tracing  taken  of  the 
movements  in  the  jugular  vein  at  the  root  of  the  neck  (see  page  285). 
This  jugular  pulse  curve,  as  it  is  called,  is  produced  mainly  by  the 
changes  of  pressure  occurring  in  the  auricle,  from  pressure  curves  of 
which  it  differs  only  in  the  relative  height  of  the  various  waves.  By 
graduating  the  intraauricular  pressure  curve  by  the  method  described 
above,  we  can  tell  exactly  the  magnitude  in  the  changes  of  pressure  oc- 
curring during  each  cardiac  cycle.  This  obviously  cannot  be  done  with 
a  tracing  taken  from  the  jugular  vein,  although  qualitatively  the  tracings 
reflect  the  changes  that  are  occurring  in  the  auricle. 

On  examining  the  auricular  pressure  curve  (consult  Fig.  34),  we 
find  that  after  the  wave  of  presystole,  which  of  course  corresponds  exactly 
with  that  on  the  intraventricular  curve,  a  second  wave  occurs  culminating 
in  a  peak  shortly  after  the  beginning  of  the  presphygmic  period.  The 
curve  rapidly  descends  during  the  first  part  of  the  sphygmic  period  and 
then  slowly  rises  throughout  the  rest  of  ventricular  systole,  until  the 
moment  of  opening  of  the  auriculoventricular  valve,  when  it  descends 
again  and  thereafter  runs  parallel  with  the  ventricular  curve. 

There  are  therefore  three  positive  waves  on  the  curve,  the  first  being 
caused  by  auricular  systole  or  presystole ;  the  second,  by  the  closure  and 
possibly  by  bulging  into  the  auricle  of  the  auriculoventricular  valve ;  and 
the  third,  by  the  gradual  filling  of  the  auricle  from  the  veins.  The 
second  wave  corresponds  to  the  wave  C  of  the  jugular  pulse  (page  286), 
which  would  seem  to  show  that  this  is  a  reflected  auricular  wave.  The 
depression  following  the  second  wave  corresponds  to  wave  X  of  the 
jugular  pulse  and  the  lowering  of  pressure  which  it  indicates  is  probably 
'&ne  to  the  cooperation  of  three  forces,  all  tending  to  increase  the  auric- 
rtlur  capacity:  (1)  The  diastole  of  the  walls  of  the  auricle;  (2)  the 


154  THE   CIRCULATION   OF   THE   BLOOD 

descent  of  the  auriculoventricular  groove,  thus  tending  to  open  out  some- 
what the  folds  in  the  walls  of  the  auricle;  and  (3),  most  important  of 
all,  the  tendency  of  the  thin-walled  auricles  to  become  dilated  as  a  result 
of  the  sudden  diminution  in  intrathoracic  pressure  which  is  produced 
at  each  heartbeat  by  the  discharge  of  blood  from  the  heart  and  intra- 
thoracic blood  vessels  into  those  of  the  rest  of  the  body.  Under  these 
conditions  all  thin-walled  structures  in  the  thoracic  cavity,  the  auricles 
included,  will  expand  to  take  up  the  extra  room  thus  created  in  the 
thoracic  cavity.  Similar  negative  heart  pulses,  or  cardiopneumatic  move- 
ments, as  they  are  called,  can  be  observed  accompanying  each  cardiac 
systole  in  the  air  passages  and  in  the  esophagus.  This  is  done  by  con- 
necting sensitive  tambours  through  tubing,  either  with  one  nostril  (while 
the  other  nostril  and  the  mouth  are  closed  and  the  breath  held)  or  with 
a  thin  rubber  bag  lying  in  the  esophagus.  Cardiopneumatic  movements 
can  sometimes  be  seen  in  the  intercostal  spaces  of  emaciated  persons, 
and  they  often  become  pronounced  in  cardiac  hypertrophy. 

THE  MECHANISM  OF  OPENING  AND  CLOSING  OF  THE  VALVES 

When  physical  valves  open  and  close  as  a  result  of  the  changes  in  pres- 
sure on  their  two  surfaces,  a  certain  amount  of  fluid  must  succeed  in 
passing  the  valve  flaps  before  these  become  perfectly  closed.  But  there 
is  every  reason  to  believe  that  such  is  not  the  case  in  the  heart,  the  flaps 
of  both  the  auriculoventricular  and  the  semilunar  valves  being  already 
completely  closed  before  pressure  conditions  entailing  a  possible  regur- 
gitation  of  blood  through  them  become  established. 

Auriculoventricular  Valves 

During  diastole  the  flaps  of  the  auriculoventricular  valves  are  hanging 
down  into  the  ventricle  and  floating  in  a  half-open  position  in  the  blood, 
which  is  meanwhile  accumulating  in  the  chamber.  This  position  is  de- 
pendent upon  the  operation  of  two  opposing  forces  on  the  valve  flaps: 
the  pressure  of  the  blood  flowing  from  the  auricle  on  their  upper  aspects, 
and  reflected  waves  of  pressure  from  the  walls  of  the  ventricle  on  their 
under  aspects  (centripetal  reflux).  When  presystole  occurs,  the  pres- 
sure of  the  auricular  stream  momentarily  increases,  thus  slightly  dis- 
tending the  wall  of  the  meanwhile  relaxed  ventricle  and  after  a  moment's 
delay  causing  the  reflected  wave  to  become  more  pronounced.  At  the 
same  time  the  muscular  fibers  in  the  valve  flaps  (Kiirschner's  fibers) 
contract  and  make  the  flaps  shorter,  the  total  effect  of  the  two  factors 
being  that  the  valve  takes  up  a  position  nearer  that  of  closure.  When 
presystole  suddenly  stops,  the  reflected  waves  will  persist  for  an  instant 


THE   PUMPING    ACTION    OF    THE    HEART  155 

of  time  longer  than  the  auricular  wave  which  causes  them,  because  of 
the  elastic  nature  of  the  ventricular  wall,  so  that  the  valve  flaps  close 
with  perfect  apposition  not  merely  at  their  edges  but  also  for  a  con- 
siderable distance  along  their  upper  surfaces. 

When  ventricular  systole  starts,  the  only  effect  of  the  high  pressure 
which  is  brought  suddenly  to  bear  on  the  under  surfaces  of  the  already 
closed  valves  is  to  cause  them  to  vibrate  and  to  bulge  into  the  auricles, 
being  meanwhile  anchored  down  and  prevented  from  flapping  into  the 
auricle  by  the  chordae  tendineae.  There  is  reason  to  believe  that  the 
musculi  papillares  to  which  these  are  attached  begin  to  contract  at  the 
very  outset  of  ventricular  systole — indeed  slightly  to  precede  it  (see 
page  274),  and  thus  keep  the  chordae  taut.  As  systole  continues  the 
contraction  of  these  muscles  becomes  more  and  more  pronounced,  and  the 
resulting  tightening  of  the  chordae  serves  to  draw  down  the  valve  flaps, 
so  that  progressively  larger  proportions  of  their  upper  aspects  tend  to 
become  opposed.  Meanwhile  the  auriculoventricular  orifice  is  also  be- 
coming narrowed  down  on  account  of  the  contraction  of  the  musculature 
of  the  auriculoventricular  groove. 

Semilunar  Valves 

The  mechanism  involved  in  the  operation  of  the  semilunar  valves  is 
somewhat  different.  It  has  been  shown  that,  when  fluid  is  flowing  in  a 
tube,  the  pressure  and  velocity  are  not  equal  in  the  axial  and  peripheral 
parts  of  the  stream.  In  the  axis  the  velocity  is  greater  than  in  the  layers 
of  fluid  next  to  the  walls,  but  the  pressure  is  less.  This  can  be  seen  by 
observing  through  a  wide  glass  tube  the  flow  of  water  in  which  are  sus- 
pended lycopodium  spores.  By  placing  within  the  wide  tube  small  bent 
tubes  so  arranged  that  one  open  end  lies  near  the  periphery  and  the  other 
near  the  axis,  the  differences  in  pressure  between  the  axial  and  peripheral 
streams  can  be  seen  to  cause  the  fluid  to  flow  in  the  narrow  tubes  from  pe- 
riphery to  axis  (centripetal  eddies). 

If  the  tube  should  suddenly  expand  the  eddy  currents  become  still 
more  pronounced  just  where  the  wider  portion  starts.  In  the  conditions 
obtaining  at  the  beginning  of  the  large  arteries  of  the  heart,  the  orifice  into 
the  ventricles  being  constricted,  a  centripetal  vortex  must  be  set  up,  tend- 
ing to  throw  the  valve  flaps  into  a  closed  position,  which,  however,  is  pre- 
vented by  the  blood  rushing  between  them  from  the  ventricles.  They  thus 
take  up  a  mid-position  and  vibrate  in  the  stream.  "When  the  efflux  from 
the  ventricle  stops  at  the  end  of  systole,  the  reflux,  lasting  for  a  moment 
longer  and  being  now  unopposed,  immediately  closes  the  valves,  in  which 
position  they  are  then  maintained  by  the  greater  pressure  on  their  aortic 
surfaces. 


156 


THE    CIRCULATION    OF    THE   BLOOD 


The  position  of  the  valves  relative  to  the  events  of  the  cardiac  cycle  is 
shown  in  Fig.  36. 

The  Venous  Reservoir  of  the  Mammalian  Heart 

In  birds  and  mammals  there  are  no  valves  between  the  venae  cavae  and 
the  auricles  such  as  there  are  in  lower  animals  at  the  sino-auricular  junc- 
tion. Coincident  with  the  appearance  of  the  diaphragm,  the  sinus  is 
merged  with  the  auricles  which  are  left  open  to  a  large  venous  cistern 
consisting  of  the  venae  cavae,  the  innominate,  iliac,  hepatic  and  renal  veins. 
This  cistern  is  shut  off  from  the  remainder  of  the  venous  system  by  six 
pairs  of  valves  at  the  femoral,  the  subclavian  and  the  jugular  veins.  Not 
only  is  it  capacious,  being  capable  of  holding  at  least  400  c.c.  of  blood  in 
man,  but  it  is  subject  to  considerable  alteration  in  capacity  because  of  the 
collapsible  nature  of  its  walls.  This  cistern  is  moreover  in  free  communi- 
cation with  another  large  cistern,  capable  of  holding  when  full  about  1000 


Fig.    36. — Diagram    to    show    the    positions    of    the    cardiac    valves:      1,    during    diastole;    2,    during 
the    presphygmic    period;     3,    during    the    sphygmic    period. 

c.c.  of  blood,  represented  by  the  liver  and  portal  system.  Alterations  in 
thoracic  and  abdominal  pressures  will  greatly  affect  the  emptying  of  this 
cistern  into  the  auricles  which  explains  the  marked  influence  of  the  tho- 
racic movements  and  of  abdominal  compression  on  the  filling  of  the  heart. 
A  most  important  function  of  this  cistern  is  to  furnish  an  immediate  re- 
serve of  blood  to  fill  the  heart  during  the  performance  of  a  great  muscular 
effort. 

THE  HEART  SOUNDS 

During  certain  phases  of  the  cycle  distinct  sounds,  the  heart  sounds, 
can  be  heard  by  applying  a  stethoscope  to  the  thoracic  wall.  The  first 
occurs  at  the  beginning  of  ventricular  systole  and  is  best  heard  over  the 
apex  beat;  the  second  occurs  at  the  beginning  of  diastole  and  is  heard 
best  at  the  second  right  costal  cartilage  or  in  the  second  left  intercostal 


THE   PUMPING   ACTION   OF    THE    HEART  157 

space.  A  third  sound,  much  less  distinct,  is  sometimes  heard  in  diastole 
a  short  time  after  the  second.  To  study  the  exact  time  relationship  of 
the  sounds  the  vibrations  which  they  set  up  can  be  recorded  graphically 
alongside  cardiac  tracings  by  means  of  a  microphone  attachment  to  the 
electrocardiograph  (see  page  270). 

Causes  of  Sounds 

It  has  been  found  that  the  first  sound  consists  of  two  distinct  elements, 
one  high  pitched  and  the  other  of  a  dull  character.  The  former  element 
is  believed  to  be  the  result  of  vibrations  set  up  in  the  flaps  of  the  auric- 
uloventricular  valves,  and  therefore  in  the  blood  in  the  heart,  by  the 
sudden  rise  in  systolic  pressure.  The  dull  element  on  the  other  hand 
is  undoubtedly  of  muscular  origin.  The  evidence  for  these  conclusions  is 
as  follows:  (1)  When  the  auriculoventricular  valves  are  prevented  from 
closing  properly  either  by  disease  or  by  pushing  a  loop  of  wire  down  the 
large  veins,  the  high  pitched  quality_disam)ears<  and  nothing  but  a  rush- 
ing sound  accompanies  the  dull  bruit  produced  by  the  contracting  muscle. 
(2)  In  a  heart  that  has  been  rendered  bloodless  by  an  incision  near  the 
apex,  or  even  in  an  excised  but  still  beating  heart,  the  dull  element  of 
the  first  sound  still  continues  to  be  heard  for  a  short  time.  That  con- 
tracting muscle  produces  a  sound  is  a  well-established  fact. 

There  are,  however,  many  obscure  phenomena  connected  with  the 
causation  of  the  first  sound,  but  we  can  not  go  into  such  controversial 
matters  here.  A  close  inspection  of  the  electrophonographic  tracing 
shows  that  the  sound  starts  at  the  beginning  of  the  presphygmic  period, 
and  that  it  lasts  with  gradually  declining  but  variable  intensity  until 
well  into  the  sphygmic  period  (Fig.  37). 

The  second  sound  occurs  accurately  at  the  beginning  of  diastole  and 
can  readily  be  shown  to  be  caused  by  the  sudden  shutting  and  stretching 
of  the  semilunar  valves,  which  throws  them,  the  blood  in  contact  with 
them,  and  the  neighboring  walls  of  the  aorta  into  vibration.  Proof  of 
this  conclusion  is  furnished  by  the  following  facts:  The  second  sound 
immediately  disappears  if  the  blood  is  let  out  of  the  heart  by  opening 
the  apex,  and  it  is  replaced  by  a  rushing  "bruit"  if  the  flaps  are  pre- 
vented from  closing  as  a  result  of  disease  or  of  hooking  them  back  by 
passing  a  wire  down  the  carotid  artery.  The  third  sound,  although  audi- 
ble only  in  some  individuals,  can  nevertheless  be  shown  to  exist  by  the 
electrophonograph,  and  since  it  occurs  at  the  time  when  the  auriculo- 
ventricular valves  open,  it  is  believed  to  depend  upon  the  sudden  inrush 
of  blood  from  auricles  to  ventricles. 

The  greatest  importance  of  the  sounds  is  in  the  clinical  diagnosis  of  val- 
vular and  other  lesions  of  the  heart.  When  a  valve  leaks,  for  example, 


158  THE    CIRCULATION    OF    THE    BLOOD 

the  blood  escapes  past  it  under  great  pressure,  and  is  ejected  into  a  mass 
of  blood  at  low  pressure,  these  being  conditions  which  are  well  known 
to  create  sounds  or  bruits.  By  examining  the  exact  relationship  of  such 
bruits  to  the  normal  heart  sounds,  deductions  can  be  drawn  concerning 
the  condition  of  the  various  valves. 

Record  of  Heart  Sounds 

The  heart  sounds  have  been  graphically  recorded  by  transmitting  them 
through  a  stethoscope  to  a  microphone  placed  in  circuit  with  a  string 
galvanometer  (electrophonograms,).  Through  this  circuit  passes  a  cur- 
rent the  strength  of  which  depends  on  the  resistance  offered  by  the 
microphone,  and  consequently  to  the  number  and  amplitude  of  the 
vibrations  of  the  sounds  transmitted  to  it  through  the  stethoscope. 
There  are  several  objections  to  this  method.  One  of  these  is  depend- 
ent on  the  varying  distance  of  the  heart  from  the  chest  wall,  which 
causes  many  of  the  sound  vibrations  to  be  lost  before  they  reach  the 
stethoscope;  another,  on  adventitious  sounds  arising  from  contracting 
muscles,  the  impact  of  the  heart  against  the  chest  wall,  etc.,  and  still 
another  on  unequal  resonation  by  the  air  in  the  neighboring  portions  of 
lungs.  To  investigate  the  problem  more  thoroughly,  Wiggers,37  using 
anesthetized  animals,  has  recorded  the  sounds  by  carefully  stitching  to 
the  heart  (exposed  through  a  small  opening  in  the  pericardium)  a  lever, 
the  end  of  which  was  attached  to  a  "transmitter"  consisting  of  a 
small  capsule  covered  with  rubber  dam.  The  transmitter  was  connected 
by  rubber  tubing  to  a  * '  recorder ' '  consisting  of  another  small  capsule  carry- 
ing on  its  membrane  (made  of  rubber  cement)  an  eccentrically  placed  small 
mirror,  on  to  which  a  beam  of  light  was  thrown.  The  movements  of  the 
beam  of  light  reflected  from  the  mirror,  and  caused  by  the  sound  vibra- 
tions, were  photographed.  Mechanical  vibrations  set  up  in  the  apparatus 
itself  were  largely  eliminated  by  a  side  opening  on  the  recorder,  and  the 
effect  of  outside  sounds  minimized  by  surrounding  the  recorder  by  a 
ventilated  glass  housing. 

Although  this  apparatus  is  not  free  from  faults  due  to  inherent  vibra- 
tion frequency  and  resonance,  the  records  secured  by  it  are  valuable  in 
showing  the  exact  relationship  of  the  sounds  to  the  events  of  the  cardiac 
cycle.  The  vibrations  from  the  two  ventricles  are  alike,  but  differ  from 
those  taken  from  the  aorta.  The  first  ventricular  sound  consists  of  from 
five  to  thirteen  irregular  vibrations,  usually  in  three  groups,  the  first 
composed  of  two  small  vibrations,  the  middle  one  of  several  large  vibra- 
tions, and  the  third  of  a  varying  number  of  small  vibrations.  The 
duration  of  the  sound  is  from  0.05  to  0.152  seconds,  and  the  periodicity 
from  0.004  to  0.054  per  second.  When  compared  with  an  intraventricu- 


THE   PUMPING   ACTION   OF    THE    HEART 


159 


lar  pressure  curve,  the  initial  vibrations  occur  0.01  second  prior  to  the  rise 
in  pressure,  the  main  vibrations  reaching  their  greatest  amplitude  before 
the  sphygniic  period  begins,  and  the  final  vibrations  occurring  during 
the  early  part  of  the  sphygmic  period  and  therefore  just  before  the  aortic 


11  I       f 

,5  -5   mm    fir    Mf.  ; 


....:• 


B. 


f,  f1** 


3'/\ 


C. 


Fig.  37. — Electrophonograms  along  with  intraventricular  pressure  curves  from  three  dif- 
ferent experiments.  In  A  the  uppermost  curve  shows  the  pressure,  the  middle  one  the  sounds 
of  the  right  ventricle,  and  the  lowermost  one  those  of  the  aorta.  P  indicates  the  relative  posi- 
tion of  the  curves.  M  is  due  to  mechanical  oscillations.  $2  indicates  the  second  sound,  and 
/,  2,  3,  and  4  the  corrected  time  relations  of  the  first  sounds.  In  B,  the  pressure  and  sound 
curves  are  both  from  the  left  ventricle  (letters  same  as  in  A).  In  C,  the  aortic  and  pulmonary 
arterial  sounds  are  shown  (letters  same  as  in  A).  (From  Wiggers  and  Dean.) 

pressure  has  reached  its  height.  The  main  vibrations  therefore  occur 
during  the  descending  limb  of  the  R  wave  of  the  electrocardiogram  (be- 
ginning 0.01  second  before  its  completion),  the  small  preliminary  vibra- 


160  THE   CIRCULATION   OF   THE   BLOOD 

tions  occurring  during  the  ascending  limb.  When  taken  from  the  aorta, 
the  record  of  the  first  sound  is  somewhat  different,  there  being  no  initial 
vibrations  and  the  main  ones  being  of  greater  frequency  and  reaching 
their  maximum  earlier  than  those  taken  from  the  ventricle.  The  sub- 
sequent vibrations  are  also  larger,  especially  when  the  aortic  pressure 
is  high  (Fig.  37). 

The  record  of  the  second  sound  at  the  ventricle  is  much  simpler  and 
usually  of  less  amplitude  than  the  first,  consisting  of  two  to  six  vibrations 
lasting  0.015  to  0.056  second.  They  begin  a  short  time  after  the  ventricu- 
lar pressure  begins  to  fall,  approximately  at  the  dicrotic  notch  of  the  aortic 
curve,  being  completed  in  from  0.015  to  0.025  second  after  the  bottom 
of  the  notch.  Their  relationship  to  the  T  wave  is  variable.  Taken  from 
the  aorta,  the  record  of  the  second  sound  shows  vibrations  of  greater 
amplitude  and  of  a  greater  frequency  than  that  from  the  ventricle. 

The  absolute  and  the  relative  intensity  of  the  heart  sounds  is  of  clin- 
ical value  in  forming  a  judgment  of  the  dynamic  state  of  the  heart  muscle 
and  of  the  tension  or  pressure  in  the  aorta  and  pulmonary  artery.  Ac- 
centuation of  the  second  sound,  for  example,  is  considered  to  indicate  a 
high  pressure  in  the  aorta.  Wjggers46  has  recently  confirmed  this  by  ex- 
perimental methods.  He  recorded  the  sounds  graphically  by  attaching 
receivers  to  the  shaved  skin  of  the  thorax  over  the  apex  and  pulmonary 
artery  in  anesthetized  dogs,  the  receivers  being  connected  with  sound- 
recording  capsules.  After  taking  normal  tracings,  various  alterations  were 
brought  about  in  the  pumping  action  of  the  heart  or  in  the  blood  pressure, 
and  the  effect  was  noted  on  the  amplitude  and  number  of  vibrations  en- 
tering into  the  sound  tracings.  It  was  found  that  the  intensity  of  the 
first  sound  varied  with  the  tension  which  was  developed  within  the  ventri- 
cles during  systole,  particularly  during. the  presphygmic  period.  When 
the  vagus  was  stimulated  for  example,  the  first  sound  diminished  because 
of  the  lower  diastolic  pressure  to  be  overcome  during  the  presphygmic 
period.  Increase  in  the  diastolic  pressure  without  change  in  heart  rate 
(by  reflex  vasoconstriction,  compression  of  aorta,  etc.)  caused  the  second 
sound  to  become  accentuated,  and  decrease  of  pressure  (by  nitrites) 
caused  it  to  become  less.  Of  course  in  both  these  experiments  the  first 
sound  was  also  affected.  It  was  possible  to  show,  further,  that  when  the 
pressure  changes  were  more  marked  in  one  circuit  of  the  circulation  than 
the  other,  the  sounds  were  more  decidedly  altered  in  the  circuit  in  which 
the  changes  predominated  (see  also  Lewis47). 


CHAPTER  XIX 
THE  NUTRITION  OF  THE  HEART 

THE  BLOOD  SUPPLY 

In  cold-blooded  animals,  such  as  the  frog,  the  heart  muscle  is  nourished 
by  blood  soaking  into  it  from  the  heart  chambers,  which  indeed  do  not 
form  definite  cavities  as  in  the  mammalian  heart,  but  exist  as  an  inter- 
lacement of  muscular  tissue.  In  the  hearts  of  higher  animals,  the  muscu- 
lature is  supplied  by  special  arteries  (the  coronary),  although  a  certain 
amount  of  blood  may  still  pass  directly  from  the  cardiac  cavities  into 
the  musculature  through  the  veins  of  Thebesius. 

The  relative  importance  of  the  various  branches  of  the  coronary  artery 
in  maintaining  an  adequate  nutrition  of  the  heart  has  been  studied  by 
observing  the  effect  of  occlusion  of  one  or  more  of  them  (W.  T.  Porter9.) 
Occlusion  of  the  circumflex  branch  of  the  left  coronary  artery  caused 
arrest  of  the  heartbeat  in  about  80  per  cent  of  cases,  the  arrest  being 
usually  accompanied  by  fibrillary  contraction.  Occlusion  of  the  right 
coronary  arrested  the  ventricular  contraction  in  about  20  per  cent  of 
the  cases.  Smaller  branches  may  be  occluded  without  any  evident 
change  in  the  heartbeat. 

These  results  indicate  that  the  capillary  areas  supplied  by  the  branches 
of  the  coronary  artery  do  not  freely  anastomose  with  one  another.  They 
are  more  or  less  terminal  arteries ;  that  is,  each  branch  supplies  a  distinct 
region  of  the  cardiac  muscle.  If  one  of  the  smaller  branches  of  the  coro- 
nary is  occluded,  although  there  is  no  immediate  stoppage  of  the  heart- 
beat, yet  after  some  time  the  area  supplied  by  that  branch  usually  under- 
goes necrosis,  again  indicating  that  collateral  circulation  can  not  have 
become  established.  It  is  interesting,  however,  to  note  in  this  connection 
that  anatomic  studies  have  shown  that  a  certain  amount  of  anastomosis 
does  occur  between  different  branches,  although  it  is  evident,  from  the 
above  observations,  that  an  adequate  collateral  circulation  does  not  im- 
mediately become  established  through  this  anastomosis. 

PERFUSION  OF  HEART  OUTSIDE  THE  BODY 

In  order  that  the  blood  supply  through  the  coronary  arteries  may 
adequately  maintain  the  normal  nutrition  of  the  cardiac  muscle,  certain 

161 


162  THE   CIRCULATION   OF   THE   BLOOD 

conditions  must  be  fulfilled.  The  recognition  of  these  conditions  has 
been  accomplished  by  observations  on  the  excised  heart,  for  it  has  been 
found  that  if  they  are  fulfilled  the  mammalian  heart  can  be  made  to  beat 
in  perfectly  normal  fashion  for  several  hours  after  its  removal  from 
the  animal's  body.  Indeed  certain  mammalian  hearts,  such  as  that  of  the 
rabbit,  may  be  made  to  beat  for  several  days  outside  the  body.  We  may 
consider  the  essential  conditions  of  the  blood  supply  under  four  headings: 
(1)  the  temperature;  (2)  the  oxygen  supply;  (3)  the  pressure;  and  (4) 
the  chemical  composition.  Successful  perfusion  may  be  performed  with 
artificial  saline  solutions  (e.  g.,  Locke's),  but  it  is  simplest  in  investigating 
the  relative  importance  of  the  above  conditions  to  start  the  heart  per- 
fusion with  defibrinated  blood. 

After  bleeding  an  anesthetized  animal,  such  as  a  dog  or  a  cat,  until 
no  more  blood  can  be  removed,  the  blood  is  defibrinated  and  filtered 
through  gauze  to  remove  the  fibrin.  The  thorax  of  the  dead  animal  is 
then  quickly  opened,  ligatures  placed  around  the  main  arteries  springing 
from  the  arch  of  the  aorta,  a  cannula  with  its  end  pointing  toward  the 
heart  inserted  into  the  descending  thoracic  aorta,  and  the  latter  cut 
across  below  the  point  of  insertion  of  the  cannula.  The  heart  is  then 
quickly  removed  from  the  thorax  and  an  artificial  saline  solution 
(Locke's)  allowed  to  run  into  the  aortic  cannula  through  a  side  tube, 
until  all  the  blood  has  been  washed  out  from  the  coronary  vessels.  Dur- 
ing this  operation  the  heart  may  develop  a  few  beats  even  though  the 
solution  is  quite  cool.  The  aortic  cannula  is  now  connected  with  a  bottle 
containing  the  defibrinated  blood  diluted  with  Locke's  solution  and 
brought  to  body  temperature  by  immersion  in  a  water-bath.  By  means 
either  of  gravity  or  of  a  suitably  regulated  air  pressure  exerted  on  the 
surface  of  the  diluted  blood  in  the  bottle,  this  is  forced  into  the  aortic 
cannula  under  pressure.  The  fluid  thus  finds  its  way  into  the  coronary 
vessels;  for  in  passing  toward  the  heart  in  the  aorta  it  will  close  the 
semilunar  valves  and  force  its  way  under  pressure  into  the  coronary 
vessels,  subsequently  escaping  by  the  coronary  sinus  into  the  right 
auricle.  Very  soon  after  the  perfusion  is  started  the  heart  begins  to  beat 
vigorously  and  regularly,  thus  offering  a  suitable  preparation  upon  which 
to  test  the  first  three  mentioned  conditions  necessary  for  the  nutrition 
of  the  cardiac  musculature. 

If  the  temperature  of  the  solution  is  allowed  to  fall  considerably,  the 
beat  becomes  much  slower,  and  if  the  cooling  is  proceeded  with,  the  heart 
will  after  a  while  cease  beating  altogether.  If  the  pressure  is  lowered, 
the  beat  will  not  necessarily  become  slower  but  very  much  feebler,  and 
will  soon  cease.  In  general  it  may  be  said  that  the  temperature  of  the 


THE    NUTRITION    OF    THE    HEART  163 

solution  affects  the  rate  of  the  beat,  and  the  pressure  affects  its  strength. 
It  is,  however,  obvious  that  in  perfused  preparations  changes  in  pres- 
sure are  likely  to  cause  alterations  in  rate  as  well  as  in  force,  unless 
great  care  is  taken  to  keep  the  heart  itself  as  warm  as  the  perfusion 
fluid. 

The  importance  of  an  adequate  pressure  in  the  coronary  vessels  has 
been  clearly  brought  out  in  certain  experiments  in  which  the  beat  has 
been  maintained  for  a  short  time  by  establishing  a  pressure  in  the  cor- 
onary vessels  by  means  of  indifferent  fluids  or  gases.  Thus,  if  oxygen 
gas  is  allowed  to  pass  through  the  vessels  under  pressure,  the  heart  will 
beat  for  a  short  time,  and  the  same  result  has  been  observed  even  when 
mineral  oil  or  mercury  has  been  perfused  under  pressure  (Sollmann). 

The  necessity  for  an  adequate  oxygen  supply  is  very  readily  demon- 
strated. If  the  darker  blood  ejected  from  the  right  auricle  with  each 
heartbeat  is  transferred  immediately  to  the  perfusion  bottle,  the  heart- 
beat will  soon  become  feeble  and  irregular,  to  be  readily  restored  to 
normal  when  this  dark  blood  is  shaken  up  with  air  or  oxygen. 

By  artificial  perfusion  in  the  manner  above  described,  the  automatism 
of  the  heart  may  be  restored  many  hours  after  death.  Partial  restora- 
tion, confined  to  the  auricles  or  to  that  part  of  the  ventricles  lying  im- 
mediately adjacent  to  the  large  blood  vessels,  can  also  be  accomplished 
in  the  heart  of  man  several  days  after  death,  provided  death  has  not 
been  caused  by  some  acute  toxic  infection  such  as  diphtheria  or  septice- 
mia.  The  Russian  physiologist  Kuliabko,  has  succeeded  in  restoring  for 
over  an  hour  the  normal  beat  of  the  heart  of  a  three-months-old  boy 
twenty  hours  after  death  from  double  pneumonia,  but  here  again  the 
pulsation  returns  only  in  certain  parts  of  the  heart.  As  will  be  pointed 
out,  the  remarkable  resistance  of  the  heart  muscle  displayed  in  these 
experiments  has  been  taken  as  an  argument  in  favor  of  the  myogenic 
hypothesis  for  automatic  rhythmic  power  of  cardiac  muscle,  the  argu- 
ment being  that  nervous  structures  could  not  live  so  long  a  time  after 
death.  The  fallacies  in  this  argument  are  discussed  elsewhere. 

Heart-Lung  Preparation. — Although  the  isolated  heart  is  most  useful 
for  the  investigation  of  many  of  the  functions  of  this  organ,  particularly 
for  the  study  of  the  effect  of  alterations  in  the  chemical  composition  of  the 
perfusion  fluid  and  the  action  of  drugs,  it  is  not  so  suitable  when  blood 
instead  of  artificial  plasma  is  to  be  perfused  or  when  the  effects  of  altera- 
tions in  the  physical  conditions  of  the  inflowing  or  outflowing  blood  are 
under  investigation.  In  such  cases  it  is  better  to  use  the  heart-lung 
preparation,  which  moreover  has  the  added  advantage  that  it  requires 
less  blood,  the  proper  aeration  of  which  is  affected  through  the  lungs 
(cf.48). 


164 


THE    CIRCULATION    OF    THE    BLOOD 


The  arrangement  for  pcrfusion  of  the  heart  and  lungs  is  shown  in  Fig.  38.  The 
blood  prevented  from  clotting  by  the  addition  of  hirudin  (page  101)  is  discharged 
from  the  left  ventricle  into  a  cannula  connected  with  the  innominate  artery,  all  other 
branches  of  the  aorta  being  tied  off.  A  side  tube,  v,  connects  with  an  air  cushion, 
afforded  by  an  inverted  test  tube  to  take  the  place  of  the  resilient  arterial  walls,  and  the 
tube  then  connects  with  a  resistance  B,  which  is  furnished  by  a  thin-walled  rubber  tube 
(rubber  finger  stall)  enclosed  in  a  glass  cylinder  into  which  air  is  pumped  so  as  to 


Fig.  38. — Arrangement  of  apparatus  for  heart-lung  preparation  of  mammalian  heart. 
(Knowlton  and  Starling.) 

compress  the  tube.  Beyond  this  resistance  the  blood  flows  into  a  wide  test  tube  con- 
nected with  a  siphon  tube  which  discharges  whenever  the  blood  has  reached  a  certain 
level  in  the  test  tube.  The  blood  discharges  into  a  reservoir,  from  which  it  flows 
through  a  spiral  immersed  in  a  water  bath,  and  thence  to  a  cannula  tied  into  the 
superior  vena  cava.  A  tambour  is  connected  with  a  lateral  tube  coming  off  the  tube 
of  the  siphon,  and  it  records  a  movement  every  time  the  discharge  occurs.  The  blood 
is  pumped  by  the  right  ventricle  through  the  lungs,  where  it  is  oxygenated,  artificial 


THE   NUTRITION    OF    THE    HEART  165 

respiration  being  maintained  throughout  the  experiment.  The  chief  source  of  difficulty 
with  the  preparation  is  edema  of  the  lungs.  This  occurs  much  more  readily  with  the 
lung  of  the  cat  than  that  of  the  dog.  Analysis  of  the  alveolar  air  in  the  preparation 
gives  information  of  great  value  regarding  the  nature  of  the  gaseous  metabolism  of  the 
heart  (consumption  of  oxygen  and  respiratory  quotient),  and  by  altering  the  CO^  eon- 
tent  of  the  inspired  air,  the  influence  of  changes  in  0H  of  the  perfusion  fluid  can  be  ob- 
served (Evans  '*9). 


RESUSCITATION  OF  THE  HEART  IN  SITU 

A  suitable  intracoronary  pressure  is  a  sine  qua  non  for  the  mainte- 
nance of  the  heartbeat,  and  this  is  a  fact  of  great  clinical  significance, 
for  it  indicates  that  any  attempts  to  resuscitate  a  dead  animal  are  cer- 
tain of  failure  unless  the  method  is  such  as  will  bring  a  nutrient  fluid 
under  a  certain  pressure  to  bear  on  the  coronary  arteries.  Injection  of 
fluid,  even  of  defibrinated  blood,  into  a  vein  will  obviously  fail  to  ful- 
fill this  condition,  for  the  perfusion  must  be  made  into  an  artery  so  that 
the  fluid  is  carried  down  the  aorta  and  thence  into  the  coronary  arteries. 

The  practical  question,  in  so  far  as  resuscitation  of  the  heartbeat  is 
concerned,  is  therefore,  How  can  we  get  the  necessary  fluid  under  pres- 
sure into  the  beginning  of  the  aorta?  Even  if  we  were  to  transfuse  fluid 
under  considerable  pressure  into  the  aorta  through  the  carotid  artery, 
it  would  mainly  follow  the  large  vessels  leading  away  from  the  heart, 
only  a  fraction  of  it  reaching  the  beginning  of  the  aorta.  To  compel  the 
fluid  to  pass  towards  the  heart  we  must  introduce  some  obstruction  to 
its  passage  peripherally.  This  can  be  done  by  the  injection  of  a  consid- 
erable dose  of  epinephrine  (adrenaline)  in  normal  saline  solution  through 
the  needle  of  a  hypodermic  syringe  inserted  into  the  tubing  leading 
from  the  burette  or  pressure  bottle  to  the  cannula  in  the  carotid  artery. 
As  the  perfusion  fluid  is  running  in,  the  epinephrine  injection  is  quickly 
made,  artificial  respiration  and  cardiac  massage  being  meanwhile  prac- 
ticed. In  the  majority  of  animals  it  will  be  found  that  complete  res- 
toration of  the  normal  blood  pressure  can  be  effected  by  this  method. 
Indeed  by  performing  the  resuscitation  under  aseptic  conditions,  some 
animals  may  be  permanently  resuscitated  so  far  as  the  circulation  is 
concerned,  although  the  nervous  structures,  even  after  a  few  minutes 
of  " death,"  never  reacquire  their  normal  condition. 

The  epinephrine  acts  mainly  by  constricting  the  small  arterioles  and 
thus  directing  the  bloodflow  towards  the  heart,  but  partly  also  by  a  direct 

I  stimulating  action  on  the  cardiac  muscle.  It  does  not,  however,  con- 
tract the  coronary  vessels;  on  the  contrary,  it  is  said  to  cause  these 
slightly  to  dilate. 


166  THE   CIRCULATION   OF   THE   BLOOD 

THE  RELATIVE  IMPORTANCE  OP  THE  VARIOUS  CONSTITUENTS 
OF  THE  PERFUSION  FLUID 

We  can  study  the  chemical  conditions  necessary  for  resuscitation 
of  the  heartbeat  by  observing  the  beat  of  an  artificially  perfused  heart 
while  solutions  of  different  chemical  composition  are  being  perfused 
through  the  coronary  vessels.  At  the  outset  we  are  impressed  with  the 
fact  that  for  successful  resuscitation  the  organic  constituents  of  the 
nutrient  fluid  are  of  trivial  importance  compared  with  the  inorganic 
constituents.  With  a  solution  containing  the  proper  proportion  of  in- 
organic salts,  and  of  course  an  adequate  supply  of  oxygen,  the  heart 
of  a  rabbit,  for  example,  may  be  made  to  continue  beating  for  several 
days.  It  is  true  that  it  will  beat  longer  if  some  of  the  organic  con- 
stituents of  the  blood  plasma,  particularly  carbohydrate,  are  present, 
but  on  the  inorganic  constituents  alone  its  ability  to  beat  is  truly 
remarkable. 

Observations  on  Cold-Blooded  Heart 

The  earlier  experiments  for  the  investigation  of  the  chemical  condi- 
tions necessary  for  the  maintenance  of  the  heartbeat  were  performed 
on  the  heart  of  the  frog  or  turtle.  By  perfusing  either  of  these  hearts 
with  physiological  sodium-chloride  solution,  it  was  observed  that  though 
the  beat  might  continue  for  some  time,  yet  it  gradually  grew  feebler 
and  feebler,  until  at  last  it  ceased  altogether  with  the  heart  muscle 
in  a  condition  of  extreme  relaxation  or  diastole.  If  small  proportions 
of  potassium  and  calcium  salts  (as  chloride)  were  added  to  the  sodium- 
chloride  solution,  the  beat  was  much  better  maintained.  Sidney 
Ringer  proved  that  the  optimum  concentration  to  produce  efficient  and 
prolonged  contraction  for  the  heart  of  the  frog  or  terrapin  is  as  follows: 
potassium  chloride,  0.03  per  cent;  calcium  chloride,  0.025  per  cent. 
The  effectiveness  of  the  solution  was  also  found  to  be  increased  by  the 
addition  of  0.003  per  cent  of  sodium  bicarbonate.  This  acts  as  a  buf- 
fer substance  (page  36),  holding  the  hydrogen-ion  concentration  at  a 
constant  level.  More  recent  work  has  shown  that  the  hydrogen-ion  con- 
centration of  the  perfusion  solutions  is  of  considerable  importance  in 
determining  the  efficiency  of  the  beat,  but  the  optimum  is  not  the  same 
for  the  hearts  of  different  kinds  of  animal,  and  indeed  it  may  differ 
for  different  parts  of  the  same  heart. 

The  question  naturally  arises  as  to  the  relative  importance  of  each 
of  the  above  salts;  or  rather,  we  should  say,  cations,  since  the  anion, 
chlorine,  is  the  same  for  all  of  them.  The  function  of  the  sodium  chlo- 
ride in  the  solutions  is  twofold:  (1)  to  endow  the  solution  with  the 


THE   NUTRITION    OF    THE   HEART  167 

proper  osmotic  pressure  (see  page  4)  ;  and  (2)  to  perform  the  special 
role  of  the  sodium  ion  in  the  origination  and  maintenance  of  the  auto- 
matic beat.  The  latter  function  of  Na  can  be  shown  by  observing  the  behav- 
ior of  strips  cut  out  from  the  ventricle  of  the  turtle  heart  and  placed 
in  solutions  of  correct  osmotic  pressure  but  containing  no  sodium  chlo- 
ride— isotonic  solutions  of  cane  sugar,  for  example.  They  soon  cease 
to  beat,  but  if  a  small  amount  of  sodium  chloride  is  added  to  the  cane 
sugar  solution,  rhythmic  contractions  return.  The  role  of  the  calcium 
ions  is  almost  entirely  a  pharmacological  one.  If  a  strip  of  turtle  ven- 
tricle which  has  been  made  to  cease  beating  by  immersion  in  isotonic 
sugar  solution  is  placed  in  a  weak  solution  of  calcium  chloride  before 
it  is  transferred  to  sodium  chloride  solution,  the  spontaneous  contrac- 
tions  will  return  earlier  and  continue  for  a  longer  time.  On  the  other 
hand,  if  more  than  the  correct  amount  of  calcium  salt  is  present  in  the 
solution,  the  beats  will  soon  be  found  to  become  smaller  and  smaller 
in  amplitude,  because  relaxation  does  not  properly  occur  between  them, 
and  ultimately  they  will  cease  altogether  with  the  ventricle  in  a  condition 
of  extreme  contraction,  called  calcium  rigor.  The  importance  of  calcium 
may  also  be  shown  by  attempting  to  perfuse  a  turtle  heart  with  blood 
serum  from  which  the  calcium  has  been  removed  by  the  addition  of 
sodium  oxalate  (which  precipitates  it  as  insoluble  calcium  oxalate).  The 
heart  soon  ceases  to  beat,  but  can  readily  be  made  to  do  so  again  by 
adding  a  slight  excess  of  calcium  chloride. 

The  potassium  ions  do  not  appear,  like  those  of  calcium  and  sodium,  to 
be  absolutely  essential  for  the  maintenance  of  the  heartbeat;  at  least  the 
heart  of  the  turtle  will  beat  for  a  long  time  when  perfused  with  a  solu- 
tion containing  only  sodium  and  calcium  salts.  The  explanation  of  this 
result  need  not,  however,  necessarily  be  that  potassium  is  an  unessential 
constituent  of  the  perfusion  fluid,  for  it  may  well  depend  on  the  fact  that 
there  is  a  sufficient  store  of  potassium  locked  away  in  the  muscle  fiber 
to  supply  the  requirements  of  the  heart  muscle  for  this  ion  for  at  least 
as  long  as  the  beat  would  continue  under  any  circumstances.  In  any 
case,  we  know  that  potassium  has  a  profound  influence  on  the  heart- 
beat, for  when  the  proportion  of  it  in  the  perfusion  fluid  is  increased,  the 
beat  becomes  very  slow  and  the  tone  of  the  heart  is  greatly  diminished — 
that  is,  it  becomes^  extremely  relaxed  between  the  beats;  and  if  the 
amount  is  further  increased,  will  very  soon  come  to  a  standstill  in  a 
greatly  dilated  or  diastolic  position. 

The  striking  antagonism  displayed  by  these  inorganic  cations  upon 
the  heartbeat  has  led  some  investigators  to  suggest  that  the  stimulus  re- 
sponsible for  the  rhythmic  activity  of  the  heart  depends  on  some  sort 
of  chemical  union  occurring  between  the  inorganic  cations  and  the  con- 
tractile substance  of  the  heart.  Union  of  calcium  with  the  contractile 


168  THE    CIRCULATION    OF    THE    BLOOD 

substance  will  lead  to  systole  or  contraction,  whereas  union  of  sodium 
or  potassiumjadll-lead  to  relaxation  or  diastole. 


Observations  on  Mammalian  Heart 

Investigation  of  the  efficiency  of  various  saline  solutions  on  the  iso- 
lated mammalian  heart  has  shown  that  the  proportion  of  the  above  salts 
must  be  somewhat  different  from  that  used  for  the  cold-blooded  heart. 
As  might  be  expected,  the  most  efficient  proportions  are  those  present 
in  the  blood  serum  of  the  particular  animal  whose  heart  is  being  per- 
fused. Basing  his  proportions  upon  the  results  of  analyses  of  the  inor- 
ganic constituents  of  mammalian  blood  serum,  Locke  found  that  an 
inorganic  solution  of  the  following  composition  is  most  efficient:  so- 
dium chloride,  0.9  per  cent;  calcium  chloride,  0.024  per  cent;  potassium 
chloride,  0.042  per  cent;  and  sodium  bicarbonate,  0.01  to  0.03  per  cent. 
When  " Locke's  solution,"  as  it  is  called,  is  perfused,  with  oxygen  in  it, 
under  pressure  through  the  isolated  mammalian  heart  at  body  tempera- 
ture, efficient  beating  can  be  maintained  for  many  hours.  More  recently 
a  solution  known  as  Tyrode  's  is  commonly  used.  It  contains  a  small  amount 
of  magnesium  and  of  phosphates.  Although  undoubtedly  superior  for 
some  perfused  preparations,  such  as  the  intestine,  it  does  not  seem  to  be 
in  any  way  superior  to  Locke's  for  the  perfusion  of  the  heart.  The  bicar- 
bonates  and  phosphates  in  these  solutions  endow  them  with  a  hydrogen-ion 
concentration  near  that  of  the  blood  (slightly  on  the  alkaline  side  of 
neutrality),  and  at  the  same  time  they  act  as  buffer  substances. 

As  already  pointed  out,  the  organic  constituents  of  such  perfusion 
fluids  do  not  appear  to  be  relatively  of  nearly  so  much  importance  as 
the  inorganic.  Nevertheless  it  appears  that  a  small  percentage  (0.1 
per  cent)  of  glucose  does  materially  improve  the  nutritive  qualities  of 
the  solution,  and  it  has  moreover  been  shown  that  after  a  while  the  con- 
centration of  glucose  in  the  perfusion  fluid  distinctly  decreases.  This 
does  not  of  itself  necessarily  mean  that  the  glucose  is  .actually  utilized 
by  the  heart  muscle:  it  might  be  stored  away  in  it  as  glycogen.  That 
some  consumption  of  carbohydrate  does  however  occur  in  the  heart  has 
been  demonstrated  by  measuring  the  intake  of  oxygen  and  the  output 
of  carbon  dioxide  through  the  lungs  of  an  isolated  heart-lung  prepara- 
tion perfused  outside  the  body  with  defibrinated  blood.  By  experiments  of 
this  type  the  attempt  has  been  made  to  show  that  the  heart  of  diabetic 
animals  loses  the  power  of  burning  glucose  as  compared  with  the. hearts 
of  normal  animals.  While  the  experiments  are  very  suggestive,  the 
results  do  not  as  yet  justify  us  in  claiming  that  in  the  latter  disease  the 
power  of  burning  glucose  in  the  tissues  has  been  materially  depressed. 

The  concentration  of  hydrogen  ions  in  the  perfusion  fluid  has  an  im- 
portant influence  on  cardiac  efficiency.  We  also  know  that  the  most 


THE    NUTRITION    OF    THE    HEART 


169 


convenient  method  for  changing  the  hydrogen-ion  concentration  of  such 
fluids  is  by  altering  their  tension  of  carbon  dioxide  (see  page  371).  In 
a  heart-lung  preparation  (page  163),  such  alteration  in  carbon-dioxide 
tension  can  very  readily  be  brought  about  by  altering  the  percentage  of 
this  gas  in  the  air  with  which  the  lungs  are  ventilated.  To  measure  the 
efficiency  of  the  heartbeat  in  such  an  experiment,  it  is  convenient  to  enclose 
the  organ  in  a  cardioplethysmograph,  the  tracing  of  which  will  tell  us  the 
degree  to  which  the  heart  is  contracted  or  relaxed,  as  well  as  the  output 
of  blood  per  minute.  By  increasing  the  tension  of  carbon  dioxide,  it 
has  been  found  in  such  experiments  that  the  dilatation  of  the  ventricle 
is  encouraged,  so  that  the  heart  with  each  beat  discharges  a  larger  quan- 
tity of  blood  (Fig.  39).  When  defibrinated  blood  is  used  the  optimum 
pressure  or  tension  of  carbon  dioxide  has  been  found  to  lie  between  5 
and  10  per  cent  of  an  atmosphere. 


Fig.  39. — Volume  curve  of  ventricles  of  cat  (lower  curve)  in  a  heart-lung  perfusion  prepara- 
tion. The  air  used  to  ventilate  the  lungs  was  replaced  between  the  arrows  by  a  mixture  con- 
taining 20%  CO2  and  25%  O2.  This  caused  dilatation  of  the  ventricles  along  with  feebler  beats 
and  a  tendency  for  the  arterial  pressure  to  fall  (upper  curve).  The  after  effect  was  an  im- 
provement of  the  beat.  (From  Starling.) 

That  the  effect  of  carbon  dioxide  in  encouraging  the  relaxation  of  the 
heart  between  beats  is  in  part  at  least  dependent  upon  the  change  in 
hydrogen-ion  concentration  of  the  perfusion  fluid  has  been  shown  by 
securing  similar  results  in  experiments  with  perfusion  fluids  to  which 
different  quantities  of  weak  nonvolatile  acids  have  been  added.  These 
observations  are  of  practical  importance  because  of  the  light  which  they 
throw  on  the  cause  of  cardiac  failure  following  upon  conditions  in  which 
there  has  been  excessive  removal  of  carbon  dioxide  from  the  blood,  as 
in  forced  ventilation  of  the  lungs.  Yandell  Henderson  has  suggested 
that  surgical  shock  may  be,  partly  at  least,  due  to  cardiac  failure  fol- 
lowing the  "washing  out"  of  carbon  dioxide  from  the  blood  by  the 
dyspnea  so  often  incident  to  the  administration  of  anesthetics  in  surgical 
operations. 


CHAPTER  XX 
THE  PHYSIOLOGY  OF  THE  HEARTBEAT 

THE  ORIGIN  AND  PROPAGATION  OF  THE  BEAT— THE  PHYSIO- 
LOGICAL  CHARACTERISTICS  OF  CARDIAC  MUSCLE 

The  origin  and  propagation  of  the  heartbeat  are  studied  on  the  excised 
heart  of  a  frog  or  turtle,  or  on  the  mammalian  heart  by  perfusing  it 
under  suitable  conditions,  which  have  already  been  described.  The  results 
obtained  on  the  cold-blooded  heart  apply  more  or  less  directly  to  the 
warm-blooded.  In  the  first  place  it  is  clear  that  the  rhythmic  contrac- 
tility of  the  heart  is  not  at  all  dependent  upon  the  central  nervous  sys- 
tem, for  if  it  were  so,  the  excised  heart  could  not  continue  beating.  This 
fact  does  not,  however,  necessarily  imply  that  the  beating  power  is  in- 
dependent of  nervous  structures,  for  in  the  heart  itself  an  extended  net- 
work of  nerve  cells  and  connecting  nerve  fibers  can  readily  be  demon- 
strated. It  might  quite  well  be  the  case  that  the  rhythmic  beat  is  de- 
pendent upon  the  transmission  to  the  muscle  fibers  of  the  heart  of 
impulses  generated  in  the  nerve  cells  and  transmitted  along  the  nerve 
fibers  of  this  local  nervous  system.  Such  is  the  neurogenic  hypothesis  of 
the  heartbeat. 

On  the  other  hand,  it  may  be  that  these  nervous  structures  are  not  at 
all  responsible  for  the  origination  of  the  beat,  but  serve  merely  as  sta- 
tions on  the  pathway  of  the  nerve  impulses,  transmitted  to  the  heart 
from  the  central  nervous  system  along  the  vagus  and  sympathetic  nerves, 
for  the  purpose  of  altering  the  rate  of  the  heartbeat  so  as  to  adjust  it 
to  the  requirements  of  blood  supply  in  the  various  parts  of  the  body.  In 
such  a  case  the  rhythmic  power  would  reside  -in  the  muscular  tissues  of 
the  heart — that  is,  each  cardiac  muscular  cell  would  have  the  power, 
not  merely  like  skeletal  muscle  of  contracting  in  response  to  a  stimulus 
transmitted  to  it,  but  also  of  originating  that  stimulus  within  itself. 
This  is  the  myogenic  hypothesis.  Much  controversy  has  raged  around 
these  two  hypotheses  and  although  space  will  not  permit  a  detailed  study 
of  the  question,  it  will  be  necessary,  on  account  of  the  great  importance  of 
the  subject  from  the  physiological  standpoint,  briefly  to  review  the  main 
arguments  of  each  school  of  thought. 

There  is  no  piece  of  evidence  offered  by  the  advocates  of  either  the 
neurogenic  or  the  myogenic  hypothesis  that  can,  taken  singly,  be  con- 

170 


THE   PHYSIOLOGY    OF    THE   HEARTBEAT  171 

sidered  as  absolutely  conclusive.  Although  some  of  "the  proofs*'  may 
at  first  sight  appear  to  be  conclusive,  yet  each  of  them  breaks  down  when 
subjected  to  a  closer  scrutiny.  It  is  only  after  we  have  collected  all  the 
evidence  for  and  against  each  view  that  we  shall  be  in  a  position  to  come 
to  any  conclusion,  and  even  then  it  will  be  plain  that  our  conclusion  can 
be  only  tentative. 

Myogenic  Hypothesis 

Taking  first  of  all  the  evidence  in  support  of  the  myogenic  hypothesis, 
the  following  stands  out  most  prominently: 

1.  The  heart  beats  in  the  embryo  chick  before  any  nerve  cells  have 
grown  into  it,  and  not  only  this,  but  if  portions  of  heart  muscle  are  re- 
moved from  the  embryo  and  placed  in  blood  plasma,  they  will  continue 
beating  for  many  days     It  has  also  been  observed  that  cells  may  wander 
off  from  this  mass  of  cardiac  muscle  and  undergo  multiplication  and 
differentiation,    so   as   to   produce   isolated  muscle   cells   which   exhibit 
rhythmic  contractility.     The  rebuttal  on  the  part  of  the  neurogenists  of 
this  apparently  unassailable  evidence  is  to  the  effect  that,  although  em- 
bryonic muscle  cells  may  exhibit  the  power  of  rhythmic  contraction,  this 
does  not  mean  that  the  fully  developed  muscle  cells  will  necessarily  have 
such  power.    In  the  eary  stages  of  embryonic  development,  it  is  of  course 
evident  that  the  functions  which  in  the  fully  developed  animal  are  del- 
egated to  various  special  organs  and  tissues  must  be  performed  by  cells 
having  several  such  functions  in  common.    The  muscle  cells  of  the  heart, 
for  example,  may  to  start  with  be  possessed  of  the  power  not  only  of  con- 
tracting but  also  of  initiating  the  contraction.     In  early  embryonic  life 
they  may  be  partly  nervous  in  character,  a  property  which  they  gradually 
lose  as  nerve  cells  and  nerve  fibers  make  their  appearance. 

2.  The  nervous  structures  in  the  heart  may  be  damaged  either  by  me- 
chanical means  or  by  drugs  without  apparently  interfering  with  the 
power  of  rhythmic  contraction;  for  example,  in  the  heart  of  large  tur- 
tles it  is  possible  to  dissect  out  a  considerable  amount  of  nervous  tissue 
without  any  disturbance  of  the  beat,  and  in  all  animals  the  administration 
of  atropine,  which  paralyzes  the  postganglionic  fibers  of  the  autonomic 
nervous  system  (see  page  231)  found  in  the  heart,  does  not  affect  it. 

3.  The  apex  of  the  ventricle  in  such  hearts  as  that  of  the  turtle  can 
be  shown,  by  careful  histological  examination,  to  contain  no  nerve  cells,  and 
although  a  few  nerve  fibers  may  be  found,  these  are  of  course  functionless 
without  nerve  cells.    This  virtually  nerveless  piece  of  heart  muscle  can 
be  made  to  contract  rhythmically  by  perfusing  it  with  suitable  saline 


172  THE   CIRCULATION   OF   THE   BLOOD 

solution  under  pressure  and  starting  the  beating  by  application  of  elec- 
trical stimuli.  Isolated  strips  of  ventricular  muscle,  in  which  also  no 
nervous  element  can  be  demonstrated,  may  under  favorable  conditions 
be  caused  to  beat  quite  regularly  if  supplied  with  proper  nutrient  fluid. 
The  rebuttal  of  this  evidence  is  twofold:  In  the  first  place,  skeletal  mus- 
cle itself  under  certain  conditions,  such  as  exposure  to  solutions  con- 
taining an  excess  of  phosphate  (Biedermann's),  may  exhibit  rhythmic 
contractility,  especially  on  cooling,  which  indicates  that  exhibition  of  rhyth- 
mic power  in  isolated  portions  of  cardiac  muscle  need  not  mean  that  under 
ordinary  conditions  such  power  is  responsible  for  the  normal  heartbeat. 
In  the  second  place,  it  is  pointed  out  that  although  we  can  not  reveal 
their  presence  by  present-day  histological  methods,  this  is  not  conclusive 
evidence  that  the  heart-muscle  fiber  may  not  possess  some  nervous  struc- 
tures capable  of  functioning  as  nerve  cells. 

The  heart  even  of  mammals  can  be  made  to  continue  beating  for  sev- 
eral days  after  excision  from  the  body.  The  nerve  cells,  as  we  know  them 
in  the  central  nervous  system  at  least,  can  not,  on  the  other  hand,  be 
made  to  functionate  for  more  than  a  few  hours  after  death.  Therefore, 
it  is  argued,  the  heartbeat  in  surviving  mammalian  hearts  can  not  de- 
pend on  the  nervous  structures.  The  argument  is  however  easily  refuted: 
on  the  one  hand,  we  do  not  know  that  the  nerve  structures  situated 
peripherally  in  the  heart  muscles  are  of  the  same  viable  nature  as  those 
composing  the  central  nervous  system;  and,  on  the  other,  the  survival 
of  the  heart  may  in  itself  be  sufficient  to  maintain  around  the  nerve  cells 
embedded  in  it  a  nutrient  environment  which  is  much  more  physiological 
than  that  which  we  can  supply  in  artificial  perfusions  of  surviving 
nervous  tissues. 

4.  Circumstantial  but  nevertheless  strong  evidence  is  furnished  by 
the  fact  that  many  other  varieties  of  involuntary  muscle  are  endowed 
with  rhythmic  contractility;  thus,  the  muscle  of  the  intestines,  of  the 
ureters,  of  the  bladder,  of  the  uterus,  of  the  blood  vessels  of  certain 
animals,  and  of  the  lymph  vessels  in  the  so-called  lymph  hearts,  main- 
tain rhythmic  contractility  after  isolation  from  the  animal  body.  The 
rhythmic  power  seems  in  certain  of  these  cases  to  be  independent  of 
nervous  control. 

Neurogenic  Hypothesis 

In  favor  of  this  hypothesis  the  following  evidence  is  offered: 
1.  The  heart  of  certain  animals — of  Limulus,  the  king-crab,  for  exam- 
ple— is  definitely  dependent  for  its  rhythmic  contractility  upon  neigh- 
boring nervous  structures.     The  heart  of  this  animal  is  a  tubular  sac- 
culated  organ,  and  along  its  dorsal  surface  there  runs  longitudinally  a 


THE   PHYSIOLOGY    OF    THE    HEARTBEAT  173 

nerve  cord  containing  ganglion  cells  and  giving  off  fibers  which  proceed 
in  part  directly  to  the  heart  and  in  part  to  lateral  cords  (Fig.  40).  Re- 
moval of  this  median  nerve  cord  is  followed  by  total  abolition  of  the 
heartbeat;  the  heart  becomes  perfectly  quiescent  like  an  unstinmlated 
skeletal  muscle.  In  appraising  this  evidence  at  its  true  value,  it  must  be 
noted  that  although  contraction  of  the  heart  can  be  produced  by  stim- 
ulation of  the  nerve  fibers,  the  contraction  is  like  that  of  a  skeletal  mus- 
cle— it  is  not  rhythmic;  and  moreover — and  this  is  most  important — if 
the  various  physiological  properties  of  muscle  as  described  below  be  stud- 
ied (page  176),  it  will  be  found  that  in  all  of  them  the  quiescent  heart 
muscle  behaves,  not  like  the  heart  muscle  of  other  animals,  but  like  that 
of  skeletal  muscle.  This  evidence,  therefore,  while  indisputably  showing 
that  the  heart  of  Limulus  depends  for  its  rhythmic  power  upon  neigh- 
boring nerve  structures,  does  not  justify  the  assumption  that  this  will  be 
the  case  in  the  heart  of  animals  having  different  physiological  properties. 
2.  The  disposition  of  the  nervous  structures  in  the  heart,  especially  of 
the  frog  and  turtle,  exactly  corresponds  to  the  degree  of  development  of 


Fig.  40. — Heart  and  cardiac  nerves  of  Limulus  polyphemus.  (Carlson.)  aa,  anterior  ar- 
teries; la,  lateral  arteries;  In,  lateral  nerves,  nine,  median  ganglionic  chain;  os,  ostii  or  afferent 
stomata,  each  pair  of  which  corresponds  to  one  of  the  segments  into  which  the  Limulus  heart 
is  divided. 

the  rhythmic  power  of  the  different  parts  of  the  heart ;  thus,  the  greatest 
rhythmic  power  is  manifested  by  the  sinus  and  the  least  by  the  tip  of  the 
ventricle  at  the  bulbus  arteriosus.  In  the  former  position  the  nerve 
structures  are  very  prominent ;  in  the  latter,  no  nerve  cells  and  but  few 
nerve  fibers  can  be  detected.  This  proof  is,  however,  easily  assailed. 
In  the  first  place,  it  may  merely  be  a  coincidence  that  the  disposition  of 
the  nerve  structures  and  the  development  of  rhythmic  power  correspond. 
The  unequal  rhythmic  powers  may  depend  primarily  on  a  difference 
in  structure  of  the  muscle  fibers  themselves,  such  differences  having 
been  shown  to  exist  between  the  muscle  cells  of  the  sinus  and  those 
of,  say,  the  ventricle.  The  former  cells,  for  example,  have  much  less 
developed  crossed  striation  and  their  protoplasm  is  much  more  gran- 
ular ;  in  short,  they  are  much  more  embryonic  in  type  than  the  cells  from 
the  tip  of  the  ventricle. 

If  a  jury  had  to  return  a  verdict  from  evidence  of  so  conflicting  a  char- 
acter, it  would  no  doubt  be  equivalent  to  that  of  the  Scottish  court — "not 


174  THE   CIRCULATION   OF   THE   BLOOD 

proven."  But  it  is  likely  that  the  majority  of  the  jury  would  vote 
in  favor  of  the  myogenic  hypothesis.  Probably  the  safest  viewpoint  to 
take  at  the  present  time  is  that  the  power  of  rhythmic  contraction  is 
inherent  in  the  cardiac  muscle  fibers,  being  most  highly  developed  in 
those  of  the  venous  end  of  the  heart,  and  least  developed  in  those  of 
the  arterial  end.  Such  a  conclusion  does  not  deny  to  the  nervous  struc- 
tures of  the  heart  the  power  under  certain  conditions  of  also  assuming 
rhythmic  activity.  In  one  case  at  least — namely,  the  hea'rt  of  Limulus — 
we  know  that  this  is  so.  For  some  reason  in  this  animal  the  cardiac 
muscle  fiber  has  lost  its  inherent  rhythmic  power,  and  is  now  dependent 
for  its  activities  upon  rhythmic  nervous  discharges  transmitted  to  it 
from  the  neighboring  nerve  cords,  a  condition  which  is  paralleled  in 
the  higher  animals  in  the  innervation  of  the  respiratory  muscles.  The 
respiratory  center  rhythmically  discharges  impulses  to  the  muscles,  which 
are  quiescent  in  the  absence  of  these  impulses. 

The  Pacemaker  of  the  Heart  and  Heart-block 

In  a  volume  of  this  nature,  devoted  primarily  to  the  practical  appli- 
cation of  physiology,  the  discussion  of  these  problems  may  seem  a  little 
out  of  place,  but  that  this  is  not  the  case  is  seen  when  we  consider  that 
the  experiments  upon  which  the  various  points  of  evidence  depend 
bring  to  light  facts  of  the  very  greatest  importance  in  the  study  of  the 
physiology  of  the  heartbeat.  One  fact  which  stands  out  prominently 
is  that  the  greatest  rhythmic  power  resides  in  the  basal  portion  of  the 
heart — that  is,  in  what  corresponds,  in  the  more  primitive  hearts,  to  the 
sinus  venosus. 

Although  the  muscle  of  the  entire  heart  possesses  rhythmic  power,  it 
does  not  do  so  to  an  equal  degree;  in  the  sinus  the  rhythmic  power  is 
extraordinarily  developed,  while  in  the  bulbus  arteriosus  it  is  scarcely 
recognizable.  This  observation  suggests  the  possibility  that  the  sinus 
may  dominate  the  heartbeat — that  it  may  be  the  "pacemaker"  for  the 
heart  as  a  whole.  The  most  natural  method  for  demonstrating  such  a 
possibility  would  be  to  observe  the  effect  on  the  heartbeat  of  some  Nock 
between  the  sinus  and  the  rest  of  the  heart.  Such  a  block  can  be  intro- 
duced in  the  heart  of  cold-blooded  animals  by  local  compression  around 
the  various  junctions.  If  a  thread  is  tied  around  the  sinoauricular 
junction,  the  sinus  will  go  on  beating  uninterruptedly,  but  the  auricles 
and  ventricles — that  is,  the  greater  part  of  the  heart  below  the  ligatures 
— will  cease  beating,  sometimes  entirely  (Stannius'  ligature).  After  a 
while,  however,  the  heart  below  the  ligature  will  usually  begin  to  beat, 
but  at  a  rhythm  which  is  slower  than,  and  independent  of,  that  of  the 
sinus. 


THE   PHYSIOLOGY    OF    THE    HEARTBEAT  175 

The  experiment  can  be  still  better  performed  by  using  a  wedge- 
shaped  clamp.  (Gaskell's  clamp.)  If  this  is  applied  so  that  the  heart 
can  be  pinched  either  at  the  sinoauricuiar  junction  or  at  the  auriculo- 
ventricular,  it  will  be  found  that,  as  the  cardiac  tissue  is  gradually 


Fig.    41. — Heart-block    produced    by    applying    clamp    at    a-v    junction.       The    clamp    was    tightened 

at    a.      (From    Brubaker.) 

pinched,  the  portion  of  the  heart  below  fails  to  beat  as  quickly  as  that 
above  the  clamp  (Fig.  41).  This  is  known  as  partial  heart-block,  and 
the  degree  of  the  block  is  indicated  by  the  numerical  expression  2  to  1, 
3  to  1,  4  to  1,  etc.,  meaning  that  the  sinus  is'  beating  either  twice  as 
quickly  as  the  ventricle,  or  three  times,  or  four  times  as  the  case  may 


Fig.  42. — Tracing  of  contraction  of  ventricle,  showing  the  effect  of  the  local  application 
of  heat  to  the  auricle  at  /,  and  to  the  apex  of  the  ventricle  at  2.  Note  that  the  rate  in- 
creased in  the  former  case. 

be.     Similar  conditions  of  heart-block  may  also  be  produced  by  cutting 
the  cardiac  tissue  partly  across  at  various  places  in  the  heart. 

Further  evidence  that  the  sinus  dominates  the  beat  in  the  heart  of 


176  THE    CIRCULATION    OF    THE   BLOOD 

cold-blooded  animals  is  furnished  by  observing  the  effects  of  local  heat- 
ing or  cooling  of  the  various  parts  of  the  heart.  In  all  rhythmically 
acting  structures  it  is  well-known  that  heat  increases  the  rate  of  the 
rhythm  and  cold  depresses  it.  If  we  locally  warm  the  region  of  the 
sinus,  as  by  holding  a  heated  wire  near  it  the  whole  heart  will  immedi- 
ately beat  quicker;  but  if  we  locally  heat  the  tip  of  the  ventricle,  no 
alteration  of  rhythm  will  be  observed  to  occur  (Fig.  42). 

The  establishment  of  the  fact  that  the  sinus  dominates  the  heartbeat 
—that  it  is  the  pacemaker  of  the  beat — raises  the  question  as  to  how  the 
impulse  originated  at  this  place  is  transmitted  over  the  rest  of  the 
heart,  and  here  again  a  neurogenic  and  a  myogenic  hypothesis  have  to 
be  considered.  Before  going  into  this  question,  however,  it  will  be  well 
for  us  to  consider  briefly  the  manner  of  response  of  cardiac  muscle 
fiber  to  a  stimulus,  because  the  behavior  of  cardiac  muscle  under  such 
conditions  is  considerably  different  in  many  regards  from  that  of  skel- 
etal muscle,  and  it  is  to  these  differences  that  many  of  the  peculiar 
alterations  in  the  beat  observed  after  interfering  with  the  conducting 
structures  between  the  sinus  and  the  rest  of  the  heart,  are  to  be  ex- 
plained. 

The  Physiological  Characteristics  of  Cardiac  Muscle 

It  is  necessary  to  bring  the  heart  into  a  quiescent  state  in  order  to 
investigate  the  properties  of  its  musculature.  This  is  accomplished  by 


Fig.  43. — Frog  heart  showing  the  position  of  the  first  and  second  ligatures  of  Stannius 
(Hedon):  /,  auricles;  2,  sinus;  j.  ventricle.  It  is  the  first  ligature  which  brings  the  heart 
to  a  standstill. 

the  application  of  the  Stannius  ligature  between  the  sinus  and  the  auri- 
cles (Fig.  43).  After  tightening  the  ligature  the  auricles  and  ventricles 
become  quiescent,  and  by  observing  the  effects  following  the  applica- 
tion of  electric  or  other  stimuli  we  can  compare  the  behavior  of  the 
cardiac  muscle  with  that  of  skeletal  mttscle  similarly  stimulated.  This 
comparison  is  made  because  of  the  assistance  which  it  offers  in  compre- 
hending the  properties  of  cardiac  muscle.  As  a  matter  of  fact,  recent 
investigations  have  shown  that  the  differences  between  the  two  types  of 
muscle  are  not  fundamental,  since  under  certain  conditions  the  one  may 


THE    PHYSIOLOGY    OF    THE    HEARTBEAT 


177 


be  made  to  behave  like  the  other.     They  are  dependent  upon  the  pres- 
ence or  absence  of  anastomosis  between  the  muscle  fibers. 

1.  When  electric  stimuli  of  varying  strengths  are  applied  to  skeletal 
muscle,  the  contraction  produced  by  each  stimulus  is  proportional  to 
the  strength  of  the  latter  until  this  has  become  of  such  a  strength  that 
the  maximal  response  is  elicited.  In  cardiac  muscle,  on  the  other  hand, 
an  entirely  different  result  is  obtained,  for  the  weakest  stimulus,  if  it 
produces  any  response  at  all,  produces  one  that  is  maximal;  that  is,  the 
height  of  contraction  is  the  same  as  it  would  have  been  had  a  much 
stronger  stimulus  been  applied.  Expressing  this  result  in  general  terms, 
we  may  say  that  in  cardiac  muscle  a  minimal  stimulus  produces  a  maxi- 


A.— Skeletal    Muscle 


B. — Cardiac    Muscle 

Fig.    44. — Effects    of    stimuli    of    increasing    strength    on    skeletal    and    cardiac    muscle    to    illustrate 
the    "all    or    nothing"    principle    in    the    latter.       (From    Practical    Physiology.) 

mal  effect,  whereas  in  skeletal,  the  effect,  as  measured  by  the  height  of 
contraction,  is  proportional  to  the  intensity  of  stimulation.  This  is  some- 
times known  as  the  "all  or  nothing  phenomenon"  (Fig.  44). 

2.  If  maximal  stimuli  are  applied  successively  and  at  short  intervals 
of  time  to  skeletal  muscle,  a  slightly  higher  response  results  from  each 
succeeding  stimulus,  until  about  ten  stimuli  have  been  applied,  after 
which  for  some  considerable  time  the  same  height  of  contraction  follows 
each  stimulus.  If  each  contraction  is  recorded,  it  will  be  seen  that  the 
first  few  contractions  give  a  staircase  effect  or  treppe;  that  is,  if  a  hori- 
zontal line  is  drawn  from  the  top  of  each  contraction  to  the  next  one,  the 


178  THE   ClftCULATlOK  OF   TSE  BLOOD 

effect  of  an  ascending  staircase  with  gradually  diminishing  steps  will  be 
produced.  If  we  repeat  this  observation  with  cardiac  muscle,  we  shall 
find  that  it  is  much  more  pronounced  than  in  skeletal  muscle;  and  more- 
over, in  obedience  to  the  all  or  nothing  principle,  the  treppe  is  obtained  in 
cardiac  muscle  whatever  may  be  the  relative  strengths  of  the  stimuli 
applied  to  the  heart,  provided  always  that  all  of  them  are  effective; 
whereas  in  the  case  of  skeletal  muscle  it  can  be  demonstrated  only  pro- 
vided the  stimuli  are  of  equal  strength  (Fig.  45). 

3.  If  an  effective  stimulus  is  applied  to  a  skeletal  muscle  while  in  process 
of  contraction,  as  in  response  to  a  preceding  stimulus,  the  second  stimulus 
prolongs  the  contraction  produced  by  the  first  one.  If,  however,  the  second 


Skeletal    muscle 


Cardiac    muscle 

Fig  45. — The   effects   of   successive  stimuli   on   skeletal   and   cardiac   muscle   to   show   the   prominence 
of    the    staircase    phenomenon,    or    treppe,    in    the    latter.      (From    T.    G.    Brodie.) 

stimulus  is  applied  during  the  latent  period*  of  the  first  one,  it  will  have  no 
effect — that  is,  the  muscle  during  this  period  is  refractory,  f  From  these 
results  it  follows  that  stimuli  succeeding  each  other  during  the  contraction 
period  will,  in  the  case  of  skeletal  muscle,  cause  a  continuous  contraction,  or 
tetanus,  as  it  is  called,  because  the  contraction  produced  by  each  stimu- 
lus will  add  itself  to  that  of  its  predecessor  before  any  trace  of  relax- 
ation has  set  in.  If,  however,  the  second  stimulus  is  applied  so  late  in 
the  contraction  period  of  the  first  that  time  is  not  available  for  the  latent 

*By  "latent  period"  is  meant  the  period  after  the  moment  of  application  of  a  stimulus  during 
which  no  effect  of  that  stimulus  is  observed. 

|By  "refractory  period"  is  meant  the  time  following  the  application  of  a  stimulus  during  which  a 
second  stimulus  develops  less  than  its  full  effect  or  no  effect  at  all. 


THE   PHYSIOLOGY    OF    THE    HEARTBEAT  179 

period  of  the  former  to  be  expended,  then  obviously  a  slight  relaxation  will 
have  occurred  before  the  effect  of  the  second  stimulus  develops  itself,  and 
tetanus  will  be  incomplete.  These  facts  will  be  evident  from  the  accom- 
panying tracings  (Fig.  46). 


Skeletal  muscle  Stannius'  heart 

ic    effects    of    successive    stimuli    and    of    tetanizing 
The    small    vertical    marks    show    when    the    stini 
from    tracings    published    by    T.    G.    Brodie    and    Leonard    Hill.) 


Fig.    46. — The    effects    of    successive    stimuli    and    of    tetanizing    stimuli    on    skeletal    muscle    and 
cardiac    muscle.      The    small    vertical    marks    show    when    the    stimuli    were    introduced.      (Compiled 


In  the  case  of  cardiac  muscle  the  above  described  properties  are  quite 
different,  for  the  refractory  phase  extends  throughout  the  whole  period  of 
contraction;  that  is,  a  second  stimulus  applied  during  the  contraction 
produced  by  a  previous  stimulus  has  no  effect  whatsoever;  it  does  not 


180  THE    CIRCULATION   OF    THE   BLOOD 

have  one  until  the  muscle  has  reached  the  full  extent  of  its  contraction 
and  is  about  to  relax.  Since  a  latent  period  must  supervene  upon  the 
application  of  this  second  stimulus,  it  follows  that  no  complete  fusion  of 
the  contractions  is  possible.  Complete  tetanus  therefore,  does  not  occur 
in  cardiac  muscle,  however  frequently  the  stimuli  may  be  applied  (Fig. 
46). 

The  refractory  phase  is  a  property  of  extreme  importance  in  under- 
standing many  of  the  peculiar  irregularities  observed  in  cardiac  action. 
If  we  observe  the  effect  of  stimuli  applied  at  varying  periods  after  the 


Fig.  47. — Myograms  of  frog's  ventricle,  showing  effect  of  excitation  by  break  induction 
shocks  at  various  moments  of  the  cardiac  cycle.  The  line  O  indicates  the  commencement  of 
all  the  beats  during  which  the  shock  is  sent  in.  It  will  be  noted  that  in  /,  2  and  3,  the  heart 
is  refractory  to  the  stimulus.  The  signals  indicate  the  moments  at  which  the  stimuli  were  ap- 
plied. From  4  to  8  the  heart  reacts  by  an  extrasystole,  after  a  delay,  which  is  progressively  less 
the  later  in  diastole  the  stimulus  enters,  as  shown  by  the  sections  shaded  obliquely  to  make  them 
more  conspicuous.  The  extrasystolcs  increase  in  height  from  4  to  8,  each  being  followed  by 
a  compensatory  pause.  (From  J^uciani's  Human  Physiology.) 

termination  of  the  refractory  phase  of  a  previous  stimulus,  we  shall  find 
that  the  height  of  the  extra  contraction  is  directly  proportional  to  the 
time  after  the  end  of  the  refractory  period  at  which  it  is  applied.  If  a 
stimulus  is  applied  at  the  very  beginning  of  diastole,  the  extra  contrac- 
tion will  be  small,  whereas  if  it  is  applied  at  the  end  of  diastole,  the 
extra  contraction  will  be  at  least  as  high  as  that  of  the  preceding.  It 
may  be  higher  because  of  the  treppe. 


THE   PHYSIOLOGY    OF    THE    HEARTBEAT  181 

These  observations  enable  us  to  interpret  the  results  obtained  by  ap- 
plying electric  shocks  (extra  stimuli)  to  the  beating  heart  during  different 
phases  of  systole  and  diastole.  During  systole,  the  muscle  being  refrac- 
tory, no  effect  is  produced  by  the  extra  stimulus,  but  during  diastole 
extra  systoles  which  are  progressively  more  pronounced  the  later  in 
diastole  they  occur,  follow  the  application  of  each  stimulus.  These  re- 
sults are  so  far  exactly  like  those  obtained  with  a  quiescent  heart.  But 
another  phenomenon  now  becomes  evident;  namely,  that  following  each 
extra  systole  there  is  a  compensatory  pause  in  the  action  of  the  heart, 
of  such  duration  that,  when  the  next  natural  beat  occurs,  it  does  so 
practically  at  the  same  time  as  it  would  have  occurred  had  no  artificial 
stimulus  been  applied.  This  will  be  apparent  from  the  accompanying 
diagram  (Fig.  47). 

It  should  be  noted  that  the  refractory  period  is  greatly  diminished  by 
raising  the  temperature  of  the  heart.  Indeed,  under  these  conditions 
and  with  strong  stimulation  it  may  be  possible  to  produce  an  almost 
complete  tetanus. 

The  importance  of  knowing  the  above  facts  is  that  we  are  thereby 
enabled  to  explain  the  peculiar  manner  in  which  the  ventricle  responds 
to  stimuli  transmitted  to  it  from  the  sinus  and  the  auricle.  The  muscu- 
lature of  the  auricle  and  ventricle  of  the  mammalian  heart  is  not  one 
continuous  sheet,  but  is  separated  by  a  space  at  the  auriculoventricular 
junction,  across  which,  in  specially  organized  structures,  the  beat  of  the 
auricle  is  transmitted  to  the  ventricle.  Sometimes  the  stimuli  are  so 
frequent  that  the  ventricular  muscle  is  unable  to  respond  to  each  stimu- 
lus transmitted  to  it,  with  the  result  that  marked  irregularities  in  con- 
traction occur  (see  page  293).  In  this  way  certain  of  the  cardiac  irregu- 
larities observed  in  man  can  be  explained.  By  slowing  the  auricular 
beats  as  by  giving  digitalis  these  irregularities  often  disappear. 

When  the  extra  systoles  occur  in  the  ventricle  itself  either  because  of 
disease  or  of  the  action  of  drugs,  the  contraction  may  be  so  feeble  that  it 
fails  to  open  the  semilunar  valves  with  the  result  that  the  second  sound 
is  not  heard — although  the  first  sound  is — and  the  arterial  pulse  shows 
a  missing  wave.  In  such  a  case  the  pause  in  the  arterial  pulse  curve 
equals  the  distance  between  two  normal  waves.  When  the  extra  systole 
is  just  strong  enough  to  open  the  semilunar  valve  a  feeble  second  sound 
is  heard  and  a  low  wave  appears  on  the  pulse  curve,  followed  by  a  com- 
pensatory pause. 


CHAPTER  XXI 
THE  PHYSIOLOGY  OF  THE  HEARTBEAT  (Cont'd) 

THE  ORIGIN  AND  PROPAGATION  OF  THE  BEAT  IN  THE 
MAMMALIAN  HEART 

As  has  been  shown  in  the  preceding  chapter,  there  is  no  doubt  that 
in  the  cold-Hooded  heart  the  beat  originates  at  the  sinus  venosus,  whence 
it  spreads  to  the  rest  of  the  heart.  Very  strong  evidence  has  also  been 
presented  to  indicate  that  the  beating  power  is  inherent  in  the  muscle 
fiber  itself  and  independent  of  nervous  structure.  This  would  suggest  the 
further  possibility  that  the  structures  through  which  the  beat  is  propa- 
gated are  the  muscle  fibers  and  not  the  nerve  fibers — in  other  words, 
that  the  propagation  of  the  heartbeat,  like  its  origination,  is  myogenic 
rather  than  neurogenic.  Direct  proof  of  this  hypothesis  is  readily  fur- 
nished by  numerous  experiments,  among  which  may  be  mentioned  mak- 
ing interdigitating  cuts  across  the  heart,  or  excising  a  ribbon  of  ven- 
tricular muscle  by  an  incision  simulating  the  walls  of  Troy.  In  both 
these  cases  the  beat  will  be  found  to  travel  from  one  end  of  the  muscular 
band  to  the  other,  although  it  is  evident  that  all  the  nerves  proceeding 
from  base  to  apex  of  the  heart  must  have  been  severed.  Of  course  this 
evidence  is  not  irrefutable,  for  it  might  be  argued  that  there  are  nerv- 
ous structures  disposed  in  the  form  of  a  plexus  continuously  all  over  the 
heart,  and  that  some  branches  of  the  plexus  remain  uncut  in  the  above 
experiments.  It  is  only  in  the  heart  of  Limulus  that  undoubted  evidence 
exists  that  the  beat  is  transmitted  by  nerves,  but  as  we  have  seen,  this 
heart  in  all  its  properties  is  probably  the  proverbial  exception  which 
proves  the  rule.  The  balance  of  evidence  stands  in  favor  of  the  view 
that  the  propagation  of  the  beat  over  the  cold-blooded  heart  is  myogenic 
and  not  neurogenic. 

CONDUCTING  TISSUE  IN  MAMMALIAN  HEART 

When  we  attempt  to  investigate  the  problems  of  the  origin  and  propa- 
gation of  the  beat  in  the  warm-blooded  heart,  many  experimental  diffi- 
culties of  course  face  us.  In  overcoming  these,  the  first  thing  we  must 
do  is  to  establish  the  structural  relationship  between  cold-blooded  and 
warm-blooded  hearts.  In  the  embryo  of  both  classes  of  animals  the 

182 


THE   PHYSIOLOGY    OF    THE    HEARTBEAT 


183 


heart  arises  as  the  so-called  cardiac  tube.  As  development  proceeds, 
diverticula  grow  out  from  the  walls  of  this  tube  to  form  the  auricles  and 
ventricles.  In  the  comparatively  simple  heart  of  the  turtle  these  dispo- 
sitions of  the  auricles  and  ventricles  in  relationship  to  the  cardiac  tube 
are  more  or  less  evident  even  in  the  fully  developed  heart,  particularly 
in  the  case  of  the  auricles  (Fig.  48)  ;  but  in  the  heart  of  the  higher 
mammalia  it  is  impossible  by  superficial  examination  alone  to  show  any 
remains  of  the  primitive  cardiac  tube.  More  careful  anatomic  investiga- 
tions during  recent  years  have,  however,  shown  that  it  exists  in  the  form 
of  certain  definite  structures  composed  of  tissue  histologically  quite  dif- 
ferent from  that  of  the  rest  of  the  heart,  and  disposed  in  such  a  manner 


TH 


TH 

Fig.   48. — Heart  of  tortoise  as  suspended.     B,  body  of  tortoise;    TH.   threads  to   levers;    CL,   clamp 
holding  aorta;  A,  auricle;    C,  coronary   nerve;    S,   sinus;    V,  ventricle.    (From  Gaskell.) 

as  would  indicate  not  only  that  it  is  derived  from  the  primitive  cardiac 
tube,  but  also  that  it  is  the  main  pathway  along  which  the  beat  is 
transmitted. 

This  primitive  cardiac  tissue  is  much  better  developed  in  certain  re- 
gions than  in  others,  the  first  portion  of  it  to  be  discovered  being  that 
known  as  the  auriculoventricular  node,  or  the  node  of  Stanley  Kent*  (Figs. 
49  and  50) .  This  structure  is  found  at  the  base  of  the  interauricular  sep- 
tum on  the  right  side  and  near  its  posterior  margin.  It  exists  as  a  collection 
of  peculiar  small  primitive  cells  and  fibers,  and  is  continued  forward  and 
downward  as  a  bundle  of  the  same  peculiar  tissue  to  the  interventricular 
septum,  where,  a  little  in  front  of  the  attachment  of  the  septal  valve,  it 

*The  discovery  of  this  node  is  often  erroneously  attributed  to  His,  and  called  after  his  name. 


184 


THE    CIRCULATION    OF    THE    BLOOD 


bifurcates  into  right  and  left  branches  which  run  down  each  side  of  the 
septum  immediately  underneath  the  endocardium.  Each  main  branch 
ultimately  divides  up  into  an  intricate  system  of  smaller  branches,  which 
become  reflected  over  the  inner  surface  of  the  ventricles  where  their  exist- 
ence has  been  known  for  some  time  as  the  so-called  Purkinje  fibers.  The 
right  bundle  remains  undivided  until  after  it  has  run  along  the  moder- 


Fig.  49. — Dissection  of  heart  to  show  auriculoventricular  bundle  (Keith) ;  3,  the  beginning  of 
the  bundle,  known  as  the  A-V  node;  2,  the  bundle  dividing  into  two  branches;  4,  the  branch  run- 
ning on  the  right  side  of  the  interventricular  septum.  (From  Howell's  Physiology.) 


Fig.  50. — Photograph  of  model  of  the  auriculoventricular  bundle  and  its  ramifications,  con- 
structed from  dissections  of  the  heart  (Miss  De  Witt).  All  of  the  branches  in  the  left  ventricle 
are  not  included.  (From  Howellj 

ator  band  or  its  representative,  but  the  left  bundle  divides  early.  The 
fibers  ultimately  end  in  close  association  with  the  papillary  muscles. 
The  node  and  main  bundle  and  the  two  branches  before  they  have 
begun  to  divide  are  surrounded  by  a  sheath  of  fibrous  tissue,  and 
they  seem  to  have  a  liberal  blood  supply.  It  is  of  interest  that  they  con- 
tain a  high  percentage  of  glycogen.  In  the  human  heart  the  auriculo- 


THE    PHYSIOLOGY    OF    THE    HEARTBEAT  185 

ventricular  node  and  bundle  measure  about  15  mm.  in  length  and  about 
2  mm.  in  width. 

The  rest  of  the  tissue  between  the  auricles  and  ventricles  is  fibrous 
in  nature,  although  other  connections  like  those  of  the  auriculoventricular 
bundle  have  been  described  by  Kent.  One  of  these,  called  the  right  lat- 
eral connection,  runs  between  the  right  auricle  and  the  external  wall  of 
the  right  ventricle. 

Another,  but  much  smaller,  mass  of  similar  embryonic  cardiac  tissue 
has  more  recently  been  discovered  by  Keith  and  Flack  in  the  parts  of 
the  auricle  which  correspond  anatomically  to  the  sinus  venosus  of  the 
heart  of  cold-blooded  animals — that  is,  in  the  area  lying  between  the 
openings  of  the  venaa  cavae  and  around  the  coronary  sinus.  To  be  more 
explicit,  this  tissue  lies  "in  the  sulcus  terminalis  just  below  the  fork 
formed  by  the  junction  of  the  upper  surface  of  the  auricular  appendix 
with  the  superior  vena  cava. "  This  sinoauricular  node,  as  it  is  called, 
is  more  or  less  club-shaped,  the  blunt  end  of  the  club  being  above,  as 
shown  in  the  accompanying  figures  (Pigs.  51  and  52).  It  is  important  to 
note  that  there  is  no  direct  connection  visible  between  the  sinoauricular 
and  auriculoventricular  nodes  (Fig.  52). 

Another  anatomic  fact  seen  also  in  the  accompanying  figure,  concerns 
the  disposition  of  the  muscular  fibers  of  the  auricle.  These  radiate  in 
bundles  in  a  peculiar  fan-shaped  manner  from  a  point  which  lies  im- 
mediately below  the  sinoauricular  node  to  all  parts  of  the  superficies  of 
the  right  auricle.  This  point  has  been  called  the  concentration  point. 
At  the  termination  of  the  venae  cavae,  the  muscle  fibers  are  arranged  more 
or  less  circularly. 

Having  become  familiar  with  the  disposition  in  the  mammalian  heart 
of  the  primitive  cardiac  tissue,  along  which  in  the  heart  of  the  lower 
animals  we  know  that  the  heartbeat  spreads,  we  may  now  proceed  to 
examine  the  evidence  showing  that  this  tissue  is  also  responsible  for  the 
origination  and  propagation  of  the  beat  in  the  heart  of  mammals.  With 
regard  to  the  origin  of  the  beat  in  a  normally  beating  mammalian  heart, 
it  is  of  course  impossible  to  see  where  this  takes  place.  If  the  heart  is 
excised,  however,  it  will  continue  to  beat  for  a  few  moments,  and  as  it 
dies  it  will  be  observed  that  the  power  of  contraction  remains  in  the  au- 
ricular region,  and  particularly  at  the  bases  of  the  venae  cavae,  for  a  con- 
siderable time  after  the  ventricles  have  ceased  to  beat.  This  part — the 
ultimum  moriens — is  situated  in  most  hearts  somewhat  lower  than  the 
sinoauricular  node.  That  it  is  the  last  part  of  the  heart  to  cease  con- 
tracting does  not  necessarily  mean  that  it  is  the  part  of  the  heart  in 
which  the  beat  ordinarily  originates;  it  means  simply  that  this  is  the 
part  of  the  auricle  in  which  the  power  of  contraction  remains  for  the 


186 


THE   CIRCULATION   OF   THE   BLOOD 


longest  time  after  death.  Although,  the  observation  does  not  enable  us 
to  determine  exactly  where  the  heartbeat  originates,  yet  it  makes  it 
very  probable  that  this  is  somewhere  in  the  auricles ;  a  conclusion  which 
is  borne  out  by  many  other  pieces  of  evidence,  such  as  those  obtained  by 


Fig.  51. — Diagram  of  an  auricle  showing  the  arrangement  of  the  muscle  bands;  the  concen- 
tration point  (C.P.);  and  the  outline  of  the  S.A.  node  (S.A.N.).  The  diagram  is  to  scale,  and 
illustrates  by  the  circles  and  connecting  dotted  lines  the  method  of  leading  off  by  paired  contacts 
and  the  subsequent  orientation.  (From  Thomas  Lewis.) 


I  Auricular  appendage 


HR- 


node 


-Auriculoventricular  node 
-Aurlculoventricular  bundle 


Right  &  left  ventricular 
* bundles 

-Musculi  papillares 


Fig.  52. — Diagram  to  show  the  general  ramifications  of  the  conducting  tissue  in  the  heart  of 
the  mammal.  It  will  be  observed  that  there  is  none  of  this  tissue  between  the  sinoauriculo-  and 
auriculoventricular  nodes. 


the  study  of  polysphygmograms  (page  285),  of  electrocardiograms  and 
of  observations  on  the  heart  during  heart-block  (page  270).  Our  problem 
therefore  narrows  itself  down  to  determining  the  exact  point  of  the  right 
auricle  at  which  the  beat  originates. 


THE   PHYSIOLOGY    OF    THE    HEARTBEAT  187 

SITE  OF  ORIGIN  OF  THE  BEAT 

The  working  hypothesis  from  which  we  may  proceed  to  attack  this 
problem  is  that  the  beat  originates  in  the  sinoauricular  node,  and  to 
put  this  to  the  test,  various  methods  have  been  employed:  (1)  Warming 
or  cooling  or  injuring  the  node  and  noting  the  effect  on  the  heartbeat. 
Such  procedures  greatly  affect  the  rate  of  the  heartbeat,  whereas  they 
produce  no  change  when  applied  to  other  parts  of  the  heart.  (2)  De- 
termination of  the  comparative  rhythmic  power  of  strips  cut  out  from 
different  regions  of  the  auricular  walls.  It  is  greatest  in  those  taken 
from  the  region  of  the  node.  (3)  Determination  by  the  use  of  galvan- 
ometric  curves  of  the  relation  of  the  node  to  the  seat  of  origin  of  cardiac 
impulse.  By  all  these  methods  the  results  indicate  clearly  that  the  beat 
originates  in  the  sinoauricular  node,  but  on  account  of  the  great  im- 
portance in  connection  with  the  interpretation  of  electrocardiograms  in 
man,  it  is  particularly  with  the  result  of  the  third  group  of  experiments 
that  we  will  concern  ourselves  here. 

Evidence  Furnished  by  Studying  the  Current  of  Action  Which 
Accompanies  the  Heartbeat 

To  start  with,  it  is  essential  that  we  make  ourselves  familiar  with 
the  principles  of  the  methods  employed.  These  principles  are  briefly  as 
follows:  When  a  wave  of  contraction  passes  along  a  muscle,  it  is  im- 
mediately preceded  by  a  change  in  electrical  potential,  which  can  be 
detected  by  means  of  a  galvanometer  connected  with  the  muscle  through 
so-called  nonpolarizable  electrodes.  The  galvanometer  employed  must 
be  extremely  sensitive,  and  must  not  vibrate  after  the  current  has  ceased 
to  pass.  The  form  generally  in  use  today  is  known  as  the  string  galva- 
nometer of  Einthoven.  It  differs  from  the  galvanometer  ordinarily  em- 
ployed in  physical  laboratories  in  that  the  current  instead  of  passing 
through  a  coil  of  wire  surrounding  a  magnetic  needle,  passes  through  a 
silverized  quartz  thread  suspended  in  the  strong  magnetic  field  which 
exists  between  the  two  opposing  poles  of  a  horseshoe  electromagnet. 
The  string  is  thus  surrounded  on  all  sides  by  innumerable  lines  of  force 
extending  between  the  two  poles  of  the  magnet.  When  a  current,  how- 
ever small,  passes  along  the  string,  it  will  generate  lines  of  force  of  its 
own,  and  these  by  reacting  with  the  stationary  lines  of  force  of  the  field 
will  cause  the  string  to  move.  The  string  is  placed  in  the  pathway  of  a 
strong  beam  of  light,  and  its  shadow,  after  being  magnified  by  lenses, 
is  projected  on  a  moving  photographic  plate  or  paper  arranged  in  a 
suitable  holder.  The  nonpolarizable  electrodes  referred  to  are  employed 
in  place  of  ordinary  electrodes  in  order  to  obviate  the  generation  of  elec- 


188  THE    CIRCULATION    OF    THE    BLOOD 

trie  currents  set  up  by  the  contact  of  metal  with  the  saline  constituents 
of  the  muscle  juices. 

If  we  connect  a  galvanometer  by  means  of  nonpolarizable  electrodes 
with  two  parts  of  a  denervated  muscle  (the  curarized  sartorius  of  the 
frog),  it  will  be  found  that  a  current  is  set  up  whenever  a  wave  of  con- 
traction passes  over  the  muscle  from  one  end  to  the  other.  The  part 
which  first  contracts  becomes  electrically  negative  to  the  rest  of  the  muscle, 
but  as  the  wave  of  contraction  passes  along  it,  the  " negativity"  de- 
creases at  the  end  at  which  the  wave  started  until,  when  the  wave  has 
reached  the  middle  of  the  strip,  neither  end  of  the  muscle  shows  any 
difference  in  potential,  so  that  the  string  comes  back  to  a  position  of 
rest.  However,  as  the  contraction  wave  reaches  the  farther  end  of  the 
muscle,  this  lead  in  turn  becomes  negative,  and  the  string  swings  in  the 


^  Fig.  53. — Diagram  to  illustrate  the  development  and  spread  of  the  wave  of  negativity  in  a 
strip  of  muscle  (curarized  sartorius)  when  stimulated  at  the  end  (P).  The  shaded  portions  show 
the  position  of  the  negativity.  The  portion  of  the  curve  drawn  by  the  deflections  of  the  galvanom- 
eter at  each  stage  are  shown  at  the  right  (a,  b,  c,  and  d).  (After  Lewis.) 

opposite  direction  (Fig.  53).  From  this  comparatively  simple  experiment 
it  can  be  seen  that  a  muscular  contraction  wave  arises  at  the  electrode  which 
is  negative  first,  and  that  the  movement  of  the  string  of  the  galvanometer  is 
most  marked — that  is,  the  deflection  is  greatest — when  the  two  electrodes 
are  applied  at  the  extreme  ends  of  the  muscle.  When  they  are  brought 
closer  together,  the  initial  deflection  becomes  much  less  marked ;  in  other 
words,  the  amplitude  of  the  negative  wave  is  greatest  when  the  time 
interval  between  the  receipt  of  the  excitation  at  the  two  contacts  is 
greatest. 

The  application  of  these  facts  to  the  study  of  the  initiation  of  the  beat 
in  the  auricle  requires  that  we  should  consider  another  proposition: 
namely,  if  a  pair  of  contacts  are  arranged  in  the  center  of  a  circular 
sheet  of  muscle  and  the  edge  of  this  sheet  is  stimulated  at  different 


THE   PHYSIOLOGY    OF    THE    HEARTBEAT  189 

points,  the  amplitude  of  deflection  of  a  galvanometer  connected  with  the 
pair  of  contacts  will  be  most  pronounced  when  these  are  radial  to  the 
points  of  stimulation,  for  under  these  conditions  it  is  evident  that  the 
greatest  possible  difference  will  exist  between  the  intervals  required  for 
the  wave  to  reach  each  contact. 

Bearing  these  principles  in  mind,  we  may  now  proceed  to  examine  the 
evidence  pointing  to  the  origin  of  the  heartbeat  at  the  sinoauricular  node: 
(1)  When  two  electrodes  are  applied  at  different  points  of  the  au- 
ricle, the  amplitude  of  movement  of  the  string  of  the  galvanometer 
produced  by  each  heartbeat  is  greatest  when  the  line  joining  the  elec- 
trodes converges  on  the  sinoauricular  node.  To  make  this  clear  the 
movement  of  the  string  must  be  photographed  in  the  manner  above 
described,  the  resulting  tracing  being  called  an  electrocardiogram.  From 
the  experiments  with  the  circular  sheet  of  muscle  alluded  to  it  is  evident 
that  the  stimulus  to  produce  this  result  must  have  arisen  in  the  neigh- 
borhood of  the  node.  (2)  If  one  electrode  is  placed  on  the  sinoauricular 
node  and  the  other  electrode  is  moved  about  from  place  to  place  on  the 
auricle,  the  deflection  being  noted  at  each  new  position,  the  electrode 
on  the  node  will  always  be  found  to  be  negative  to  the  other  electrode.* 
No  such  consistency  will  be  manifest  if  both  electrodes  are  moved  about 
on  other  parts  of  the  auricle. 

(3)  As  we  shall  see  immediately,  the  current  of  action  of  the  beating 
heart  may  be  recorded  by  connecting  a  galvanometer  with  various  parts 
of  the  body;  for  example  with  the  right  fore  limb  and  the  left  hind 
limb.     On  the  electrocardiogram  thus  obtained  are  several  waves,  one 
of  which,  called  the  P-wave,  can  easily  be  shown  to  correspond  to  the 
contraction  of  the  auricle  (see  Fig.  272).    If  now  we  compare  such  electro- 
cardiograms with  those   obtained  during  contractions    of    the    auricle 
caused  by  applying  electrical  stimulation  to  various  parts  of  it,  it  will  be 
found  that  the  electrocardiogram  of  the   artificial  beat   simulates   the 
normal  curve  only  when  the  stimulated  part  is  in  the  neighborhood  of 
the  sinoauricular  node.    In  other  words,  it  is  only  when  the  stimulus  is 
applied  to  the  sinoauricular  node  that  a  characteristic  P-wave  is  obtained. 
When  the  appendix  or  the  superior  vena  cava  is  stimulated,  the  P-wave  is 
distorted  although  the  other  waves  of  the  electrocardiogram  may  be  normal. 

(4)  By  taking  electrocardiograms  from  various  direct  leads  placed 
on   the   auricle   and   comparing  the   records   with   that   of    a   standard 
limb  lead  taken  simultaneously,  we  shall  find  by  exact  measurement  that 
the  time  of  onset  of  the  excitation  wave  of  the  auricle,  as  measured  in 
relationship  to  the  P-wave  on  the  standard  electrocardiogram,  is  shortest 

*The  connections  between  the  electrodes  and  galvanometer  are  always  arranged  so  that  any 
upward  movement  of  the  shadow  of  the  string  above  the  line  of  equal  potential  at  the  two  electrodes 
indicates  electric  negativity. 


190 


THE    CIRCULATION    OF    THE    BLOOD 


when  one  electrode  is  over  the  upper  end  of  the  sinoauricular  node,  and 
that  in  other  regions  of  the  auricle  it  always  appears  at  a  later  interval. 
Further  details  on  this  subject  will  be  found  in  the  papers  by  Eyster  and 
Meek8  and  in  Lewis  monographs. 

Frequently,  in  taking  electrocardiograms  from  different  parts  of  the  auricle,  it  is 
found  that  certain  of  the  curves  show  small  waves  of  positivity  below  the  line  of  equal 
potential  preceding  the  main  wave  of  negativity.  These  initial  deflections  are  most 
marked  when  both  the  electrodes  are  far  removed  from  the  sinoauricular  node — for  ex- 
ample, when  they  are  placed  on  the  auricular  appendix ;  but  they  are  never  present  when 


Fig.  54. — Simultaneous  electrocardiograms  to  show  the  cause  for  extrinsic  deflections.  The 
upper  curves  are  from  the  appendix  and  the  lower  ones  from  lead  II.  The  chief  or  intrinsic 
deflection  (Tn)  is  seen  to  disappear  in  the  right-hand  appendix  electrocardiogram,  because  the 
base  of  the  appendix  has  been  crushed.  The  extrinsic  deflection  (Ex)  remains,  as  do  the  ven- 
tricular deflections  (V1  F2),  (From  Lewis.) 

one  of  the  electrodes  is  placed  on  the  sinoauricular  node  itself.  In  other  words,  curves 
taken  from  leads  at  a  distance  from  the  sinoauricular  node  are  more  or  less  composite 
in  form,  being  made  up  partly  of  the  main  deflection  due  to  the  arrival  of  the  excitation 
and  partly  of  the  secondary  deflections  dependent  upon  extrinsic  influences  acting  on 
the  electrodes;  that  is,  the  electrode  picks  up  electric  discharges  from  distant  areas  of 
muscle  while  these  are  in  a  condition  of  contraction  (Fig.  54).  From  these  considera- 
tions it  follows  that  the  intervals  between  the  intrinsic  and  extrinsic  deflections 
should  be  longest  in  leads  that  are  farthest  from  the  node,  and  gradually  become 
less  as  one  of  the  contacts  approaches  the  node,  until  over  this  structure  the  ex- 
trinsic deflection  is  no  longer  recorded.  Such  has  been  found  to  be  the  case.  (Lewis.) 


CHAPTER  XXII 
THE  PHYSIOLOGY  OF  THE  HEARTBEAT  (Cont'd) 

THE  ORIGIN  AND  PROPAGATION  OF  THE  BEAT  (Cont'd)— 

FIBRILLATION 

Mode  of  Propagation  in  the  Auricles 

From  the  mass  of  evidence  we  have  little  doubt  that  the  heartbeat 
originates  in  the  sinoauricular  node,  and  the  question  now  presents  itself 
as  to  how  the  beat  is  propagated  over  the  remainder  of  the  auricles  and 
into  the  ventricles.  Regarding  the  propagation  of  the  beat  over  the 
auricles,  two  possibilities  exist:  (1)  it  may  spread  uniformly  over  the 
muscular  tissue  of  the  auricular  wall  until  it  reaches  the  auriculoventric- 
ular  node,  or  (2)  there  may  be  laid  down  between  the  sinoauricular  and 
the  auriculoventricular  node  a  special  strand  of  highly  conducting  tissue. 
It  is  no  argument  against  this  second  possibility  that  we  should  so  far 
have  been  unable  by  histological  methods  to  differentiate  any  such  struc- 
tures. 

There  is  considerable  practical  importance  attached  to  the  solution  of 
these  questions,  particularly  with  regard  to  the  cause  of  certain  types 
of  cardiac  arrhythmia,  such,  for  example,  as  that  known  as  nodal  rhythm. 
Thus,  it  is  evident  that  if  the  beat  is  transmitted  uniformly  over  the 
muscular  tissue  of  the  auricle,  then  the  whole  auricle  will  have  con- 
tracted before  the  beat  has  reached  the  auriculoventricular  bundle,  by 
which  it  is  then  transmitted  to  the  ventricles.  On  the  other  hand,  if  the 
beat  should  travel  between  the  two  nodes  by  special  conducting  tissue, 
then  the  impulse  will  have  arrived  at  the  auriculoventricular  node  be- 
fore the  auricle  has  contracted.  As  a  matter  of  fact,  it  is  not  quite  settled 
yet  as  to  which  of  these  two  views  is  the  correct  one,  although  the  balance 
of  evidence  seems  to  favor  the  former — that  is,  that  the  wave  is  transmitted 
uniformly  over  the  muscular  tissue  of  the  auricle.  (Lewis.) 

The  methods  employed  in  attacking  the  problem  have  been  essentially 
the  same  as  those  described  above.  One  of  them  may  be  called  the  direct, 
the  other  the  indirect.  In  the  former,  a  series  of  pairs  of  contacts  is 
placed  on  the  auricle,  each  pair  being  in  a  radial  direction  to  the  sino- 
auricular node.  The  time  at  which  the  excitatory  process  arrives  at  that 
contact  of  each  pair  which  is  proximal  to  the  sinoauricular  node  is  accu- 

191 


192  THE  CIRCULATION  OF  THE  BLOOD 

rately  determined  from  the  galvanometric  record.  The  exact  distance  be- 
tween the  contact  and  the  sinoauricular  node  is  then  measured  and  from 
the  data  the  average  transmission  time  is  estimated.  From  his  results 
Lewis  concludes  that  the  transmission  rates  are  uniform  from  the  node 
to  all  parts  of  the  auricle,  with  the  exception  of  the  superior  vena  cava, 
in  which  the  rate  is  considerably  lower.  One  thousand  millimeters  per 
second  represents  very  fairly  the  average  rate  at  which  the  excitation 
wave  travels.  On  the  other  hand,  Eyster  and  Meek8  state  that  the  wave 
is  propagated  throughout  the  sinus  node,  and  that  it  spreads  to  the 
contiguous  venae  cavse  and  to  the  auriculoventricular  node  with  con- 
siderable rapidity,  reaching  the  mouth  of  the  superior  vena  cava  in  0.01 
second,  whereas  its  passage  to  the  auricle  itself  takes  0.02  second.  There  is 
therefore  a  delay  in  the  passage  of  the  wave  to  the  auricle,  which  indi- 
cates that  the  excitation  must  spread  to  the  auriculoventricular  node  be- 
fore involving  the  right  atrium.  These  authors  conclude  that  "this  leads 
to  the  inevitable  conclusion  that  the  cardiac  impulse  spreads  to  the  ven- 
tricle and  to  the  right  auricle  by  different  paths,  and  does  not  pass  to 
the  ventricle  through  the  auricle,  as  ordinarily  stated." 

In  the  second,  or  indirect,  method,  the  onset  of  the  negative  wave  from 
different  leads  in  the  auricle  is  compared  against  a  standard.  For  the 
standard  Eyster  and  Meek  have  used  the  record  of  the  mechanical  sys- 
tole of  the  auricle,  but  the  interpretation  of  the  result  is  extremely  dif- 
ficult on  account  of  the  rate  at  which  the  changes  are  occurring.  Lewis, 
on  the  other  hand,  has  used  the  standard  electrocardiogram  for  purposes 
of  comparison. 

Mode  of  Propagation  of  the  Beat  to  the  Ventricles 

After  reaching  the  auriculoventricular  node,  the  beat  is  transmitted  to 
the  ventricles  along  the  auriculoventricular  bundle — a  fact  which  has  been 
most  clearly  demonstrated  by  the  experiments  on  heart -block.  "We  have  al- 
ready seen  (page  174)  that  although  each  chamber  of  the  heart  of  a 
turtle  or  frog  has  a  rhythm  of  its  own,  this  is  much  more  pronounced  at 
the  venous  end  of  the  heart,  and  when  the  transmission  of  the  beat  to  the 
ventricles  from  the  auricles  is  obstructed  or  blocked,  as  by  compression 
or  partial  cutting  at  the  auriculoventricular  junction,  the  ventricles, 
after  coming  to  a  standstill  for  a  time,  subsequently  contract  with  a 
rhythm  which  is  entirely  independent  of  that  of  the  auricles. 

In  the  mammalian  heart  the  same  results  may  be  obtained  by  arrang- 
ing a  clamp  so  that  it  compresses  practically  nothing  but  the  auriculo- 
ventricular bundle  (Erlanger.)  If  the  compression  is  extreme,  the 
rhythm  of  the  ventricles  is  quite  independent  of  that  of  the  auricles,  but 
if  it  is  only  partial,  the  ventricular  systoles  follow  regularly  every  sec- 


THE   PHYSIOLOGY    OF    THE    HEARTBEAT  193 

ond,  third,  or  fourth  auricular  contraction.  If  after  such  a  complete  or 
partial  heart-block  has  been  instituted,  the  clamp  is  removed,  it  will 
usually  be  found  that  the  heart-block  disappears  and  the  auricular  and 
ventricular  contractions  fall  back  into  their  usual  sequence.  The  im- 
portance of  this  discovery,  apart  from  its  physiological  interest,  rests  in 
the  fact  that  it  is  exactly  duplicated  in  clinical  experience.  If  the  pulse 
tracing  of  the  radial  artery  is  compared  with  that  of  the  jugular  vein 
in  certain  types  of  heart  disease,  it  will  be  found  that  the  auricle  is  beat- 
ing two  or  three  times  more  quickly  than  the  ventricles.  In  many  of 
these  cases  it  has  been  found  on  autopsy  that  definite  lesions  often  syphi- 
litic in  nature  involve  the  auriculoventricular  bundle.  In  other  cases, 
however,  such  lesions  have  not  been  discovered.  Sometimes  the  bundle 
is  so  severely  diseased  that  the  block  is  complete,  the  ventricles  con- 
tracting quite  independently  of  the  auricle.  In  such  cases  it  is  assumed 
that  the  beat  originates  in  the  uninjured  part  of  the  bundle  below  the 
seat  of  the  block.  It  should  be  pointed  out  here,  however,  that  all  cases  of 
slow  pulse  in  the  arteries  are  not  necessarily  dependent  upon  heart-block, 
but  may  depend  upon  a  slow  beat  of  the  auricle  itself.  This  is  called 


Sometimes  after  complete  destruction  of  the  auriculoventricular  bun- 
dle the  beat  continues  to  be  transmitted  to  the  ventricle,  and  conversely 
this  transmission  has  sometimes  been  observed  to  be  upset  by  lesions  not 
affecting  the  bundle.  The  explanation  of  both  of  these  exceptional  re- 
sults almost  certainly  is  that  the  right  lateral  connection  described  above 
(page  184)  is  serving  as  the  main  pathway  of  transmission  for  the  beat. 

The  facility  of  conduction  through  the  auriculoventricular  bundle  is 
subject  to  alteration  by  the  impulses  passing  to  it  along  the  vagus  nerve, 
particularly  the  left  vagus.  It  can  also  be  altered  by  certain  drugs, 
especially  digitalis  and  strophanthin.  The  clear  demonstration  that  it  is 
along  this  bundle  that  the  beat  is  transmitted  is  strong  evidence  in  favor 
of  the  myogenic  hypothesis  (page  171)  concerning  the  transmission  of 
the  heartbeat,  but  it  does  not  necessarily  disprove  the  neurogenic  hypoth- 
esis, for  histological  investigation  has  shown  that  the  bundle  is  closely 
surrounded  by  an  intimate  plexus  of  nerve  fibers. 

Spread  of  the  Beat  in  the  Ventricle 

After  the  impulse  has  been  transmitted  by  the  bundle  into  the  ven- 
tricles, it  spreads  along  the  many  branches  into  which,  as  we  have  seen, 
the  two  main  divisions  of  this  bundle  separate.  The  first  part  of  the 
ventricular  musculature  to  contract  is  therefore  located  near  the  ter- 
mination of  these  branches,  at  the  papillary  muscles.  That  these  should 
contract  before  the  rest  of  the  muscle  of  the  ventricles,  has  an  obvious 


194 


THE   CIRCULATION    OP    THE   BLOOD 


significance  in  connection  with  their  function  of  tightening  the  chordae 
tendinese  so  as  to  prevent  any  bulging  of  the  flaps  of  the  auriculoven- 
tricular  valve  into  the  auricles  when,  at  the  beginning  of  the  presphygmic 
period,  the  high  intraventricular  pressure  is  brought  to  bear  on  their 
under  surfaces.  After  starting  at  this  point  in  the  ventricle,  the  con- 
traction wave  seems  to  spread  farther  through  the  ventricular  muscle  at 
a  fairly  uniform  rate. 

Investigation  of  this  problem  by  means  of  the  galvanometer  has  been 
technically  a  very  difficult  matter.  According  to  the  researches  of 
Lewis  and  his  associates,  however,  it  appears  that,  when  a  series  of 
nonpolarizable  electrodes  are  placed  at  various  parts  of  the  outer 


Fig.  55. — Diagram  of  experiment  by  Lewis  showing  the  times  at  which  the  excitation  wave 
appeared  on  the  front  of  the  heart  relative  to  the  upstroke  of  R  in  lead  II.  R.A.,  right  appen- 
dix; D.B.L.,  descending  branch  of  left  coronary  artery.  (From  Thomas  Lewis.) 

aspect  of  the  ventricle,  and  comparison  made  of  the  moments  at  which 
the  cardiac  impulse  arrives,  as  judged  by  the  appearance  of  the  excita- 
tion wave  relative  to  R.  in  a  standard  electrocardiogram,  it  has  been 
found  that  the  time  of  arrival  bears  no  relationship  to  the  anatomical  ar- 
rangement of  the  muscle  bundles  of  the  ventricle.  It  arrives  early  and 
simultaneously  over  an  area  of  the  surface  near  the  anterior  attachment 
of  the  wall  of  the  right  ventricle  to  the  septum.  It  arrives  late  at 
the  base  of  the  right  ventricle  and  in  the  part  near  the  posterior 
intraventricular  groove.  The  actual  rate  of  spread  is  moreover  much 
greater  than  the  transmission  rate  through  ventricular  muscle.  His- 
tological  examination  has  shown  that  the  branches  of  the  right  division 


THE   PHYSIOLOGY    OP    THE    HEARTBEAT  195 

of  the  auriculoventricular  bundle  are  most  closely  connected  with  the 
place  where  the  wave  arrives  earliest.  Somewhat  different  results  are 
obtained  from  the  left  ventricle,  but  again  they  are  dependent  upon  the 
relationship  of  the  part  to  the  Purkinje  fibers  (Fig.  55).  A  further  dis- 
cussion of  the  manner  of  spread  of  the  impulse  in  the  ventricles  will  be 
found  in  the  chapter  devoted  to  interpretation  of  the  electrocardiogram 
(page  270). 

FIBRILLATION  OF  THE  HEART 

Ventricles 

The  even  spread  of  the  wave  of  contraction  over  the  heart  depends  on 
the  uniform  excitability  of  the  muscular  fibers.  If  certain  of  the  muscu- 
lar fibers,  or  bundles  of  fibers,  have  a  greater  or  less  excitability  than 
others,  then,  when  the  stimulus  to  contract  arrives,  it  will  not  produce 
a  uniform  contraction  of  neighboring  bundles,  and  coordinated  action  of 
the  cardiac  musculature  will  give  place  to  a  confused  movement  in  which 
each  part  of  the  heart  is  contracting  independently  of  the  rest.  This 
fibrillation,  or  delirium  cordis,  as  it  is  called,  can  be  produced  by  a  large 
variety  of  experimental  methods,  such,  for  example,  as  by  stimulating 
the  ventricles  with  induced  electric  shocks,  or  by  ligation  of  a  large 
branch  crfrtfre-coronary  artery,  or  by  the  injection  of  lycopodium  spores 
into  the  coronary  circulation,  or  by  mechanical  stimulation  of  the  heart 
in  the  region  of  the  auriculoventricular  bundle. 

Fibrillation  of  the  ventricles  is  undoubtedly  a  common  cause  of  death 
in  man,  for  of  course  the  confused  movements  make  the  ventricles  in- 
capable of  contracting  on  the  contents  of  the  heart.  It  is  a  condition 
which  can  probably  never  be  recovered  from  in  the  higher  animals,  but 
it  is  of  interest  that  the  ease  with  which  it  is  set  up  as  the  result  of  the 
application  of  an  electric  stimulus  varies  to  a  marked  degree  in  differ- 
ent animals,  and  that  in  those  hearts  in  which  fibrillation  can  be  elic- 
ited only  with  difficulty,  recovery  can  usually  be  effected  either  by  stop- 
ping the  heart  by  means  of  cold  and  then  allowing  it  to  beat  again,  or 
by  the  administration  of  epinephrine.  Of  the  hearts  investigated  in 
this  way,  that  of  the  rat  has  been  found  to  be  most  resistant  to  stimula- 
tion; then  in  order  come  those  of  the  rabbit,  the  cat,  the  dog,  and  the 
horse.  There  is  good  reason  to  believe  that  the  heart  of  man  is  readily 
affected.  Fibrillation  of  the  ventricle  is  undoubtedly  the  main  cause  of 
death  in  most  cases  of  electrocution.  Curiously  enough,  however,  it  has 
been  stated  that,  whereas,  a  current  of  ordinary  intensity  (2300  volts 
alternating  current)  produces  ventricular  fibrillation  in  the  heart  of  cer- 
tain of  the  lower  animals,  at  least  in  that  of  the  horse,  a  very  much 
stronger  current  does  not  do  so,  and  may  indeed  cause  ventricular  fibril- 


196  THE    CIRCULATION   OF    THE   BLOOD 

lation  produced  by  a  more  moderate  voltage  to  disappear.  Unfortu- 
nately, however,  these  stronger  currents  produce  irreparable  damage  in 
the  central  nervous  system,  so  that  the  method  of  applying  stronger  cur- 
rents, even  were  it  feasible  to  do  so  quickly  enough,  would  be  of  no 
therapeutic  value  in  removing  fibrillation. 

The  disappointing  results  that  have  followed  the  repeated  attempts 
to  resuscitate  persons  killed  accidentally  by  electric  shocks  is  undoubt- 
edly dependent  upon  the  fact  that  in  the  heart  of  man  it  is  impossible 
to  bring  back  the  normal  beat  after  the  ventricles  have  been  thrown  into 
fibrillation.  Fibrillation  of  the  ventricle  is  also  the  cause  of  the  sudden 
cardiac  failure  occurring  when  blood  clots  or  emboli  cause  a  blockage 
of  the  coronary  circulation  (it  is  sometimes  the  cause  of  angina  pec- 
toris,  for  example).  It  must  also  be  remembered  in  clinical  practice 
that  mechanical  stimulation  of  the  ventricles  may  produce  fibrillation,  so 
that  in  attempted  resuscitation  by  cardiac  massage  care  should  be  taken 
not  to  apply  this  too  vigorously. 

Auricles 

Although  ventricular  fibrillation  is  seldom  recovered  from,  it  has  been 
clearly  shown  in  recent  years  that  fibrillation  of  the  auricles  is  relatively 
common  and  that  it  is  by  no  means  immediately  fatal.  Indeed  it  is  one 
of  the  most  common  of  the  chronic  cardiac  disorders  in  man.  Auricular 
fibrillation  can  be  produced  experimentally  by  the  application  of  a 
strong  electric  stimulus  to  the  auricles.  If,  however,  a  weaker  stimulus 
is  applied,  the  auricles  do  not  go  into  typical  fibrillation,  but  come  to 
beat  at  a  very  rapid  and  regular  rate,  perhaps  three  or  four  hundred  a 
minute.  This  condition  is  called  "auricular  flutter,"  and  is  quite  fre- 
quently observed  in  the  clinic.  The  cause  of  flutter  might  be  either  a 
paroxysm  of  extrasystoles  or  a  so-called  circus  movement.  The  latter 
possibility  was  demonstrated  by  Mines13  in  rings  of  tissue  cut  from  the 
auricle  of  the  ray  fish;  when  a  stimulus  was  applied  at  one  point  a  con- 
traction wave  was  set  up  which  went  round  and  round  the  ring,  so  that 
a  series  of  contractions  were  the  result  of  one  stimulus.  If  such  circus 
movements  were  associated  with  depressed  conduction  of  the  muscular 
fibers  the  excitation  wave  would  be  irregularly  transmitted  and  account 
for  fibrillation.  Garrey59  and  Lewis  both  subscribe  to  these  views. 

The  influence  of  auricular  fibrillation  and  flutter  on  the  beat  of  the  ven- 
tricle is  an  extremely  important  one  in  connection  with  the  irregular- 
ities of  the  heart  observed  in  man,  and  this  influence  in  most  cases  is 
explained  by  considering  (1)  the  narrowness  of  the  path  (in  the  auric- 
uloventricular  bundle)  along  which  the  impulses  have  to  travel,  and  (2) 


THE   PHYSIOLOGY   OF   THE   HEARTBEAT  197 

the  varying  conditions  of  excitability  of  the  ventricular  muscle,  depend- 
ing upon  the  existence  of  the  refractory  phase  (page  178). 

In  auricular  flutter,  when  three  or  four  hundred  impulses  per  minute 
are  passing  along  the  bundle  to  the  ventricle,  the  contraction  produced 
by  the  first  one  will  scarcely  have  started  before  the  second  and  imme- 
diately succeeding  ones  arrive,  so  that  the  ventricle  will  beat  at  a  rate 
that  is  much  less  than  that  of  the  auricle,  and  a  condition  simulating 
heart-block  will  become  established.  The  characteristic  feature  which 
distinguishes  this  from  true  heart-block,  however,  is  the  fact  that  the 
ventricular  rate  is  above  normal,  whereas  in  true  heart-block  the  rate 
is  much  below  normal.  By  means  of  the  electrocardiogram  or  by 
polysphygmographic  tracings,  it  can  also  be  shown  that  the  auricle  is 
beating  with  perfect  regularity  although  very  rapidly. 

In  auricular  fibrillation  the  ventricles  obviously  will  respond  at  a  very 
irregular  rate  to  the  impulses  transmitted  to  them,  and  the  auricular 
contractions,  if  examined  by  the  methods  above  described,  will  show  no 
regular  sequence.  Further  details  of  the  method  of  eliciting  these  signs 
will  be  described  later  (page  285). 


CHAPTER  XXIII 
THE  BLOODFLOW  IN  THE  ARTERIES 

THE  PULSES 

Returning  to  the  physical  laws  that  govern  the  circulation  of  the  blood, 
we  may  now  consider  the  temporary  changes  produced  in  the  bloodflow 
in  the  arteries  by  each  systolic  discharge.  These  changes  go  under  the 
general  term  of  the  pulses,  of  which  three  may  be  distinguished:  (1) 
the  pressure  pulse,  or  the  pulsatile  increase  of  pressure  produced  by 
each  heartbeat  (see  page  129)  ;  (2)  the  velocity  pulse,  or  pulsatile  accel- 
eration of  velocity;  and  (3)  the  palpable  pulse,  or  the  pulsatile  expansion 
of  the  walls  of  the  blood  vessels  produced  by  the  sudden  change  of  blood 
pressure  in  their  interior.  The  general  characteristics  of  the  three 
pulses  are  the  same,  certain  features  being  however  more  pronounced 
in  one  than  in  another. 

General  Characteristics 

Rate  of  Transmission  of  Pulse  Wave. — The  rate  of  transmission  of 
the  pulse  wave  can  be  determined  by  taking  simultaneous  tracings  of 
the  pulses  from  two  far  distant  parts  of  the  arterial  system  along  with 
accurate  time-tracings.  From  records  (cf.  Fig.  95)  taken  from  the  apex  or 
the  carotid  and  radial  arteries  we  can  determine  how  long  it  takes  for 
the  beginning  of  the  pulse  wave  to  travel  to  the  radial  artery  from  the 
point  in  the  aorta  from  which  the  carotid  artery  springs.  We  shall  find 
that  it  takes  about  one-tenth  of  a  second,  which,  considering  the  length 
of  the  artery  involved,  would  work  out  as  a  transmission  velocity  of 
about  seven  meters  per  second  or  about  seventeen  miles  an  hour.  The 
pulse  therefore  travels  along  the  blood  vessels  at  a  much  greater  speed 
than  the  blood  itself  is  moving,  this  being,  as  we  shall  see  immediately, 
about  0.5  meters  per  second  in  the  larger  blood  vessels. 

The  pulse  is  a  wave  of  sudden  increase  in  pressure  and  velocity  pass- 
ing along  a  stream  which  is  flowing  in  the  same  direction  with  a  cer- 
tain more  permanent  pressure  and  velocity.  A  simple  physical  experi- 
ment may  serve  to  make  this  clear:  If  the  first  of  a  row  of  billiard  balls 
be  tapped  with  the  cue,  the  end  balls  will  fly  off  while  the  others  are 
moving  slowly  along  in  the  direction  of  the  stroke.  Each  ball  becomes 
accelerated  by  the  ball  behind  it,  and  imparts  its  influence  to  the  ball 

198 


THE   BLOODFLOW    IN    THE    ARTERIES  199 

in  front.  In  other  words,  a  pulsatile  acceleration  of  velocity  is  produced 
by  a  pulsatile  change  in  pressure  between  each  two  balls.  The  existence 
of  a  pulse  wave  going  in  the  same  direction  but  quicker  than  a  moving 
column  of  fluid  can  also  be  illustrated  by  observing  the  waves  traveling 
down  a  stream  when  a  stone  is  thrown  into  it. 

The  length  of  the  pulse  wave  is  such  that  the  beginning  of  it  has  ar- 
rived at  the  periphery  of  the  arterial  system  before  the  end  has  disap- 
peared from  the  beginning  of  the  aorta.  This  is  important  to  remem- 
ber, for  it  is  a  common  mistake  to  think  of  the  wave  as  being  a  local 
one.  The  determination  of  the  length  of  the  pulse  wave  depends  upon 
the  following  equation:  L  =  VT,  where  L  equals  the  length  of  the  pulse 
wave,  V  its  velocity  of  transmission,  and  T  its  duration  at  a  given  point 
in  the  artery.  Under  ordinary  circumstances  L  would  usually  work  out 
from  3.25  to  4.5  meters. 

The  rate  of  transmission  of  the  pulse  wave  varies  according  to  the 
rigidity  of  the  walls  of  the  arteries.  To  understand  why  this  should  be 
so,  it  will  be  well  for  a  moment  to  consider  the  physical  conditions 
upon  which  the  pulse  wave  depends.  If  we  connect  a  piece  of  rigid 
tube  with  the  nozzle  of  a  large  syringe,  with  each  movement  of  the  pis- 
ton a  wave  of  pressure  will  be  transmitted  to  the  fluid  in  the  tube,  along 
which  it  will  travel  at  such  a  high  velocity  that  it  will  arrive  at  the 
free  end  of  the  tube  almost  instantaneously,  and  incidentally  the  out- 
flow of  fluid  from  the  end  of  the  tube  with  each  compression  of  the 
pump  will  be  exactly  equal  to  that  represented  by  the  movement  of  the 
piston.  If,  on  the  other  hand,  an  elastic  tube  is  employed,  it  will  be 
found  that  the  sudden  increase  of  pressure  produced  by  each  stroke  of 
the  pump  causes  a  distention  of  the  walls,  which  travels  along  the  tube 
as  a  wave  at  a  readily  measurable  velocity,  which  is  slower  the  more 
extensible  the  tube.  Moreover,  the  outflow  of  fluid  from  the  free  end 
of  the  tube  will  continue  for  some  time  after  the  cessation  of  the  move- 
ment of  the  pump.  What  happens  in  the  tube  with  each  discharge  of 
the  fluid  is  that  the  portion  which  is  immediately  adjacent  to  the  pump 
undergoes  distention  and,  being  elastic,  tends  immediately  afterward  to 
recoil  and  thus  exert  a  recoil  pressure  on  the  fluid  contained  in  the  tube. 
As  a  result,  pressure  wTaves  are  set  up  in  the  fluid  in  all  directions.  Those 
that  travel  back  come  to  a  stop  because  of  the  piston,  while  those  that 
travel  distally  act  on  the  fluid  in  front  of  them  so  as  to  accelerate  it 
and  by  temporarily  raising  its  pressure  distend  the  next  segment  of  the 
vessel  wall,  until  the  end  of  the  tube  is  reached.  From  this  considera- 
tion it  is  clear  that  the  more  extensible  and  elastic  the  wall  of  the  tube 
is,  the  longer  will  it  take  for  the  wave  of  pressure  to  travel  from  one 
end  to  the  other. 


200 


THE    CIRCULATION    OF    THE    BLOOD 


Alteration  in  the  rate  of  transmission  of  the  pulse  wave  in  the  ar- 
teries of  man  depends  entirely  upon  an  application  of  these  principles. 
When  the  arteries  become  hardened  in  old  age,  the  rate  of  transmission 
of  the  pulse  wave  is  markedly  increased.  The  pulse  is  also  transmitted 
more  rapidly  in  the  vessels  of  the  lower  extremities  than  in  those  of  the 
upper,  since  in  the  former  the  blood  vessels  are  somewhat  more  rigid. 
Delay  in  the  transmission  of  the  pulse  wave  is  further  observed  as  one 
of  the  signs  of  aneurism  in  a  vessel;  as  is  well  known,  aneurism  of  the 
subclavian  artery  on  one  side  causes  a  delay  of  the  pulse  on  that  side 
that  is  perceptible  to  the  fingers. 

The  Contour  of  the  Pulse  Curves 

For  more  particular  study  of  the  exact  contour  of  the  pulse  wave,  and 
especially  for  determining  the  time  relationships  of  the  secondary  waves, 


Fig.  56. — Diagram  of  Chauveau's  dromograph.  a,  tube  for  introduction  into  the  lumen  of  the 
artery,  and  containing  a  needle  or  vane,  which  passes  through  the  elastic  membrane  in  its  side 
and  moves  by  the  impulse  of  the  blood  current;  c,  graduated  scale  for  measuring  the  extent  of 
the  oscillations  of  the  needle. 

a  large  variety  of  methods  of  varying  degrees  of  accuracy  have  been 
elaborated  for  each  kind  of  pulse. 

Those  devised  for  measuring  the  pressure  pulse  have  already  been  de- 
scribed (see  page  128),  and  for  the  other  pulses  they  are  as  follows: 

Velocity  Pulse. — Much  ingenuity  has  been  displayed  in  the  elabora- 
tion of  methods  for  recording  the  velocity  pulse.  In  one  of  these  the 
artery  is  cut  across  and  the  ends  attached  to  a  tube,  into  the  lumen 
of  which  projects  a  paddle  or  vane  articulated  with  a  light  lever,  which 
passes  through  its  wall  (see  Fig.  56).  The  vane  floats  in  the  blood 
stream,  and  the  outer  end  of  the  lever  to  which  it  is  attached  is  con- 
nected with  some  device  to  record  its  movements,  which  vary  with  the 
velocity  of  bloodflow  (hemodromograph).  Another  method  depends  on 
the  application  of  the  instrument  known  as  Pitot's  tube  used  by  phys- 
icists. This  consists  of  a  horizontal  tube  having  two  side  tubes,  each  of 


THE   BLOODFLOW    IN    THE    ARTERIES 


201 


which  is  connected  at  its  outer  end  with  a  manometer  and  prolonged 
inside  the  horizontal  tube,  where  they  are  bent  at  opposite  right  angles, 
so  that  the  inner  end  of  one  of  them — the  proximal  tube — points  up 


D 


Fig.   57. 


Fig.    58. 


Fig.  57. — Diagram  to  show  principle  of  Pilot's  tubes  for  measuring  velocity  pulse.  In  both 
tubes  the  fluid  will  rise  because  of  lateral  pressure,  but  in  the  proximal  (left-hand)  tube  it  will 
rise  higher  than  in  the  distal,  because  it  will  also  be  affected  by  the  velocity  of  flow. 

Fig.  58. — Diagram  to  illustrate  the  principle  of  Cybulski's  Photo-hematotachometer.  The  fluid 
in  C  stands  higher  than  that  in  D  in  proportion  to  the  velocity  of  flow  of  the  blood  along 


Fig.    59. — Dudgeon's  sphygmograph.      (From  Jackson.) 

stream,  and  records  not  only  the  lateral  pressure  but  also  the  pressure 
produced  by   the   sudden   increase   in  velocity   of  the  flow,   while  the 


202  THE    CIRCULATION   OF   THE   BLOOD 

other — the  distal  tube — being  bent  down  stream,  records  merely  lateral 
pressure.  A  photographic  record  of  the  movement  of  the  fluid  in  the 
two  tubes  gives  the  velocity  pulse  (see  Fig.  57).  For  physiological  pur- 
poses the  form  of  apparatus  used  is  constructed  as  shown  in  Fig.  58. 

Palpable  Pulse. — To  secure  a  record  of  the  palpable  pulse,  the  so- 
called  sphygmograph  is  employed,  although  a  tambour  having  a  button 
in  the  center  which  is  made  to  press  on  the  artery  may  also  be  em- 
ployed. The  commonest  form  of  sphygmograph  is  that  known  as 
Dudgeon's  (Fig.  59).  It  consists  of  a  small  button  connected  with  a 
spring,  the  movements  of  which  are  transmitted  and  magnified  by  means 
of  a  system  of  levers  connected  with  a  writing  point  arranged  so  as 
to  inscribe  its  movements  on  a  moving  surface. 

The  Analysis  of  the  Curve 

The  general  contour  of  the  pulse  waves  taken  by  any  of  the  above 
methods  are  in  general  very  much  the  same.  The  pressure  and  velocity 


Fig.  60. — Pulse  tracing  (sphygmogram)  taken  by  sphygmograph.  a  d,  the  period  of  the  pulse 
curve;  b,  the  primary;  c,  the  dicrotic  wave.  Time  marked  in  fifths  of  a  second.  (From  Prac- 
tical Physiology.) 

pulse  curves  are,  however,  not  usually  taken  for  the  purpose  of  observ- 
ing the  contour  of  the  wave  but  rather  for  measuring  the  difference  in 
pressure  or  velocity  actually  produced  during  each  pulse.  It  is  a  record 
of  the  palpable  pulse  that  is  usually  employed  for  studying  the  contour 
of  the  wave  and  the  presence  of  secondary  waves.  A  record  of  the  pal- 
pable pulse  wave  (Fig.  60)  shows  two  separate  waves  on  the  descending 
limb  of  the  main  wave.  If  a  large  number  of  similar  pulse  curves  are 
taken  from  different  individuals  or  from  the  same  individual  under 
different  conditions,  it  will  be  found  that  of  these  two  waves  the  secQnjj 
one  is  by  far  the  more  constant ;  and  if  the  waves  are  timed  in  relation 
ship  to  the  heart  sounds,  this  second  wave  always  occurs  immediately 
after  the  second  sound,  allowance,  of  course,  being  made  for  the  time 
required  for  the  pulse  to  be  transmitted  from  the  heart  to  the  artery 
from  which  the  pulse  tracing  is  being  taken.  If  the  observation  is 
made  very  carefully,  it  can  indeed  be  shown  that  the  second  sound  cor/ 
responds  exactly  to  the  notch  which  precedes  this  wave.  The  waves  that 


THE   BLOODFLOW   IN   THE   ARTERIES  203 

precede  this  notch  can  not  be  related  to  definite  changes  occurring  in 
the  heart.  Evidently,  then,  the  secondary  pulse  waves  are  not  all  of 
equal  significance,  by  far  the  most  important  being  that  which  occurs 
immediately  after  the  second  sound,  called  the  dicrotic  wave  (c),  the 
notch  in  front  of  it  being  called  the  dicrotic  notch.  Any  secondary 
waves  occurring  before  the  dicrotic  are  called  predicrotic,  or  if  they 
occur  on  the  ascending  limb  of  the  main  pulse  wave,  as  they  sometimes 
do,  they  are  called  anacrotic.  Waves  occurring  after  the  dicrotic  are 
called  postdicrotic. 

The  relative  importance  of  the  dicrotic,  in  comparison  with  the  pre- 
dicrotic  and  postdicrotic  waves,  is  further  evidenced  by  the  fact  that 
it  alone  is  seen  on  a  so-called  hemataugram,  which  is  the  tracing  ob- 
tained by  allowing  a  fine  stream  of  blood,  escaping  from  a  pinhole  made 
in  the  wall  of  an  artery,  to  impinge  upon  a  moving  sheet  of  white  blot- 
ting paper.  That  such  a  tracing  shows  a  dicrotic  but  no  secondary  wave, 
indicates  that  only  the  former  is  present  in  the  blood  stream  itself,  and 
that  the  other  secondary  waves  must  be  produced  by  some  condition 
arising  either  in  the  elastic  tissue  of  the  walls  of  the  blood  vessels,  or 
in  the  elastic  properties  of  the  instruments  used  for  taking  the  pulse 
tracing. 

The  Dicrotic  Wave. — Because  of  its  obviously  greater  significance,  we 
shall  first  of  all  consider  the  exact  flanse  of  the  di^rotic  wave  and  of  the 
notch  preceding  it.  Theoretically,  two  possible  causes  might  explain 
the  wave:  either  it  is  due  to  some  secondary  wave  set  up  at  the  heart, 
or  it  is  dependent  upon  waves  reflected  from  the  periphery  of  the  cir- 
culation back  along  the  blood  stream,  just  as  secondary  waves  are  re- 
flected from  the  walls  of  a  tub  of  water  when  a  stone  is  thrown  in  the 
center.  In  considering  this  second  possibility,  we  are  of  course  making 
the  assumption  that  at  the  ends  of  the  arterial  system  there  is  a  sudden 
resistance  to  the  onward  movement  of  blood.  The  frequent  branching 
which  occurs  when  the  arterioles  open  into  the  capillaries  no  doubt  of- 
fers many  opportunities  for  the  reflection  of  pulse  waves  back  to  the 
heart,  but  these  waves  must  be  reflected  at  such  varying  distances  along 
the  arterial  system  that  there  can  be  little  opportunity  for  them  to  be- 
come added  together  so  as  to  form  a  wave  of  sufficient  magnitude  to 
make  itself  perceptible  in  the  blood  flowing  in  the  larger  arteries.  These 
waves  are  relatively  so  small  and  they  occur  at  such  different  times  that 
the  net  result  of  their  addition,  so  far  as  the  production  of  a  larger 
wave  is  concerned,  must  be  practically  nil.  Notwithstanding  these  con- 
siderations, it  is  possible  that  under  some  conditions,  such  as  in  cases 
of  high  arterial  tension,  certain  of  the  predicrotic  or  postdicrotic  waves 
may  be  due  to  the  above  causes. 


204  THE    CIRCULATION   OF   THE   BLOOD 

That  the  dicrotic  is  not  a  reflected  wave  is  clearly  established  by  the 
fact  that  if  the  distance  between  the  dicrotic  wave  and  the  main  pulse 
wave  is  measured  at  different  points  of  the  arterial  stream,  it  will  al- 
ways be  found  to  be  the  same,  which  obviously  would  not  be  the  case 
were  the  dicrotic  wave  reflected.  If,  for  example,  we  were  to  examine 
the  contour  of  the  wave  produced  by  throwing  a  stone  into  a  tub  of 
water,  we  should  find  that  near  the  edge  the  secondary  wave  was  very 
close  to  the  main  wave,  whereas  near  the  center  the  secondary  wave 
would  occur  much  later. 

Our  problem  therefore  narrows  itself  down  to  an  investigation  of 
the  cause  for  the  dicrotic  wave  at  the  central  end  of  the  circulation.  It 
occurs,  as  we  have  seen,  immediately  after  the  beginning  of  diastole. 
That  it  can  not  be  due  to  anything  taking  place  in  the  ventricle  itself  is 
evidenced  by  the  fact  that  such  a  wave  is  absent  from  an  intracardiac 
pressure  curve  (see  page  151),  although  it  is  present  in  the  very  begin- 
ning of  the  aorta.  Now,  the  only  structures  existing  between  those  two 
points  which  could  be  held  responsible  for  this  wave  are  the  semilunar 
valves — a  conclusion  which  is  sustained  by  the  fact  that,  if  the  aortic 
valves  are  rendered  incompetent  by  hooking  them  back,  or  if  the  pulse 
beat  is  examined  in  patients  suffering  from  an  aortic  insufficiency,  it 
will  be  found  that  the  dicrotic  wave  is  not  nearly  so  evident  as  usual. 

To  understand  how  the  valves  are  responsible  for  the  production  of  the 
wave,  the  mechanical  changes  occurring  at  the  root  of  the  aorta  must 
be  clearly  understood  (see  page  155).  The  stretching  of  the  elastic  walls 
of  the  aorta  which  occurs  with  each  systolic  outrush  of  blood  is  fol- 
lowed by  a  powerful  and  sudden  contraction  of  the  stretched  walls, 
and  the  pressure  thus  brought  to  bear  on  the  column  of  blood  in  the  aorta 
tends  to  impel  it  both  forward  and  backward.  The  forward  movement 
adds  itself  to  the  wave  of  increased  pressure  already  produced  by  the 
ventricular  contraction.  The  backward  component  travels  as  far  as  the 
semilunar  valve,  from  which  it  is  reflected,  and  now  proceeds  peripher- 
ally along  the  blood  stream  during  the  time  at  which  the  original  pres- 
sure pulse  is  declining.  It  therefore  imprints  itself  on  the  pulse  trac- 
ing as  a  separate  wave,  and  does  so  all  the  more  markedly  when  the 
decline  in  the  main  pulse  wave  is  rapid,  as  in  cases  in  which  the  periph- 
eral resistance  is  low,  but  fails  to  be  prominent  when,  on  account  of 
a  high  peripheral  resistance,  the  decline  in  the  main  pulse  wave  is  tardy. 
This  explanation  coincides  exactly  with  the  well-known  clinical  fact 
that  the  dicrotic  wave  is  conspicuous  in  pulses  of  low  tension,  but  ill 
marked  or  absent  in  pulses  of  high  tension. 

One  point  remains  to  be  considered,  and  that  is  the  cause  for  the 
sudden  decline  in  the  main  wave  at  the  cessation  of  the  ventricular  out- 


THE   BLOODFLOW   IN    THE   ARTERIES  205 

put,  for,  it  might  be  said,  why  should  there  be  such  a  sudden  fall  in 
pressure  near  the  heart,  whereas  toward  the  periphery,  as  we  have  seen, 
the  pressure  between  the  heartbeats  tends  to  be  maintained  on  account 
of  the  elastic  recoil  of  the  stretched  arterial  walls.  The  explanation 
usually  given  is  that  the  sudden  cessation  of  outflow  ^f-h^^d  from  the 
ventricle  at  the  end  of  the  sphygmic  period  causes  a  negative  pressure 
to  be  produced  in  the  blood  aOhe  beginning  of  the  aorta,  thus  tending 
to  cause  jjjreflux  of  blood  towards  the  he^rt^Jthe  .effect  of  which  is  (1)  to 
,  and  (2)  *.n  prnrf"^  tbA  rpflpptprl  rHp.rot.if>.  wave. 


If,  while  fluid  is  flowing  under  pressure  along  a  tube,  the  flow  is  sud- 
denly arrested  by  turning  a  stopcock,  it  is  possible  by  the  use  of  manom- 
eters to  show  that  a  negative  wave  is  set  up  immediately  beyond  the 
stopcock,  and  that  this  negative  wave  travels  along  the  tube  at  a  rate 
depending  on  the  elasticity  of  its  walls. 

Causes  for  Disappearance  of  the  Pulse  in  the  Veins 

The  disappearance  of  the  pulse  in  the  capillaries  and  its  consequent 
absence  in  the  veins  we  have  already  seen  to  be  owing  to  the  combined 
influence  of  the  elasticity  of  the  vessel  walls  and  the  peripheral  resist- 
ance. On  account  of  these  tAVO  factors  the  pressure  conveyed  to  the 
blood  during  systole  is  stored  up  to  be  released  during  diastole  by  the 
recoil  of  the  stretched  vessels.  Sometimes,  however,  the  pulse  gets 
through  to  the  veins,  either  because  the  elasticity  of  the  vessels  is  not  so 
marked,  or  because  the  peripheral  resistance  has  been  lowered  (vaso- 
dilatation).  In  patients  with  hardened  arteries,  or  in  normal  individu- 
als after  taking  nitrite,  which  dilates  the  peripheral  arterioles,  a  pulse 
may  come  through  at  the  periphery  and  appear  in  the  veins.  This  may 
be  called  the  peripheral  venous  pulse,  and  it  is  to  be  carefully  distin- 
guished from  the  central  venous  pulse  observed  in  the  large  veins,  as 
at  the  root  of  the  neck,  before  any  valves  have  intervened  to  block  the 
transmission  of  the  auricular  pressure  wave  back  into  the  column  of 
blood  in  the  veins.  If  a  pulse  is  seen  in  a  large  vein  and  there  is 
doubt  as  to  whether  it  is  peripheral  or  central  in  origin,  this  doubt  can 
be  immediately  removed  by  locally  constricting  the  vein;  if  the  pulse 
is  peripheral,  it  will  disappear  on  the  heart  side  of  the  constriction;  if 
it  is  central,  on  the  side  away  from  the  heart. 


CHAPTER  XXIV 

THE  KATE  OF  MOVEMENT  OF  THE  BLOOD  IN  THE 
BLOOD  VESSELS 

Since  the  object  of  the  circulation  is  to  maintain  an  adequate  move- 
ment of  blood  in  the  tissues  and  capillaries,  it  is  evident  that  besides 
measuring  the  pressure  of  bloodflow,  we  should  also  measure  the  rate 
of  its  movement,  or,  as  it  is  often  called,  the  mean  velocity.  This  measure- 
ment may  be  undertaken  either  for  a  given  vessel  or  for  a  complete 
vascular  area,  such,  for  example,  as  that  of  one  of  the  viscera  or  one 
of.  the  extremities — the  mass  movement  of  the  blood.  Or  instead  of 
measuring  the  mean  velocity  we  may  desire  to  know  how  long  it  takes 
for  a  particle  of  blood  to  traverse  a  given  vascular  area.  Such  a  meas- 
urement is  called  the  circulation  time;  it  does  not  at  all  tell  us  how  long 
it  takes  for  all  the  blood  to  pass  through  the  given  area,  but  only,  as 
stated,  the  time  required  for  the  circulation  of  a  fraction  of  the  blood 
through  a  particular  field. 

VELOCITY  OF  FLOW  IN  A  VESSEL 

Special  methods  have  been  devised  for  the  measurement  of  each  of 
these  three  velocities.  For  the  measurement  of  the  velocity  of  flow 
through  a  main  artery  or  vein,  methods  similar  to  those  employed  by 
hydraulic  engineers  are  employed;  that  is  to  say,  the  volume  of  blood, 
in  cubic  centimeters, .  which  passes  a  given  point  is  measured  for  < 
given  time,  and  the  result  divided  by  the  cross  section  of  the  vessel  at 
the  point  of  observation.  The  result  gives  us  the  mean  lineal  velocity. 
To  measure  the  outflow  of  blood  in  a  given  time,  the  simplest  method 
would  be  to  cut  across  the  vessel  and  collect  the  blood  in  a  graduate, 
but  obviously  in  this  method  an  error  would  be  introduced,  because 
cutting  the  vessel  would  lower  the  peripheral  resistance  and  remove  the 
natural  obstruction  to  the  flow  present  in  the  intact  animal.  Moreover, 
the  hemorrhage  would  in  itself  introduce  a  disturbing  factor  on  account 
of  the  loss  of  circulating  fluid. 

To  make  such  measurements  of  any  value,  it  is  obviously  necessary  to 
retain  the  peripheral  resistance.  For  smaller  vessels  this  can  be  done 
by  introducing  in  the  course  of  the  artery  a  long  glass  tube  bent  in  the 

206 


RATE   OF    MOVEMENT   OF   THE   BLOOD 


207 


shape  of  the  letter  U  (Fig.  61 — No.  1),  or  by  merely  allowing  the  vessel  to 
bleed  into  a  graduated  tube  and  seeing  how  long  the  blood  column  takes 
to  travel  from  one  end  to  the  other.  This  method  is  of  considerable 
value  in  measuring  the  velocity  of  flow  from  small  vessels  such  as  the 
veins  coming  from  glands  and  muscles.  For  larger  vessels  a  so-called 
stromuhr  is  employed.  There  are  numerous  forms  of  stromuhr;  that 
shown  in  the  diagram  (Ludwig's)  (Fig.  61 — No.  2)  consists  of  two  glass 
bulbs  united  above,  and  connected  below  with  tubes  that  open  flush  with 
the  surface  of  a  circular  platform  of  brass.  This  is  pivoted  at  its  center 
with  another  similar  platform  also  having  flush  with  the  surface  the  open- 
ings of  two  tubes  which  are  connected  below  with  the  cut  ends  of  the 
artery  or  vein.  In  a  certain  position  of  the  upper  platform,  the  tubes' 
from  the  artery  or  vein  are  exactly  opposite  those  of  the  bulbs,  so  that  the 


Fig.   61. — Forms  of  apparatus  for  measurement  of  blood  velocities. 

/.  Volkman-n's  hemodromometer.  The  blood  vessel  is  attached  to  the  two  short  side  tubes, 
and  according  to  the  position  of  the  stopcock,  the  blood  flows  either  directly  between  them  or 
through  the  U-shaped  glass  tube. 

2.  Ludwig's  stromuhr.  The  tubes  on  the  lower  end  of  each  of  the  two  glass  bulbs  pierce 
a  circular  brass  platform  and  end  flush  with  its  surface.  This  platform  pivots  at  its  center  on 
a  similar  lower  platform  with  two  openings  connected  with  the  tubes  that  lead  to  the  blood 
vessel. 

blood  can  flow  through  the  bulbs  from  the  one  end  of  the  blood  vessel  to 
the  other.  To  use  the  instrument  the  proximal  bulb  is  filled  with  oil  and 
the  peripheral  one  with  physiological  saline.  The  clip  is  then  removed 
from  the  artery  or  vein  and  the  blood  flows  in  and  displaces  the  oil,  which 
in  turn  displaces  the  saline  into  the  peripheral  end  of  the  blood  vessel. 
When  the  blood  has  risen  to  a  mark  on  the  tube  joining  the  two  bulbs,  the 
instrument  is  rapidly  rotated  so  that  the  oil  is  brought  back  again  into  the 
proximal  position,  the  rotation  being  effected  so  quickly  that  there  is  no 
distinct  interruption  in  bloodflow.  The  operation  is  repeated  in  this  way 
for  a  given  period  of  time.  Counting  accurately  the  number  of  revolu- 
tions, then  multiplying  the  number  of  revolutions  by  the  capacity  of  the 


208  THE   CIRCULATION    OF   THE   BLOOD 

bulbs,  we  get  in  cubic  centimeters  the  amount  of  blood  that  has  flowed 
through  the  instrument  in  a  definite  unit  of  time.  This  gives  us  the  vol- 
ume flow  and,  if  the  result  is  divided  by  the  cross  section  of  the  vessel  in 
square  centimeters,  we  obtain  what  is  known  as  the  mean  lineal  velocity. 
Many  modifications  have  been  made  of  this  instrument,  but  it  is  unneces- 
sary to  go  into  them  here. 

The  general  result  of  such  measurements  has  been  to  show  that  the 
lineal  velocity  is  inversely  proportional  to  the  cross  section  of  the  vessel 
at  the  point  of  observation.  It  is  obvious  that  the  volume  of  blood 
flowing  out  of  the  heart  to  the  aorta  in  a  given  time  is  exactly  equal 
to  that  flowing  into  it  by  the  vena  cava,  and  likewise  that  the  volume 
flowing  into  an  organ  is  exactly  equal  to  that  which  flows  out.  Conse- 
quently the  lineal  velocity  will  be  inversely  proportional  to  the  sec- 
tional area  of  the  vessel.  The  principle  is  the  same  as  that  which  gov- 
erns the  velocity  of  flow  of  a  stream:  when  the  bed  is  narrow,  the  cur- 
rent is  swift,  but  it  becomes  sluggish  when  the  bed  is  wide.  If  the 
arteries  were  of  the  same  caliber  as  the  veins,  the  mean  velocity  of  the 
bloodflow  through  the  two  would  be  the  same,  but  actually  it  is  much 
greater  in  the  arteries  because  the  lumen  of  these  at  a  given  point  in  the 
circulation  is  only  from  one-third  to  one-half  that  of  the  corresponding 
vein. 

It  must  be  understood  that  we  are  dealing  above  with  the  mean 
velocity  in  a  unit  of  time,  and  that  there  must  be  considerable  alteration 
with  each  systole  and  diastole,  constituting  the  velocity  pulse  (page  200). 
The  degree  of  this  alteration  with  each  velocity  pulse  is  much  less  at 
the  periphery  of  the  circulation  than  near  the  heart.  As  the  periphery 
is  reached,  the  flow  becomes  more  uniform.  It  must  further  be  re- 
membered that,  although  the  mean  velocity  depends  essentially  upon 
the  area  of  the  vascular  bed,  yet  it  is  subject  to  considerable  variations 
as  a  result  of  changes  either  in  the  force  or  rate  of  the  heartbeat  or 
in  the  facility  of  outflow  from  the  ends  of  the  arterial  system — that  is, 
changes  in  peripheral  resistance. 

It  is  usually  stated  that  the  mean  lineal  velocity  in  the  carotid  artery 
is  about  300  millimeters  per  second;  and  in  the  jugular  vein,  about  150 
millimeters;  whereas  in  the  capillaries,  where  the  total  area  of  the 
vascular  bed  has  become  enormously  increased,  being  perhaps  some  800 
times  that  of  the  aorta,  the  velocity  of  flow  is  only  about  half  a  milli- 
meter per  second. 

MASS  MOVEMENT  OF  THE  BLOOD  IN  A  VASCULAR  AREA 

Methods. — In  considering  the  Hood/low  or  mass  movement  of  the  blood 
in  the  different  regions  of  the  body,  it  is  usually  more  practical  to 


BATE   OF    MOVEMENT   OF    THE   BLOOD  209 

measure,  not  the  mean  lineal  velocity  of  the  inflowing  and  outflowing 
blood,  but  rather  how  many  cubic  centimeters  of  blood  are  traversing 
the  part  per  100  grams  of  organ  or  tissue  per  unit  of  time.  Such  meas- 
urements may  be  made  in  a  variety  of  ways.  If  there  are  but  one  artery 
and  one  vein  to  the  part,  the  stromuhr  may  of  course  be  employed,  and 
it  may  be  inserted  in  either  the  arterial  or  the  venous  circuit.  For 
measuring  the  mass  movement  of  blood  through  such  large  viscera  as 
the  liver,  this  is  indeed  the  only  method  that  can  be  employed.  The 
stromuhr  is  inserted  either  in  the  course  of  the  portal  vein  and  he- 
patic arteries,  or,  better  still,  in  the  vena  cava  just  below  the  openings 
of  the  hepatic  vein,  the  vena  cava  being  shut  off  for  a  moment  between 
the  liver  and  the  heart,  and  the  blood,  as  it  flows  from  the  hepatic  vein, 
allowed  to  collect  in  the  stromuhr.  For  other  organs  and  tissues,  how- 
ever, methods  which  do  not  involve  any  interference  with  the  blood 
vessels  may  be  employed.  One  of  these  is  the  so-called  plethysmo  graphic 
method  of  Brodie.  An  organ,  such  as  the  kidney,  is  enclosed  in  a  plethys- 
mograph  (see  page  235),  and  while  a  record  of  its  volume  is  being 
inscribed  on  a  quickly  revolving  drum,  the  vein  is  suddenly  clamped, 
with  the  result  that  the  kidney  volume  expands  in  proportion  to  the 
mass  of  blood  flowing  into  it.  When  the  expansion  has  reached  a  cer- 
tain degree,  the  clamp  is  removed  and  the  bloodflow  allowed  to  pur- 
sue its  course.  It  is  then  an  easy  matter,  by  graduating  the  plethys- 
mograph, to  determine  how  many  cubic  centimeters  of  blood  must  have 
flowed  into  the  organ  in  a  given  time.  To  avoid  serious  local  asphyxia 
in  the  tissue,  the  clamp  must  be  applied  to  the  vein  for  only  the  briefest 
period  of  time.  This  method  may  also  be  employed  for  measuring  the 
bloodflow  through  the  extremities.  Thus,  if  the  arm  is  enclosed  in  the 
plethysmograph  (Fig.  62)  and  a  band  encircling  the  arm  above  the 
plethysmograph  is  tightened  so  as  to  constrict  the  veins  but  not  the  ar- 
teries, the  rate  at  which  the  volume  of  the  arm  within  the  plethysmograph 
expands  will  correspond  to  the  rate  at  which  blood  is  flowing  into  it 
(Hewlett). 

For  the  purpose  of  measuring  blood  flow  through  the  upper  or  lower 
extremities,  a  much  more  serviceable  clinical  method  is  that  of  G.  N. 
Stewart.  This  depends  on  the  principle  that,  provided  the  blood  passing 
from  the  thorax  to  the  hands  or  feet  is  of  constant  temperature,  the 
rate  at  which  heat  is  dissipated  from  the  hands  or  feet  will  be  directly 
proportional  to  the  rate  of  movement  of  the  blood  through  these  parts. 
Fortunately  for  the  method,  the  hands  particularly,  but  also  the  feet, 
are  more  or  less  perfect  radiators — at  least  they  are  to  this  extent,  that 
if  the  temperature  in  their  environment  is  not  much  lower  than  the 
temperature  of  the  blood,  then  while  this  is  traversing  the  part,  it  will 


210 


THE    CIRCULATION    OF    THE    BLOOD 


lose  heat  to  the  environment  until  the  outflowing,  or  venous  blood,  is  at 
exactly  the  same  temperature  as  the  environment;  for  example,  if  the 
hand  is  placed  in  water  that  is  a  little  cooler  than  that  of  the  blood, 
and  the  temperature  of  the  blood  in  one  of  the  large  veins  of  the  hand 
is  measured,  it  will  be  found  to  be  the  same  as  that  of  the  water  in  the 
water-bath. 

To  measure  the  rate  of  flow,  therefore,  we  must  ascertain:  (1)  how 
much  heat  has  been  given  out  by  the  part  to  the  water  surrounding  it 
in  a  given  time,  and  (2)  the  difference  in  temperature  of  the  inflowing 
(arterial)  and  outflowing  (venous)  blood.  We  measure  the  amount  of 


Fig.  62. — Plethysmograph  for  recording  volume  changes  in  the  hand  and  forearm.  By  observ- 
ing the  rate  with  which  the  volume  increases  when  the  arm  is  compressed,  the  mass  movement  of 
the  blood  can  be  determined.  (From  Jackson.) 

heat  given  out  to  the  water  in  calories,  a  calorie  being  the  amount  of 
heat  required  to  raise  the  temperature  of  1  c.c.  of  water  from  0°  C. 
to  1°  C..  Suppose,  for  example,  a  hand  were  placed  in  3,000  c.c.  of 
water  at  33°  C.,  and  that  after  ten  minutes  the  temperature  had  risen 
to  33.5°  C.,  then  the  amount  of  calories  given  out  would  be  3,000x0.5= 
1500.  Since  calories  equal  cubic  centimeters  multiplied  by  change  in 
temperature,  it  follows  that  if  we  divide  the  figure  representing  them  by 
the  actually  observed  difference  in  temperature  between  inflowing  and 
outflowing  blood,  the  result  must  equal  the  number  of  cubic  centimeters 
of  blood  that  has  flowed  through  the  part.  The  temperature  of  the  in- 
flowing blood  has  been  found  to  be  practically  identical  with  that  of  the 


RATE   OF    MOVEMENT   OP    THE    BLOOD  211 

mouth  under  the  tongue;  whereas  of  course  the  temperature  of  the  venous 
blood,  as  already  explained,  is  equal  to  the  mean  temperature  of  the 
water  during  the  time  that  the  hand  was  immersed  in  it.  Further  de- 
tails of  the  technique  of  this  method  will  be  found  eJsewhere,  but  it  may  be 
said  here  that  it  is  extremely  simple  and  accurate,  and  that  it  requires 
nothing  more  than  (1)  an  accurate  thermometer  ranging  between  about 
25°  C.  and  50°  C.,  with  a  scale  so  drawn  out  that  readings  can  be  made 
to  %oo  of  a  degree,  and  (2)  a  well-constructed  vessel  of  about  3,000 
c.c.  capacity,  with  double  walls,  the  space  between  them  being  packed 
with  some  heat-insulating  material  such  as  ground  cork. 

Results. — Regarding  the  results  obtained  with  these  methods,  it  has  been 
found  that  the  blood  supply  for  each  100  grams  of  tissue  per  minute  in  the 
viscera,  as  measured  by  the  stromuhr  method,  is  about  as  follows:  stomach, 
21  c.c. ;  intestine,  71  c.c.;  spleen,  58  c.c.;  liver,  arterial,  25  c.c.;  liver, 
venous,  59  c.c,;  liver,  total,  84  c.c.;  brain,  136  c.c.;  kidney,  150  c.c.;  thy- 
roid gland,  560  c.c.  The  large  blood  supplies  of  the  thyroid  gland  and 
of  the  kidney  are  the  most  striking  results  of  these  observations. 

By  the  use  of  the  calorimeter  method  the  bloodflow  through  the  hands 
and  feet  of  a  healthy  young  man  has  been  found  to  be  about  13  grams 
per  100  c.c.  of  hand  per  minute  for  the  right  hand,  and  about  half  a 
gram  less  for  the  left.  The  footflow  is  only  about  one-third  to  one-half 
that  of  the  hand  per  100  c.c.  of  tissue — a  difference  which  is  largely 
owing  to  the  greater  proportion  of  skin  and  the  smaller  proportion  of 
bone  in  the  hand.  The  average  footflow  or  handflow  for  a  given  indi- 
vidual under  ordinary  conditions  is  remarkably  constant  from  time  to  time, 
but  it  is  extraordinarily  sensitive  to  changes  in  the  temperature  of  the 
environment  in  which  the  subject  has  been  living  for  some  time  previous 
to  the  measurement.  In  one  individual,  when  the  room  temperature  was 
20°  C.,  the  flow  in  the  right  hand,  expressed  in  grams  of  blood  per  100 
c.c.  of  hand  or  foot,  was  10.1;  when  it  was  22.8°  C.,  the  flow  was  12.8; 
when  it  was  25°  C.,  12.1;  when  it  was  30°  C.,  18.5.  On  account  of  the 
influence  of  temperature  on  the  flow,  it  is  extremely  important  that  the 
measurements  should  be  made  in  a  small  room  the  temperature  of  which 
is  kept  constant,  or  if  it  must  be  made  in  the  wards,  the  bed  should  be  sur- 
rounded by  curtains.  The  measurements  made  on  the  hands  of  dispensary 
patients  shortly  after  coming  in  from  outside  air  are  very  likely  to  be 
fallacious.  The  importance  of  making  such  bloodflow  measurements  in 
the  clinic  will  be  alluded  to  later. 

Of  course  the  measurements  made  by  the  above  method  in  man  tell  us 
only  the  rate  of  flow  in  the  periphery  of  the  body,  and  furnish  us  with  no  in- 
formation regarding  the  flow  of  blood  through  the  viscera.  It  is,  how- 


212  THE   CIRCULATION   OF   THE   BLOOD 

ever,  a  well-established  fact  that  the  bloodflow  in  the  central  part  of  the 
circulation  is  more  or  less  reciprocal  with  that  at  the  periphery,  an 
increase  in  the  one  place  being  accompanied  by  a  corresponding  de- 
crease in  the  other. 

The  Visceral  Bloodflow  in  Man 

The  visceral  bloodflow  in  man  can  be  measured  indirectly  in  the  case 
of  the  lungs,  either,  (1)  by  finding  the  quantity  of  oxygen  absorbed  by  the 
blood  during  an  interval  of  time  that  is  less  than  that  required  for  the 
blood  to  travel  once  round  the  circulation  (60  seconds)  and  comparing 
this  with  the  oxygen  content  of  samples  of  arterial  and  venous  blood,  or  (2) 
by  causing  a  person  to  breathe  a  known  quantity  of  nitrous-oxide  gas  and 
then  finding  how  much  is  taken  up  by  the  blood  in  the  lungs.  In  the  for- 
mer method  the  difference  in  oxygen  percentage  between  arterial  and 
venous  blood  will  be  less  for  a  given  absorption  of  oxygen  from  the  alveoli 
the  more  rapid  the  circulation  of  blood  through  the  lungs;  in  the  latter 
method,  the  absorption  of  a  given  amount  of  nitrous  oxide  will  be  pro- 
portional to  the  rapidity  of  the  bloodflow.  Obviously  these  estimations 
must  be  made  only  over  periods  of  time,  less  than  that  taken  for  any  of 
the  blood  to  complete  one  circuit  of  the  circulation. 

Since  it  is  likely  that  such  measurements  will  find  some  application  in  the  study 
of  cardiovascular  disease,  it  may  be  well  to  indicate  briefly  how  they  are  carried  out. 
In  the  oxygen  absorption  method,  the  amount  of  this  gas  that  is  absorbed  from  the 
lungs  in  one  minute  is  determined  by  analysis  of  inspired  and  expired  air.  The  ar- 
terial blood  is  considered  as  saturated  with  oxygen,  and  the  percentage  of  this  gas  in 
the  venous  blood  (entering  the  lungs)  is  computed  by  using  the  dissociation  curve. 
Suppose  1,000  e.c.  of  O2  was  absorbed  in  one  minute*  and  that  the  arterial  blood  con- 
tained 10  per  cent  more  O2  than  the  venous,  then,  since  each  100  c.c.  of  blood  carried 
away  10  c.c.  of  gas  it  would  take  10,000  c.c.  to  carry  away  the  1,000  c.c.  of  O  actually 
absorbed;  and  suppose  the  pulse  to  be  80  per  minute  then,  with  each  heart  beat 
10,000 
— £o — =  125  c.c.  of  blood  must  have  flowed  through  the  lungs.  In  the  nitrous  oxide 

method1*1*  the  person  inspires  a  deep  breath  of  a  mixture  of  this  gas  and  oxygen  from  a 
meter,  and  after  holding  the  breath  for  a  few  seconds  (to  allow  the  gas  to  mix  uni- 
formly with  the  alveolar  air)  he  expires  sufficiently  to  bring  the  lungs  to  their  mid 
position  and  again  holds  the  breath  for  about  30  seconds,  after  which  he  finally  expires 
forcibly.  Samples  of  the  expired  air  are  taken  from  the  last  portions  of  the  two  expira- 
tions, and  the  percentage  of  nitrous  oxide  in  them  determined.  From  the  percentages 
of  nitrous  oxide  found  in  the  two  samples,  the  amount  of  the  gas  in  the  air  of  the  lungs 
at  the  beginning  and  at  the  end  of  the  period  can  be  estimated.  Suppose  that  55  c.c. 
N2O  was  found  to  be  absorbed  in  0.327  minutes,  that  the  percentage  of  NoO  is  11.08 
then,  since  the  absorption  coefficient  of  N"2O  in  blood  at  37°C  is  0.405  (i.  e.,  1  c.c.  of 
blood  dissolves  0.405  c.c,  NoO  at  37°C.,  Krogh  and  Lindhard  the  amount  of  blood  re- 


*The  average  consumption  of  an  adult  at  rest  is  only  about  230-250  c.c.  of  Os,  the  above  value 
of   1,000  c.c.  being  however  observed  during  muscular  exercise. 


RATE   OF    MOVEMENT    OP    THE   BLOOD  213 

55 
quired  to  absorb  55  c.c.  is —1.230  c.c.   (1.23L.)   or  in  one  minute 

1.230 

=  3.75  liters. 
0.327 

The  methods  are  admittedly  only  approximate,  but  the  results  are  of 
much  interest,  mainly  because  of  the  indication  they  give  us  as  to  the 
amount  of  blood  pumped  out  by  the  ventricle  with  each  heartbeat,  or 
during  a  given  period  of  time.  The  results  have  been  found  to  vary 
considerably;  thus,  Krogh  and  Lindhard45  give  the  output  of  blood  per 
minute  as  between  2.3  and  8.7  liters,  which  would  correspond,  at  a 
pulse  rate  of  70,  to  an  output  per  heartbreat  of  from  40  to  120  c.c.  An 
immediate  and  very  marked  increase  has  been  found  to  occur  during 
muscular  work.  By  comparing  the  bloodflow  through  the  hand  with 
that  through  the  lungs,  an  estimate  can  be  formed  in  a  given  individual 
as  to  the  relative  magnitude  of  the  peripheral  and  visceral  moieties  of 
blood.  Interesting  results,  which  will  be  referred  to  later,  have  been 
obtained  from  such  measurements. 

The  Work  of  the  Heart 

Meanwhile  it  is  of  interest  to  note  that  we  may  calculate  from  the 
ventricular  output  of  the  blood  the  amount  of  work  that  the  heart  is  doing 
in  maintaining  the  circulation.  Of  course  the  calculation  is  again  only 
approximate,  since  we  have  to  assume  certain  figures.  If  we  assume  that 
in  a  70-kilogram  man  the  quantity  of  blood  is  4,200  c.c.  (see  page  85), 
and  that  it  takes  about  one  minute  for  all  the  blood  to  complete  a  cir- 
culation, then  the  work  performed  by  the  left  ventricle  in  one  minute 
will  be  equal  to  that  done  in  raising  the  above  quantity  of  blood  to  a 
height  corresponding  to  the  mean  pressure  in  the  aorta.  If  we  take  this 
pressure  as  130  millimeters  of  mercury,  which  would  correspond  to  a 
column  of  blood  1,755  meters  high  (13.5x130=1755  mm.  blood,  or  1.755 
meter),  the  work  done  by  the  left  ventricle  would  be  1.755x4.2=7.37 
kilogram-meters  in  one  minute,  or  in  twenty-four  hours  roughly  about 
10600  kilogram-meters.  The  work  done  by  the  right  ventricle  is  probably 
about  one-third  that  of  the  left,  this  being  about  the  ratio  of  the  pres- 
sures in  the  two  chambers.  The  total  work  of  the  two  ventricles  is  there- 
fore about  14000  kilogram-meters.  This  represents  an  enormous  amount 
of  work;  indeed  it  has  been  computed  that  it  is  sufficient  to  raise  a  man 
of  70  kilograms  to  about  twice  the  height  of  the  highest  skyscraper  in 
New  York.  The  work  thus  expended  in  forcing  the  blood  through  the 
capillaries  becomes  converted  by  friction  in  the  small  blood  vessels  into 
heat,  the  heat  equivalent  of  the  above  amount  of  work  being  roughly 
about  350  calories  (see  page  571). 


214  THE    CIRCULATION   OF    THE   BLOOD 

THE  CIRCULATION  TIME 

The  circulation  time,  or  the  time  taken  by  a  drop  of  blood  to  travel 
between  two  points  in  the  circulation,  can  be  determined  in  laboratory 
animals  by  a  variety  of  methods,  all  depending  on  the  principle  of  seeing 
how  long  it  takes  for  a  drop  of  some  substance  injected  into  one  vessel  to 
appear  in  the  blood  of  another.  For  example,  to  determine  the  time 
taken  for  a  drop  of  blood  to  pass  from  the  jugular  vein  into  the  carotid 
artery  in  a  rabbit,  a  solution  of  methylene  blue  in  isotonic  saline  is  in 
jected  into  the  former  vessel  and  the  moment  of  its  appearance  through 
the  walls  of  the  artery  determined  by  a  stop-watch.  If  the  walls  are  too 
thick  to  admit  of  the  employment  of  this  method,  a  strong  solution  of 
sodium  chloride  may  be  substituted  for  the  methylene  blue,  and  the  mo- 
ment of  its  appearance  at  another  point  of  the  circulation  determined  b\ 
observing  the  electrical  conductivity  of  the  vessel.  Since  the  con- 
ductivity of  a  blood  vessel  depends  partly  on  the  concentration  of  elec- 
trolytes in  the  blood  flowing  through  it,  the  moment  at  which  the  salt 
solution  appears  will  be  indicated  by  a  change  in  electrical  resistance 
(G.  N.  Stewart). 

By  such  methods,  it  has  been  found  that  the  time  for  the  pulmonary 
circulation  is  very  short  compared  with  that  of  the  systemic  circulation. 
In  a  rabbit  it  is  usually  a  little  less  than  four  seconds;  in  an  average- 
sized  dog  of  about  12  kilograms,  it  is  about  eight  seconds;  and  in  man 
it  is  computed  to  be  about  fifteen  seconds.  On  the  other  hand,  the  cir- 
culation time  in  such  viscera  as  the  spleen  and  kidney  is  relatively  long, 
and  more  susceptible  than  that  of  the  lungs  to  different  conditions  of 
temperature.  In  a  dog  in  which  the  pulmonary  circulation  time  was 
about  8.5  seconds,  that  of  the  spleen  was  about  11  seconds,  and  of  the 
kidney  about  17.5  seconds.  The  shortest  circulation  time  of  all  is  of 
course  that  in  the  coronary  artery,  but  that  through  the  retina  can  not  fall 
far  behind  it. 

To  determine  the  total  circulation  time,  we  must  know:  (1)  the  average 
amount  of  blood  passing  by  each  part  in  a  given  time,  and  (2)  the  average 
circulation  time  of  each  part.  From  such  computations,  which  however 
are  obviously  subject  to  considerable  error,  it  has  been  reckoned  that  the 
total  circulation  time  in  man  must  lie  somewhere  between  1  and  1.25 
minutes. 

MOVEMENT  OF  BLOOD  IN  VEINS 

Before  leaving  this  part  of  our  subject,  a  few  words  may  be  said  con- 
cerning the  forces  concerned  in  the  movement  of  Wood  in  the  veins  from 


RATE   OF    MOVEMENT   OF    THE   BLOOD  215 

the  capillaries  to  the  heart.  By  the  time  that  the  venules  are  reached, 
owing  to  friction  in  the  capillaries  the  blood  will  have  lost  most  of  the 
force  imparted  to  it  by  the  heart  action.  Nevertheless,  this  remaining 
vis  a  tergo  must  be  considered  as  the  basic  cause  for  the  movement  of 
the  venous  blood  near  the  periphery.  As  the  venules  get  larger,  two 
other  factors  come  into  play:  the  massaging  influence  of  the  muscles, 
and  the  valves  of  the  veins.  By  the  movements  of  the  muscles  the  veins 
which  lie  between  will  be  rhythmically  compressed,  and  this  will  tend  to 
cause  the  blood  to  be  moved  forward  and  backward  in  them,  the  back- 
ward movement  being  however  prevented  by  the  operation  of  the  valves. 
When  the  tonicity  of  the  muscles  is  subnormal,  as  in  conditions  of  ill 
health,  the  absence  of  this  massaging  action  permits  the  blood  to  stag- 
nate in  the  veins,  especially  in  those  of  the  lower  extremities  in  upright 
animals,  with  the  consequence  that  the  veins  become  dilated,  particularly 
just  above  the  valves,  thus  causing  the  condition  known  as  varicose  veins. 

As  the  thorax  is  approached,  two  other  factors  become  operative:  the 
aspirating  influence  of  the  thorax  during  inspiration,  and  the  negative 
intraventricular  pressure  (see  page  152).  There  is  no  doubt  that  the 
former  of  these  is  of  considerable  importance  in  maintaining  the  venous 
return  near  the  heart,  for  although  the  change  of  pressure  induced  by  in- 
spiration amounts  to  only  5  millimeters  of  mercury,  yet  it  acts  so 
slowly  that  it  produces  a  considerable  influence.  The  aspirating  effect 
of  the  ventricle  at  the  beginning  of  diastole  is,  however,  of  no  sig- 
nificance in  attracting  blood  to  the  heart,  for  although,  as  we  have  seen, 
it  may  be  considerable,  yet  it  lasts  for  so  short  a  time  that  it  could  not 
overcome  the  inertia  of  the  column  of  blood  in  the  vena  cava.  Even  if 
the  negative  pressure  did  last  for  a  longer  period,  it  could  not  attract 
more  than  a  small  amount  of  blood,  because  it  would  cause  the  thin 
collapsible  walls  of  the  veins  to  come  together  and  thus  block  the  pas- 
sage towards  the  heart. 


CHAPTER  XXV 

THE  OUTPUT  OF  THE  HEART  IN  RELATION  TO  THE  VENOUS 
INFLOW,  CHANGE  OF  RATE,  ETC. 

The  Output  of  the  Heart  per  Beat 

In  the  heart-lung  preparation  described  on  page  163  it  is  possible  to 
make  comparison  between  the  output  of  the  heart  and  such  conditions 
as  its  rate  of  filling  during  diastole,  the  frequency  of  its  beat  and  the 
resistance  offered  to  its  systolic  discharge.  Starling  and  his  pupils  have 
in  this  way  thrown  much  light  on  the  methods  by  which  the  cardiac  out- 
put is  adjusted  so  as  to  meet  the  ever-varying  demands  of  the  body  for 
blood.  According  to  these  workers  the  fundamental  principle  which 
determines  cardiac  output  may  be  stated  thus:  the  force  with  which  the 
heart  contracts  during  systole  varies  directly  with  its  volume  at  the  end 
of  diastole.  When  the  venous  inflow  is  rapid,  the  heart  becomes  dilated 
and  it  contracts  to  its  full  force;  when  the  inflow  is  slow,  it  is  imper- 
fectly dilated  and  when  contraction  supervenes  the  beat  is  feeble.  This  is 
the  law  of  the  heart,  and  in  the  case  of  the  cold-blooded  heart,  it  is  rigidly 
obeyed  as  is  demonstrated  by  the  fact  that  when  the  perfusion  fluid  flow- 
ing into  the  venous  end  is  suddenly  increased  by  a  certain  amount,  the 
ventricular  output  with  the  next  beat  is  correspondingly  augmented,  and 
the  volume  of  the  heart  remains  unchanged  at  the  end  of  systole,  though 
it  has  of  course  become  greater  during  diastole  because  of  the  increased 
filling. 

In  the  warm-blooded  heart,  at  least  under  the  conditions  of  experi- 
mentation (heart-lung  preparation),  there  is  some  lag  in  the  adaptation 
of  the  strength  of  systole  to  diastolic  filling,  although  the  law  of  the 
heart  is  ultimately  obeyed.  This  is  well  shown  in  the  tracings  in  Fig.  63, 
in  which  C  is  a  tracing  of  the  volume  of  the  isolated  heart  (obtained  by 
using  a  cardiac  plethysmograph),  B.P.  the  arterial  blood  pressure  and 
V.P.,  the  venous  blood  pressure.50 

According  to  these  views  the  factor  that  primarily  determines  the  sys- 
tolic discharge  is  the  extent  to  which  the  cardiac  muscle  fiber  becomes 
stretched  by  the  venous  filling  of  the  heart,  i.e.,  the  initial  length  of  the 
fibers.  If  the  muscle  be  depressed  on  account  of  malnutrition,  or  fatigue, 
or  disease,  its  response  for  an  equal  degree  of  stretching  will  be  lessened 
so  that  to  bring  about  an  equal  discharge  during  systole  the  heart  will 

216 


OUTPUT  OF  HEART  AND  VENOUS  INFLOW 


217 


have  to  become  more  dilated  (i.e.,  more  stretched)  during  diastole  than 
would  a  normal  heart.  If  this  condition  is  maintained,  the  muscle  hyper- 
trophies with  the  result  that  less  diastolic  dilatation  becomes  necessary 
because  of  the  cumulative  effect  of  the  larger  number  of  fibers.  Increase 
in  arterial  pressure  within  certain  limits  does  not  affect  the  amount  of 
the  systolic  discharge  so  long  as  the  inflow  is  kept  constant. 

It  will  be  observed  in  the  preceding  paragraph  that  nothing  is  said 
about  the  tension  of  the  musculature  at  the  beginning  of  systole;  only  its 
length  is  considered  to  be  important.  More  recent  work  by  Straub  and 
Wingers61  shows  however  that  in  this  particular  Starling  has  erred  and 


BP 


VP 


Fig.  63. — It  will  be  observed  that  when  V.P.  is  suddenly  increased,  the  cardiac  volume  im- 
mediately becomes  greater  (indicated  by  a  general  fall  in  the  level  of  C),  and  that,  although  the 
contractions  of  the  ventricle  also  become  more  vigorous,  they  do  not  do  so  with  sufficient  prompti- 
tude to  maintain  the  systolic  volume  constant.  In  other  words  the  output  of  the  heart  does  not  at 
first  keep  pace  with  the  inflow,  so  that  the  mean  volume  of  the  heart  becomes  progressively 
greater,  and  it  is  onjy  after  some  moments  that  the  contractile  power  -increases  sufficiently  so 
that  the  output  equals  the  inflow  and  the  mean  volume  becomes  steady. 


the  latter  investigator  has  pointed  out  that  this  is  probably  due  to  the 
fact  that  a  heart-lung  preparation  is  too  artificial  (e.g.,  the  coronary 
blood  flow  is  certainly  abnormal  and  the  pericardium  is  usually  opened) 
to  represent  the  conditions  actually  obtaining  in  the  intact  animal.  The 
advantage  claimed  for  the  preparation  was  that  the  rate  of  heart  could 


218  THE    CIRCULATION   OF    THE   BLOOD 

be  kept  constant — or  altered  at  will — while  venous  filling,  or  arterial 
pressure,  was  independently  altered.  But  this  is  no  advantage  because 
the  same  conditions  can  be  fulfilled  after  vagotomy  in  otherwise  intact 
animals ;  for  example,  by  clamping  the  aorta  in  order  to  raise  the  arterial 
resistance,  or  by  injection  of  saline  or  clamping  of  the  vena  cava  in  order 
to  vary  the  venous  inflow.  Each  of  these  experimental  procedures  can 
be  maintained  for  several  beats  without  causing  changes  that  spread  suf- 
ficiently to  cause  alteration  in  the  other  factor  and  during  these  few  beats, 
intracardiac  pressure  curves  can  be  taken  by  the  optical  method  and  the 
response  of  the  heart  precisely  analyzed. 

The  important  pressures  to  measure  are  that  just  before  systole  (initi;il  pressure) 
and  that  at  the  height  of  systole  (maximal  pressure).  By  clamping  the  vena  cava,  for 
example,  the  initial  and  maximal  pressures  in  both  ventricles  were  immediately  de- 
creased whereas  by  injecting  saline  into  the  jugular  vein  both  of  these  were  increased. 
By  raising  the  arterial  resistance  (clamping  the  aorta  or  by  causing  reflex  general 
vasoconstriction),  the  initial  pressures  for  a  beat  or  two  were  not  affected  at  all  in 
the  right  ventricle  and  only  moderately  so  in  the  left,  but  the  maximal  pressures 
were  decidedly  increased.  By  measuring  the  volume  changes  along  with  those  of 
pressure  it  was  found  that  there  was  always  an  increase  in  initial  pressure  (in  the 
right  ventricle)  accompanying  an  increase  in  initial  volume — a  result  which  shows 
that  Starling  is  wrong  in  concluding  that  it  is  only  the  initial  length  of  the  fibers 
that  determines  their  contractile  power.  These  relationships,  moreover,  break  down 
entirely  both  when  the  initial  pressure  is  excessively  elevated  (in  which  case  there  is 
a  diminished  pressure  maximum  and  a  lessened  discharge)  and  when  the  myocardium 
is  depressed,  as  by  poisoning  with  chloral.  While  admitting  that  the  initial  length 
of  the  cardiac  muscle  is  a  most  important  factor  in  determining  the  strength  of  the 
succeeding  contraction,  as  it  is  also  in  skeletal  muscle,  Wiggers  concludes  that  changes 
in  volume  cannot  occur  without  accompanying  alteration  in  initial  tension.  He  there- 
fore considers  the  tone  of  the  heart  in  diastole  as  an  important  factor  in  determining 
its  systolic  force. 

The  Effect  of  Alteration  in  Rate  of  Heart  Beat  on  Output  of  Blood 

At  this  stage  it  is  important  to  analyze  the  effect  on  the  output  of  the  heart  per 
minute  (the  minute  volume)  brought  about  ~by  inert  a.^r  in  (lie  rate  of  beat.  When 
the  venous  inflow  is  slow,  the  ventricle  does  not  dilate  to  its  full  capacity  in  diastole 
and  acceleration  of  the  beat  does  not  improve  the  output  in  a  unit  of  time.  The 
same  is  true  when  the  inflow  is  just  sufficient  to  dilate  the  ventricle  to  the  maximal 
extent  at  the  moment  that  systole  supervenes,  for  although  more  blood  is  discharged 
than  in  the  first  case,  acceleration  cannot  improve  the  output.  When,  on  the  other 
hand,  the  inflow  is  sufficiently  rapid  so  that  the  ventricle  is  practically  filled  to  its 
limit  some  time  before  diastole  ends,  the  output  is  increased  by  acceleration.  In 
other  words,  when  there  is  no  so-called  period  of  diastasis  following  active  diastole, 
acceleration  of  the  beat  will  not  increase  the  output  in  a  unit  of  time. 

The  condition  in  which  increased  heart  rate  occurs  with  greatest  certainty  is  mus- 
cular exercise.  The  initial  quickening  is  due  to  impulses  travelling  to  the  cardiac 
centers  in  the  medulla  from  centers  in  the  cerebrum  (see  page  229),  and  it  is  clear 
that  the  acceleration  will  be  of  value  in  increasing  the  cardiac  output  in  proportion 


OUTPUT   OP   HEART   AND   VENOUS   INFLOW  219 

to  the  relation  between  active  and  passive  diastole  prior  to  the  exercise.  The  venous 
inflow  also  increases  because  of  the  muscular  activity,  so  that  the  diastolic  filling  is 
more  complete,  the  initial  tension  higher,  and  the  systolic  discharge  greater.  As  the 
muscular  activity  continues,  the  heart  rate  continues  to  accelerate,  partly  because  of 
increase  in  the  temperature  and  in  CH  of  the  blood  (see  pages  162  and  168)  and 
partly  because  of  increase  in  venous  pressure  (Hooker  ™  and  Bainbridge).  This  in- 
creased pressure,  probably  by  the  tension  produced  on  the  walls  of  the  ventricle  (right) 
during  diastole,  sets  up  afferent  impulses  which  act  on  the  vagus  and  sympathetic 
cardiac  centers. 

Dilatation  and  Tonus 

We  have  seen  that  in  the  healthy  heart  the  extent  of  dilatation  and  tension 
during  diastole  determines  the  discharge  during  systole.  When  the  dilation  is  not 
accompanied  by  a  large  discharge  (i.  e.,  the  volume  does  not  diminish  properly  during 
systole),  "pathological  dilatation"  is  said  to  exist.  The  essential  difference  between 
physiological  and  pathological  dilatation  depends  on  the  presence  or  absence  of  tonus, 
by  which  is  meant  a  sustained  partial  contraction  ' '  by  virtue  of  which  the  muscle 
fibers  resist  stretching  more  than  they  would  by  virtue  of  inherent  elasticity."  In 
other  words,  for  a  given  volume  of  venous  inflow,  a  greater  pressure  will  exist  in  the 
ventricle  when  the  tonus  is  high  than  when  it  is  low.  Being,  therefore,  already  partly 
contracted  at  the  end  of  diastole  the  tonic  heart  will  develop  greater  force  than  the 
atonic,  during  systole;  it  has  less  slack  to  take  up,  as  it  were. 

The  Dynamics  of  the  Circulation  in  Heart  Disease 

When  the  myocardium  is  weakened,  as  after  debilitating  diseases  or  in  poisoning 
by  chloral,  chloroform,  etc.,  the  systolic  force  is  diminished  so  that  all  the  blood  is 
not  discharged  with  each  beat,  and  the  ventricle  consequently  becomes  overdistended 
by  the  inflow  of  the  venous  blood.  Although  the  elongation  of  the  fibers  and  the 
greater  tension  to  which  they  are  subjected  does  not  at  first  succeed  in  calling  forth  a 
sufficiently  greater  systolic  contraction  to  maintain  an  adequate  discharge,  as  would 
be  the  case  in  health,  a  compensation  may  ultimately  set  in  and  the  heart  contract 
more  powerfully  so  that  the  intraventricular  pressure  increases  sufficiently  to  maintain 
the  normal  discharge.  If  this  compensation  does  not  occur  the  pressures  rise  in  the 
pulmonary  circuit  without,  however,  causing  as  a  rule  serious  congestion  of  the  lungs 
because  the  systolic  discharge  of  the  right  heart  is  lessened  to  a  corresponding  degree 
to  the  left.  The  congestion  therefore  usually  occurs  further  back  in  the  venous  sys- 
tem and  in  the  liver.  Both  first  and  second  sounds  are  weak  until  compensation  oc- 
curs. Cardiac  stimulants  such  ;is  strophanthin  and  digitalis  assist  in  the  development 
of  compensation. 

When  the  aortic  pressure  is  decidedly  increased,  the  pressure  maximum  of  the  suc- 
ceeding systoles  is  insufficient  to  expel  all  the  blood  that  has  collected  in  the  ventricle 
during  diastole.  The  resulting  greater  stretching  and  initial  tension  within  the  ven- 
tricle immediately  stimulate  more  powerful  contractions  and  if  the  pressure  be  not  too 
great  the  discharge  returns  to  the  normal  in  a  few  beats.  If  the  pressure  be  excessive 
however,  or  if  it  be  maintained  for  too  long  this  compensation  begins  to  fail,  the  iso- 
metric phase  of  systole  becomes  more  gradual,  the  first  sound  becomes  feebler  (while 
the  second  sound  is  still  intense)  and  the  venous  bloods  dams  back  in  the  left  auricle 
and  pulmonary  veins  in  which  the  pressure  becomes  raised  so  that,  with  the  right 
ventricle  meanwhile  discharging  its  full  load  of  blood,  extreme  congestion  of  the  lungs 
occurs.  Only  later  does  the  right  ventricle  fail  to  maintain  its  output  and  when  this 
occurs  venous  congestion  a  IK!  fall  of  pulmonary  pressure  become  evident. 


220  THE   CIRCULATION   OF   THE   BLOOD 

When  the  aortic  valve  leaks  the  ventricle  becomes  overfilled  with  blood  during  diastole 
so  that  the  initial  tension  is  elevated  and  in  the  subsequent  systole  the  pressure  at- 
tained is  sufficient  to  compensate  for  the  regurgitation  in  the  sense  that  a  normal 
mass  movement  of  the  blood  is  maintained  (page  208).  If  the  tonus  of  the  myo- 
cardium be  depressed  however,  the  initial  pressure  does  not  properly  increase  and 
consequently  the  maximum  pressure  attained  is  inadequate,  i.e.,  decompensation 
occurs.  Decompensation  may  also  be  the  result  of  exhaustion  of  the  reserve  power 
of  the  heart.61  To  understand  what  this  means  we  must  remember  that  the  systolic 
pressure  and  discharge  are  proportional  to  the  initial  pressure  until  this  reaches  a 
certain  limit  beyond  which  with  further  increase  the  discharge,  etc.,  decline.  This 
optimal  initial  pressure  varies  with  the  condition  of  the  myocardium ;  it  is  the  index  of 
the  reserve  power.  When  it  is  low,  decompensation  soon  occurs  so  that  "back  pressure 
effects"  become  evident;  when  it  is  normal,  the  response  of  the  ventricle  is  adequate 
to  compensate  for  the  leak  and  the  circulation  may  be  maintained  for  a  long  time 
without  any  pulmonary  stasis  or  venous  congestion. 

When  the  auriculoventricular  valve  leaks  (mitral  incompetence)  the  back  pressure 
in  the  auricle  occurs  mainly,  not  during  the  presphygmic  period  of  ventricular  systole 
— as  might  be  expected — but  during  the  first  part  of  the  sphygmic  period  (Wiggers 
and  Feil). 

The  Reserve  Power  of  the  Heart 

When  the  heart  is  well  developed,  as  in  a  trained  athlete,  the  increase  in  venous 
inflow  which  occurs  during  exercise  (see  page  219)  will  stimulate  the  ventricle  so 
that  the  output  per  beat  exactly  corresponds  to  the  inflow,  and  the  rate  is  only 
moderately  increased.  But  when  the  musculature  is  feeble,  as  in  a  person  of  sedentary 
habits,  the  dilatation  must  become  considerably  greater  in  order  to  call  out  sufficient 
contractile  power;  the  output  per  beat,  therefore,  only  increases  moderately  and  con- 
siderable quickening  has  to  occur  so  that  the  minute  volume  may  be  adequate  to 
meet  the  increased  demands  of  the  muscles  for  blood.  This  means  that  there  must 
be  a  certain  optimal  initial  pressure  in  the  ventricle  and  that  when  this  is  exceeded 
the  systolic  discharge  becomes  less.  The  exact  pressure  which  is  optimal  will  vary 
with  the  condition  of  the  myocardium,  being;,  low  when  this  is  subnormal.  When  the 
reserve  power  of  the  heart  is  very  low,  even  extreme  dilatation  during  diastole  may 
be  insufficient  to  stimulate  contractions  that  are  powerful  enough  to  empty  the  heart; 
blood  is  therefore  left  over  in  it  at  the  end  of  systole,  and  when  the  venous  blood 
becomes  superadded  during  diastole,  extreme  dilatation  occurs,  the  beat  becomes  very 
rapid  in  the  attempt  to  maintain  an  adequate  output  and  "back  pressure  effects" 
become  evident.  The  maximal  pulse  rate  that  can  ultimately  be  attained  during 
exercise  is  about  160  beats  per  minute. 

The  Testing  of  Cardiac  Efficiency 

The  most  practical  method  for  testing  the  reserve  power  of  the  heart  is  to  observe 
the  pulse  rate  and  the  systolic  blood  pressure  at  frequent  stated  intervals  after  a 
prescribed  amount  of  muscular  work.  Dumb-bell  exercises  are  useful  for  this  purpose. 
The  pulse  rate  should  be  back  to  normal  in  at  least  4  minutes  after  the  exercise.  The 
blood  pressure  behaves  peculiarly;  immediately  after  the  exercise  it  falls  below  its 
height  during  it,  but  soon  rises  again  and  finally  returns  to  normal  within  at  least 
four  minutes.  If  the  pulse  rate  and  blood  pressure  are  not  restored  to  normal  in  four 
minutes  after  moderate  exercise,  the  cardiac  reserve  is  presumed  to  be  low. 


CHAPTER  XXVI 
THE  CONTROL  OF  THE  CIRCULATION 

The  available  blood  in  the  body  is  parceled  out  to  the  various  organs 
and  tissues  according  to  their  relative  activities,  and,  since  these  vary 
from  time  to  time,  the  question  arises  as  to  the  nature  of  the  mechanism 
or  mechanisms  involved  in  bringing  about  this  adjustment.  Two  possible 
methods  of  increasing  the  supply  are:  an  increase  in  the  mass  movement 
of  all  the  blood  in  circulation,  and  a  reciprocal  adjustment  of  the  resistance 
to  the  flow  in  different  vascular  areas  brought  about  by  vasodilatation 
in  one  and  vasoconstriction  in  others.  Both  of  these  methods  might 
operate  together. 

Two  agencies  can  be  thought  of  as  responsible  for  bringing  about 
the  above  changes:  (1)  chemical  substances  or  hormones,  present  in 
the  blood,  and  (2)  the  nervous  system. 

The  influence  of  chemical  substances,  or  hormones  (page  766),  in  the 
control  of  the  circulation  is  undoubtedly  an  important  one,  and  of  those 
known  at  the  present  time  two  groups  may  be  mentioned:  (1)  sub- 
stances which  alter  the  hydrogen-ion  conp.ftnt.rfl.timi  of  the  blood,  and 
(2)  so-called  pressor  and  depressor  substances,  produced  either  by  duct- 
less glands,  such  as  the  adrenal,  or  by  the  activity  of  tissues.  An  in- 
crease in  hydrogen-ion  concentration  of  the  blood  not  only  affects  the 
heartbeat  (see  page  168),  but  causes  a  marked  dilatation  of  the  blood 
vessels,  so  that  both  the  central  and  the  peripheral  changes  will  be  such 
as  to  encourage  an  increased  flow  of  blood  through  the  active  organ 
or  viscus.  Thus,  during  muscular  activity  of  the  leg  muscles  there  will 
be  a  tendency  to  an  increase  in  the  hydrogen-ion  concentration  of  the 
blood  as  a  whole,  resulting  in  a  greater  cardiac  activity  and  a  greater 
outrush  of  blood  through  the  aorta,  and  at  the  same  time  the  vessels  of 
the  acting  muscle  will  have  become  especially  dilated  because  of  the 
production  by  the  active  muscles  either  of  lactic  acid  or  of  carbonic  acid. 
The  active  muscle  also  produces  such  substances  as  imidazole,  which 
have  a  powerful  vasodilating  action.  Such  substances  are  sometimes 
called  depressor. 

Though  the  hormone  control  of  the  circulation  is  undoubtedly  of  great 
importance,  it  is  probably  much  less  so  than  that  exercised  through  the 
nervous  system,  and  here  again  the  control  is  centered  partly  in  the 

221 


222  THE    CIRCULATION    OF    THE   BLOOD 

heart  and  partly  in  the  peripheral  resistance.  The  nerve  control  of  the 
heart  is  effected  through  the  vagus  and  sympathetic  nerves,  and  that 
exercised  on  the  blood  vessels,  through  the  so-called  vasoconstrictor  and 
vasodilator  nerves. 

The  activity  of  the  nerve  centers  from  which  the  cardiac  and  vaso- 
motor  impulses  are  discharged  is  controlled  by  afferent  impulses  com- 
ing from  the  various  regions  of  the  body.  When  a  gland  becomes  more 
active,  we  must  suppose  that  stimulation  of  the  sensory  fibers  has  caused 
afferent  impulses  to  be  transmitted  to  the  cardiac  and  vasomotor  centers, 
upon  which  they  act  in  such  a  way  as  to  produce  increased  heart  ac- 
tion and  a  local  dilatation  of  the  blood  vessels  of  the  active  gland,  with 
perhaps  a  constriction  of  the  blood  vessels  of  the  rest  of  the  body. 

THE  NERVE  CONTROL  OF  THE  HEARTBEAT 

The  Vagus  Control 

With  regard  to  the  control  exercised  through  the  vagus  nerve,  we  have 
already  seen  that  the  cutting  of  the  two  nerves  in  the  neck  causes  the 
heart  to  quicken  and  the  arterial  blood  pressure  to  rise,  whereas  a 
stimulation  of  the  peripheral  end  of  the  nerve  causes  the  heart  to  be- 
come slowed,  if  not  stopped  altogether,  and  the  blood  pressure  to  fall. 

For  the  more  detailed  investigation  of  the  nature  of  the  vagus  control 
of  the  heart,  it  is  necessary  to  observe  the  exposed  heart  itself — an  ex- 
periment which,  for  obvious  reasons,  can  be  most  simply  performed  in 
a  cold-blooded  animal,  such  as  the  frog  or  turtle,  but  which  can  also 
be  performed  in  mammals  provided  artificial  respiration  is  maintained. 
The  general  effect  of  the  vagus  in  both  groups  of  animals  is  the  same, 
although  apparent  differences  may  exist  on  account  of  the  relative  im- 
portance of  the  different  parts  of  the  heart  in  the  origination  and  propa- 
gation of  the  heartbeat. 

The  Cold-Blooded  Heart. — If  the  vagus  nerve  on  the  right  side  in  the 
turtle  (the  left  nerve  is  usually  more  or  less  inactive  in  this  animal)  is 
stimulated  with  a  very  feeble  electric  current,  while  simultaneous  records 
are  being  taken  of  the  contractions  of  the  auricles  and  ventricles  in  the 
manner  shown  in  the  accompanying  tracing  (Fig.  64),  it  will  often  be 
found  that  there  is  a  weakening  of  the  auricular  beats  without  any  change 
in  those  of  the  ventricle.  If  the  strength  of  stimulus  is  somewhat  in- 
creased, the  auricular  beat,  besides  becoming  weaker,  will  also  become 
slower,  but  meanwhile  the  ventricular,  although  also  slower,  may  become 
distinctly  stronger.  At  first  sight  this  result  may  be  a  little  confusing, 
because  it  would  seem  to  indicate  that  the  vagus  nerve  weakens  the  auricu- 


THE    CONTROL   OF   THE    CIRCULATION  223 

lar,  but  strengthens  the  ventricular  beat.  It  is  clear,  however,  that  the 
strengthening  of  the  ventricular  beat  is  merely  due  to  the  fact  that  the 
cavity  has  become  better  filled  with  blood  during  diastole  as  a  result  of 
the  slowing  of  the  auricle.  These  results  indicate,  then,  that  with  weak 
stimulation  the  vagus  exerts  its  direct  influence  only  on  the  auricle.  If 


Fig.  64. — Simultaneous  tracings  from  auricle  and  ventricle  of  turtle's  heart.  Between  the  crosses 
the  vagus  was  stimulated,  with  the  effect  that  the  auricular  beat  diminished  in  force  but  not  in 
frequency,  while  the  ventricular  beats  were  practically  unaffected.  (From  Howell's  Physiology.) 

the  stimulation  is  strong  enough  both  auricles  and  ventricles  cease  to 
beat  altogether,  and  if  the  stimulus  is  maintained,  the  inhibition  may  go 
on  for  a  very  long  time  (Fig.  65). 
Usually,  even  though  the  stimulus  is  maintained  the  heart  begins  to 


Fig.    65. — Effect   of   vagus    stimulation    on    heart    of    turtle.      Note    the    after    effect    of   augmentation. 

beat  again  after  a  time,  at  first  only  occasionally  but  gradually  more 
rapidly.  This  is  known  as  escapement,  and  it  indicates  that  the  energy 
pent  up  in  the  heart  during  the  vagus  inhibition  has  at  last  overcome 
the  inhibiting  influence  of  the  nerve,  which  is  meanwhile  becoming 
fatigued.  All  of  these  results  could  be  quite  satisfactorily  explained  on 
the  assumption  that  the  action  of  the  vagus  is  confined  to  the  sinus, 


224 


THE    CIRCULATION    OF    THE   BLOOD 


which,  it  will  be  remembered,  dominates  the  beat  in  the  rest  of  the 
heart.  There  is  evidence,  however,  that  the  vagus  also  directly  affects 
the  rhythm  of  the  ventricle.  It  may  be  stated  as  a  general  conclusion 
from  these  results  that  the  influence  of  the  vagus  upon  the  heartbeat  is 
chiefly  centered  upon  those  parts  of  the  organ  in  which  the  rhythmic  power 
is  most  highly  developed. 

Besides  affecting  the  rate  and  strength  of  the  heartbeat,  the  vagus  also 
exercises  a  control  on  the  conductivity  of  the  cardiac  muscle.  Thus,  if 
a  partial  block  is  instituted  in  the  turtle  heart  by  applying  a  clamp  be- 
tween the  auricles  and  ventricles,  stimulation  of  the  vagus  enfeebles  the 
auricular  beat  and  may  also  cause  a  complete  heart-block  as  shown  in 
the  tracing  reproduced  in  Fig.  66.  It  is  important  to  point  out  here, 
however,  that  under  certain  conditions  the  vagus  may  appear  to  increase 
rather  than  decrease  the  conductivity  of  the  tissue  in  the  auriculoven- 


Fig.  66. — Tracing  to  show  that  vagus  stimulation  may  diminish  transmission  from  auricles  to 
ventricles.  It  shows  the  effect  of  stimulating  the  left  vagus  on  partial  (2/1)  block  produced  on 
heart  of  turtle  by  application  of  clamp  at  auriculoventricular  junction.  Stimulation  at  4-  depressed 
the  conductivity  and  weakened  the  auricular  contractions  (lower  tracing)  without  slowing  their 
rate.  The  result  was  an  increase  in  the  degree  of  block  with  cessation  of  ventricular  contractions 
(upper  tracing).  Initial  auricular  rate  •=.  35  per  minute.  (From  Carrey.) 

tricular  junction;  for  example,  it  has  been  observed  in  the  turtle  heart 
that  when  a  clamp  is  so  tight  as  to  produce  complete  block — that  is  to 
say,  to  render  the  ventricle  inactive  while  the  auricle  is  still  beating  at 
the  usual  rate — stimulation  of  the  vagus,  besides  causing  the  auricles  to 
become  distinctly  slowed,  may  at  the  same  time  cause  the  ventricles  to 
respond  to  the  auricular  beats.  This  result  is  probably  due  to  the  better 
chances  of  slow  beats  getting  through  the  junction  than  those  which  are  so 
frequent  as  to  crowd  one  another  on  the  narrow  bridge  which  the  con- 
stricted tissue  offers  to  their  passage  (Fig.  67). 

Very  important  work  was  contributed  in  this  field  by  G.  R.  Mines13 
shortly  before  his  lamentable  death.  He  found  that  the  local  applica- 
tion of  atropine  to  the  sinus  eliminates  the  effect  of  stimulation  of  the 
(intracranial)  vagus  on  the  rate  of  the  heartbeat,  while  the  effect  .on  the 


THE   CONTROL   OF   THE    CIRCULATION  225 

auriculoventricular  junction  and  on  the  ventricle  remains.  After  the 
atropinization,  vagus  stimulation  delays  the  transmission  of  beat  from 
auricle  to  ventricle  and  shortens  the  time  of  each  beat  in  the  ventricle. 
It  was  further  found  that  by  the  local  application  of  atropine  various 
parts  of  the  ventricle  can  be  rendered  irresponsive  to  the  influence  of 
the  vagus  and  the  effects  of  this  nerve  on  the  form  of  the  cardiogram 
modified  at  will.  These  results  have  an  important  bearing  in  the  in- 
terpretation of  the  cause  of  the  T-wave  of  the  electro-cardiogram 
which  will  be  referred  to  later.  Mines'  results  show  that  the  proba- 
ble explanation  is  that  the  T-wave  is  due  to  the  greater  duration  of  the 
excitatory  state  at  the  base  than  at  the  apex,  for  by  altering  the  relative 
duration  of  this  state  at  base  and  apex  by  the  above  methods,  he  could 
cause  the  T-wave  to  appear  or  disappear. 

The  direct  excitability  of  the  heart  muscle  to  external  stimuli  is  also 
depressed  during  vagus  stimulation.     This  effect  is,  however,  not  evi- 


Fig.  67. — Tracing  to  show  that  vagus  stimulation  may  facilitate  transmission  from  auricles  to 
ventricles.  It  shows  the  effect  of  right  vagus  stimulation  on  heart-block  produced  in  the  turtle  by 
a  clamp.  Upper  tracing  records  ventricle;  lower  tracing,  auricles.  Weak  faradization  of  the  right 
vagus  nerve  beginning  at  A  affected  the  degree  of  block  only  at  -f  ,  when  a  lengthened  period 
between  auricular  contractions  caused  a  single  ventricular  contraction.  At  B  stronger  faradiza- 
tion of  the  same  nerve  produced  marked  slowing  of  the  auricles,  in  consequence  of  which  the  block 
disappeared  and  the  ventricles  contracted  after  each  auricular  contraction.  Block  reappeared  when 
the  rate  again  became  rapid.  Initial  auricular  rate  =  36  per  minute.  (From  Carrey.) 

dent  in  the  case  of  all  hearts,  but  is  seen  in  those  of  certain  fishes  (e.  g., 
the  eel). 

The  Mammalian  Heart, — The  action  of  the  vagus  on  the  mammalian 
heart  may  be  investigated  either  by  exposing  the  heart  and  connecting 
the  auricles  and  ventricles  with  specially  designed  recording  levers 
(myocardiograph),  or  if  we  desire  to  study  the  influence  on  the  heart  as 
a  whole,  by  taking  a  blood-pressure  tracing  from  one  of  the  large  arteries 
by  means  of  a  spring  manometer.  The  results  are  in  general  similar  to 
those  observed  on  the  frog  or  turtle  heart,  the  main  effects  being  de- 
veloped on  the  auricle.  Considerable  differences  are  found  in  the  effect 
on  the  heart  as  a  whole  in  different  animals,  particularly  with  regard  to 
the  facility  with  which  escapement  occurs.  In  the  dog  when  the  vagus 


226  THE    CIRCULATION   OF    THE   BLOOD 

is  continuously  stimulated,  the  heart  is  likely  to  remain  inhibited  for  a 
long  time,  whereas  in  the  cat  the  inhibition  is  very  quickly  broken  into 
by  escapement.  If  the  tracing  is  taken  directly  from  the  heart,  it  will 
frequently  be  observed  in  the  dog  that,  when  the  escapement  occurs  dur- 
ing vagus  stimulation  it  is  only  the  ventricle  that  is  beating,  the  auricles 
still  remaining  inhibited. 

If  the  stimulation  of  the  vagus  is  discontinued  after  some  time  in  an 
animal  whose  blood  pressure  is  being  recorded,  the  pressure  will  not 
only  quickly  recover,  but  will  usually  overshoot  the  normal  level,  mainly 
because  of  the  asphyxia  which  has  been  produced  during  the  period  of 
inhibition.  The  asphyxia  raises  the  hydrogen-ion  concentration  of  the 
blood  and  this  stimulates  both  the  vasoconstrictor  center  and  the  heart 
action  (page  168).  The  increased  heart  action  is,  also  partly  owing  to  the 
fact  that  during  vagus  inhibition  the  beating  pOAver  of  the  heart  becomes 
improved  (page  230). 

As  an  outcome  of  recent  work,14  it  has  been  show 
nerve  acts  mainly  on  the  sinoauricular  node,  and  the  left  vagus  on  the 
auriculoventricular  bundle.  This  is  in  agreement  with  the  observations 
described  above  on  the  cold-blooded  heart  (page  222).  Stimulation  of  the 
right  vagus  always  causes  slowing  and  weakening  of  both  the  auricular 
and  the  ventricular  beats,  but  stimulation  of  the  left  vagus  is  sometimes 
observed  to  have  but  little  influence  on  the  auricular  beat,  although  it 
may  produce  a  condition  of  partial  heart-block;  or,  if  a  clamp  is  ap- 
plied to  the  auriculoventricular  bundle  so  as  to  produce  a  partial  heart- 
block,  then  during  stimulation  of  the  left  vagus,  the  block  may  become 
complete.  There  is,  however,  a  considerable  overlapping  of  these  in- 
fluences, at  least  in  the  case  of  the  left  vagus,  for  this  nerve  also  acts 
considerably  on  the  ventricle,  influencing  perhaps  not  so  much  the  rate 
as  the  force  of  the  contraction.  It  has  been  found  experimentally  that, 
in  order  to  demonstrate  the  specific  action  of  the  left  vagus  on  the  bun- 
dle, it  is  most  suitable  to  study  the  relationship  between  auricular  and 
ventricular  beats  when  the  auricle  is  beating  rapidly  as  during  the 
application  of  artificial  (electrical)  stimuli  to  it.  Ordinarily  the  con- 
traction produced  by  each  stimulus  passes  into  the  ventricle,  but  during 
stimulation  of  the  left  vagus  it  is  found  that  every  contraction  does  not 
pass.  These  experiments  raise  the  question  as  to  what  the  influence  of 
either  nerve  may  be  in  blocking  impulses  from  the  auricles  to  the  ven- 
tricles when  auricular  fibrillation  is  present.  It  might  be  expected  that 
the  left  vagus  would  prove  more  effectual  in  this  regard,  but  actually  it 
has  been  found  that  both  vagi  have  the  same  effect. 

Tonic  Vagus  Action. — Impulses  are  constantly  passing  along  the  vagi 
to  the  heart.  On  account  of  this  so-called  tonic  action,  the  heart  rate 


THE    CONTROL    OF    THE    CIRCULATION  227 

increases_jyhpri  the  continuity  of  the  vagus  nerve  is  broken  either  by 
cutting  or  by  freezing  a  portion  of  nerve  (Fig.  27).  The  effect  is  usually 
inconspicuous  when  one  nerve  only  is  cut,  but  in  most  mammals  it  be- 
comes quite  marked  when  both  are  cut.  Change  in  the  heart  rate  pro- 
duced by  muscular  effort  is  much  more  gradual  in  animals  with  marked 
vagus  tone,  such  as  hunting  dogs,  than  in  those  with  little  vagus  tone,  as  in 
domestic  rabbits.  The  degree  of  vagus  tone  therefore  bears  a  relation- 
ship to  the  staying  power  of  the  animal  for  prolonged  muscular  effort. 
It  is  usually  ill  developed  in  cold-blooded  animals.  It  is  quite  marked 
in  the  case  of  man,  as  is  evident  on  observing  the  heartbeat  before  and 
after  giving  a  sufficient  dose  of  atropine  to  paralyze  the  termination  of 
the  vagus  in  the  heart. 

The  exact  location  of  the  nerve  cells  that  form  the  center  of  discharg- 
ing impulses  along  the  vagus  fibers  to  the  heart  can  not  be  made  out 
with  certainty,  but  they  are  no  doubt  part  of  the  great  motor  nucleus 
(ambiguus),  from  which  arise  the  fibers  not  only  of  the  vagus  but  of 
the  glossopharyngeal  nerve.  The  tone  of  this  vagus  center  is  almost 
without  doubt  dependent  upon  the  constant  transmission  to  it  along  the 
sensory  or  afferent  fibers  of  impulses  coming  from  various  portions  of 
the  body.  According  to  the  strength  or  number  of  these  impulses,  the 
tone  may  be  increased  or  diminished,  thus  altering  the  rate  of  the  heart. 
It  is  possible  of  course  that  the  tone  can  be  maintained,  independently 
of  the  afferent  impulses,  by  the  action  on  the  center  of  chemical  meta- 
bolic products  or  hormones  produced  in  the  cells  or  carried  to  them  in 
the  blood.  We  know  at  least  that,  like  the  respiratory  center,  that  of 
the  vagus  is  excitable  by  such  hormones  as  the  hydrogen-ion  concen- 
tration of  the  blood.  The  tonicity  of  the  vagus  center  is,  however,  mainly 
dependent  upon  the  passage  to  it  of  afferent  impulses,  and  as  evidence 
for  this  conclusion  may  be  cited  the  observation  that,  after  section  of 
most  of  the  afferent  nerves  to  the  medulla  (as  by  cutting  the  spinal  cord 
high  up  in  the  cervical  region),  subsequent  section  of  the  two  vagi  does 
not  produce  anything  like  the  usual  degree  of  change  in  the  heart  rate. 

The  Afferent  Vagus  Impulses.— The  afferent  vagus  impulses  may  come 
from  practically  any  part  of  the  body,  having  been  first  discovered  by 
the  simple  experiment  of  tapping  the  abdomen  of  the  frog  with  the  han- 
dle of  a  scalpel,  when  slowing  of  the  heart  rate  is  observed.  Cutting  the 
vagi  abolishes  the  reflex.  Similar  cardiac  inhibition  is  produced  by  me- 
chanical stimulation  of  the  tail  or  gills  of  an  eel.  In  mammals  stimula- 
tion^ of  the  central  end  of  any  sensory  nerve  usually  slows  the  heart, 
though  sometimes  the  opposite  effect  occurs.  The  pulmonary  branches 
of  the  vagus  are  particularly  sensitive  in  producing  reflex  inhibition, 
and  distinct  results  are  usually  obtained:  by  stimulation  of  the  termina- 


228  THE   CIRCULATION    OP   THE    BLOOD 

tions  of  the  fifth  nerve  in  the  mucosa  of  the  upper  respiratory  passages, 
as  by  inhaling  ammonia  vapor;  by  stimulation  of  the  sensory  nerve  end- 
ings in  the  pharynx,  as  by  swallowing ;  and  of  the  mucosa  of  the  larynx, 
as  when  a  substance  is  "swallowed  the  wrong  way."  The  sensory 
nerves  of  the  abdominal  viscera  seem  to  be  particularly  active  on  the 
vagus  center,  as  is  seen  in  irritation  of  the  sensory  nerves  of  the  stom- 
ach such  as  occurs  in  gastritis.  Profound  inhibition  may  also  be  caused 
by  violent  stimulation  of  the  mesentery,  as  from  a  blow  on  the  abdo- 
men, or  by  irritation  of  the  sensory  nerves  of  the  intestine,  either  me- 
chanical or  because  of  disease.  Another  interesting  illustration  of  affer- 
ent vagus  stimulation  is  obtained  by  pressure  on  the  outer  canthus  of 
the  eye.  This  oculomotor  vagus  reflex,  as  it  is  called,  is  very  marked 
in  some  individuals. 

Through  which  of  these  afferent  paths  it  may  be  that  the  constant 
stimuli  are  transmitted  to  the  vagus  center  to  enable  it  to  maintain  its 
tone,  can  not  be  said,  although  it  is  very  likely  to  be  through  the  vis- 
ceral nerves. 

In  considering  the  cause  for  an  observed  change  in  heart  rate,  we 
must  of  course  bear  in  mind  the  possibility  that  the  action  may  have 
occurred,  not  through  the  vagus  center,  but  through  the  sympathetic 
center.  Thus,  when  the  heart  becomes  quicker,  it  may  be  owing  either 
to  diminution  in  the  vagus  tone  or  to  an  increase  in  the  discharges 
along  the  sympathetic  nerve  from  the  augmentor  center.  That  such 
reflex  action  through  the  augmentor  center  does  occur  under  experi- 
mental conditions  has  been  clearly  shown;  for  example,  if  both  vagus 
nerves  are  cut  and  the  peripheral  end  of  one  of  them  stimulated  mod- 
erately, so  as  to  hold  the  heart  at  about  its  normal  rate,  the  stimulation 
of  certain  sensory  nerves  may  cause  increase  in  the  heart  rate.  Reflex 
sympathetic  control  of  the  heartbeat  is  however  no  doubt  much  less 
important  than  control  through  the  vagus  center.  When  it  does  exist 
it  means  that  the  actual  rate  of  the  heartbeat  at  any  given  moment 
must  represent  the  algebraic  sum  of  two  opposing  influences,  with  that 
of  the  vagus  preponderating.  The  advantage  of  such  a  double  inner- 
vation  is  that  it  insures  prompter  adjustment  of  the  beat.  If,  for  ex- 
ample, for  any  reason  quickening  of  the  heart  rate  is  necessary,  it  is 
brought  about  most  promptly  if  the  vagus  tone  is  diminished  at  the  same 
moment  that  the  sympathetic  tone  is  increased.  Such  reciprocal  action 
of  antagonistic  influences  is  the  usual  rule  in  the  animal  economy.  Thus, 
when  the  knee  joint  flexes,  it  does  so  not  merely  because  stimulating 
impulses  are  transmitted  to  the  hamstring  muscles,  but  also  because  at 
the  same  moment  inhibiting  impulses  are  transmitted  to  the  extensor 
muscles  (see  page  915). 


Left  Ant  Caval  vein  .Right  Ant  Caval  vein 


Preganqf  ionic  rrettrdn 

^  l  ionic  neuron 


'Auricular  sfeptum 
Position 


vonBezold's  Ganqlion 
in  Auricular  septum 


In f  Vena 


Hook  from 
'Heart  lever 


didders   Gdnqlion 
in  auriculo-ventricular  junction 


Simulating  electrodes 
c  . .     .  ,       .„  in  sino-auricu/ar  junction  [Crescent] 

Sympathetic  fibres-  dotted  lines 

Fig.  68. — Diagram  to  show  the  innervation  of  the  heart  in  the  frog  or  turtle.  The  electrodes 
are  represented  as  applied  to  the  white  creseentic  line  where  they  will  stimulate  some  postganglionic 
libers.  (From  Jackson.) 


THE   CONTROL   OF   THE   CIRCULATION  229 

Several  possibilities  have  to  be  kept  in  mind  when  we  attempt  to 
determine  the  exciting  cause  for  an  observed  change  in  the  heart  rate  in 
man.  Thus,  a  slowing  of  the  rate  may  be  due  to  mechanical  stimulation 
of  the  vagus  trunk,  as  in  pressure  on  the  nerves  by  a  tumor  or  aneurism 
in  the  neck.  That  such  mechanical  irritation  may  stimulate  the  vagus 
is  easily  demonstrated  in  many  individuals  by  applying  pressure  to  the 
vagus  where  it  lies  in  the  neck  in  front  of  the  sixth  cervical  vertebra. 
Such  pressure  sometimes  produces  so  profound  an  inhibition  of  the  heart 
that  temporary  loss  of  consciousness  occurs.  It  is  often  an  unsafe  ex- 
periment to  perform. 

Change  in  the  heart  rate  in  man  may  be  caused  by  direct  stimulation 
of  the  vagus  center,  as  by  the  presence  of  a  tumor  or  a  blood  clot  in  the 
medulla,  or  by  the  action  on  the  center  of  some  unusual  hormone  in  the 
blood.  A  general  increase  in  intracranial  pressure  also  stimulates  the 
vagus  center.  The  slowing  of  the  heart  which  occurs  in  asphyxia  might 
be  due  either  to  the  action  of  hormones  (hydrogen-ion  concentration) 
in  the  blood  as  the  result  of  the  asphyxia,  or  to  the  increased  intra- 
cranial pressure.  That  the  latter  is  the  more  important  cause  is  shown 
by  the  fact  that,  if  the  rise  in  blood  pressure  is  prevented  by  connecting 
an  artery  with  a  mercury  valve, — that  is,  with  a  tube  dipping  into  a 
cylinder  of  mercury  to  a  depth  corresponding  to  the  normal  blood 
pressure,  so  that  when  the  pressure  tends  to  rise  the  blood  escapes, — 
the  slowing  of  the  heart  is  not  observed.  The  excitability  of  the  afferent 
vagus  fibers  in  the  lungs  is  greatly  increased  during  the  earlier  stage 
of  chloroform  administration. 

Finally  it  should  be  pointed  out  that,  although  we  have  no  voluntary 
control  of  the  activity  of  the  vagus  center,  its  activities  are  subject 
to  great  variation  as  a  result  of  impulses  transmitted  from  centers  higher 
up  in  the  cerebrospinal  axis.  It  is  by  the  operation  on  the  vagus  center  of 
such  impulses  that  changes  in  heart  rate  occur  during  emotional  ex- 
citement, fright,  etc.  The  increased  heart  rate  in  muscular  exercise  is 
probably  dependent  upon  a  number  of  causes,  such  as  the  irradiation  of 
the  motor  impulses  on  to  the  cardiac  centers  (see  page  430),  the  rise  in 
temperature  and  changes  in  the  hydrogen-ion  concentration  of  the  blood, 
etc. 

Mechanism  of  Action  of  Vagus  on  the  Heart. — Physiologists  have  nat- 
urally been  curious  as  to  the  exact  manner  in  which  the  vagus  nerve 
brings  about  inhibition  of  heart  action.  Similar  inhibition  as  a  result 
of  stimulation  of  efferent  nerves  exists  in  the  case  of  the  dilator  fibers 
to  the  blood  vessels  (page  239)  and  the  sympathetic  nerve  to  the  intes- 
tine (page  501).  Inhibition  of  voluntary  muscles  can  be  produced  only 
through  the  central  nervous  system  by  stimulation  of  afferent  nerves 


230  THE    CIRCULATION   OF    THE   BLOOD 

(page  915).  It  is  not  the  nerve  fibers  themselves  that  are  responsible 
for  the  inhibitory  effect,  for  it  has  been  found  that  if  the  peripheral 
end  of  a  cut  vagus  nerve  is  connected  with  the  central  end  of  one  of 
the  anterior  roots  of  the  cervical  portion  of  the  spinal  cord,  the  axons 
of  the  latter  when  they  grow  down  into  the  vagus  trunk  during  the 
regeneration  which  follows,  stimulation  of  the  regenerated  fibers  will 
still  produce  inhibition  of  the  heart.  The  nature  of  the  fibers  can  not 
therefore  be  the  factor  upon  which  the  inhibiting  influence  of  the  vagus 
is  dependent.  This  leaves  the  terminal  apparatus  of  the  vagus  fibers  in 
the  heart  as  the  structures  in  which  the  stimulus  conveyed  to  them  is 
rendered  inhibitory  in  nature. 

There  has  been  considerable  speculation  as  to  what  kind  of  change 
must  be  occurring  in  the  heart  in  order  to  cause  the  inhibition,  but 
practically  nothing  that  is  definite  is  known.  One  significant  fact,  how- 
ever, is  that  the  electrical  current  led  off  through  nonpolarizable  elec- 
trodes from  two  portions  of  the  auricle  one  of  which  is  injured,  does  not 
take  the  same  direction  when  the  vagus  nerve  is  stimulated  as  that  which 
it  takes  when  the  motor  nerve  of  a  similarly  observed  muscle  is  stimu- 
lated. A  positive,  instead  of  a  negative  variation  is  observed.  Now, 
since  a  negative  variation  is  always  accompanied  by  active  chemical 
breakdown  changes  occurring  in  the  muscle  to  supply  its  energy  of 
contraction,  it  is  assumed  that  the  positive  variation  accompanying  stim- 
ulation of  the  vagus  must  indicate  that,  instead  of  a  katabolic  process, 
a  building  up,  or  anabolic  process,  is  being  excited.  This  conclusion 
would  fit  in  perfectly  with  the  well-known  fact  that,  after  the  heart  has 
been  held  in  standstill  for  some  time  by  vagus  stimulation,  the  beats  are 
stronger  after  the  inhibition  has  passed  off  than  they  were  before.  The 
vagus  seems  to  have  a  conserving  influence  on  the  heart.  During  the 
inhibition  produced  by  it  energy  material  is  apparently  stored  up  in  the 
heart,  so  that  when  the  beat  is  reestablished  it  is  stronger  than  before. 

The  Manner  of  Termination  of  the  Vagus  Fibers  in  the  Heart. — This 
subject  is  of  considerable  pharmacological  and  therefore  therapeutic  in- 
terest. In  approaching  the  problem  it  must  be  remembered  that  the 
vagus  fibers  belong  to  the  so-called  bulbar  autonomic  system  of  nerves 
(see  page  894).  They  are  therefore  fibers  which  have  cell  stations  situ- 
ated near  their  peripheral  termination — cell  stations,  that  is  to  say,  in 
which  ganglionic  medullated  fibers,  by  forming  synapses  around  nerve 
cells,  become  connected  with  postganglionic  nonmedullated  fibers.  The 
existence  of  ganglia  in  the  heart,  particularly  of  the  frog,  has  been 
known  for  a  long  time.  These  ganglia  are  located  at  the  sinoauricular 
junction,  at  the  interauricular  septum,  and  in  the  ventricle  near  the 


THE   CONTROL   OF   THE    CIRCULATION 


231 


auriculoventricular  junction.    The  function  of  the  ganglia  is  to  serve  as 
cell  stations  on  the  course  of  the  vagus  nerves.     (Fig.  68.)* 

Nicotine  is  a  drug  which  in  certain  concentrations,  if  applied  locally 
to  sympathetic  ganglia,  specifically  paralyzes  the  synapses  between  the 
ends  of  the  preganglionic  fibefs  and  the  cells  from  which  the  prost- 
ganglionic  fibers  arise.  If  this  drug  is  applied  in  a  1  per  cent  solution 
to  the  heart,  stimulation  of  the  vagus  trunk  no  longer  produces  inhibi- 


Fig.  69. — Frog  heart  tracing  showing  the  action  of  nicotine.  The  vagus  trunk  was  stimulated 
as  indicated.  In  the  normal  (lower)  tracing  inhibition  occurs  hut  after  nicotine  (second  tracing) 
no  inhibition  follows.  Stimulation  of  the  crescent  in  the  next  two  lines  still  is  followed  by  inhibi- 
tion. The  final  effects  of  the  drug  are  shown  in  the  last  two  (upper)  tracings.  (From  Jackson.) 

tion,  but  if  the  stimulus  is  applied  to  a  portion  of  the  heart  known  as 
the  white  crescentic  line,  inhibition  still  occurs,  because  at  this  point  the 
postganglionic  nerve  fibers  come  near  to  the  surface  and  therefore  are 
stimulated  (Fig.  69).  On  the  other  hand,  atropine  is  a  drug  which 
paralyzes  the  postganglionic  fibers,  so  that  after  its  application  to  the 
heart  inhibition  cannot  be  produced  by  stimulating  either  the  vagus 

'The    reader    is    referred    to    (lie    chapter   dealing   with    the    autonomic    nervous    system    for   a   de- 
scription  of  the   relationships   of   the   fibers   and   ganglia. 


232  THE    CIRCULATION   OF   THE   BLOOD 

trunk  or  the  white  crescentic  line.  Pilocarpine  and  muscarine  are  drugs 
which  have  an  action  exactly  opposite  or  antagonistic  to  that  of  atro- 
pine;  that  is,  they  stimulate  the  postganglionic  fibers  and  produce  a 
slowing  and  possibly  an  enfeebling  of  the  beat. 

In  the  mammalian  heart  a  large  number  of  the  fibers  in  the  right 
vagus  nerve  proceed  directly  to  the  sinoauricular  node,  where  it  can 
be  shown  histologically  that  considerable  masses  of  nervous  tissue  exist. 
On  the  other  hand,  the  great  majority  of  the  fibers  in  the  left  vagus 
proceed  to  the  auriculoventricular  bundle,  in  which  also  nervous  struc- 
tures are  abundant  (page  183).  As  already  indicated,  the  experimental 
results  which  follow  stimulation  of  either  nerve  can  be  explained  by  the 
influence  which  the  nerve  exerts  on  the  particular  structure  to  which 
the  majority  of  its  fibers  proceed.  In  brief,  stimulation  of  the  right 
vagus  is  likely  to  produce  slowing  and  weakening  of  the  beat,  whereas 
stimulation  of  the  left  vagus  is  more  likely  to  institute  a  condition  of 
partial  heart-block. 

On  account  of  the  different  results  which  may  be  obtained  by  stimu- 
lating the  vagus,  some  authorities  have  assumed  that  the  heart  must 
contain  four  kinds  of  fiber,  more  strictly,  of  vagus  nerve  endings,  one  for 
each  kind  of  influence  which  the  vagus  can  develop.  These  four  influ- 
ences are,  it  will  be  remembered,  on  the  strength,  the  rate  and  the 
propagation  of  the  heartbeat,  and  the  excitability  of  the  cardiac  muscle. 
It  is,  however,  almost  certainly  unnecessary  to  make  such  an  assump- 
tion, for  the  results  can  be  explained  as  merely  dependent  upon  dif- 
ferent degrees  of  stimulation  of  the  same  kind  of  fiber  and  upon  the 
exact  part  of  the  heart  to  which  the  fiber  runs.  Sometimes,  for  ex- 
ample, when  the  right  vagus  nerve  is  stimulated  very  feebty,  there  may 
be  only  a  diminution  in  the  force  of  the  beats  without  any  change  in 
their  rate,  indicating  that  the  effect  has  been  upon  the  musculature  of 
the  auricular  walls  and  not  on  the  sinoauricular  node.  If  the  stimulus 
is  increased  a  little,  then  both  an  enfeebling  and  a  slowing  of  beat  occur, 
indicating  that  the  stimulus  has  now  passed  both  to  the  auricular  mus- 
culature directly  and  to  the  sinoauricular  node. 

The  Sympathetic  Control 

The  effect  of  the  sympathetic  nerve  on  the  heart  may  be  described  as 
being  exactly  opposite  to  that  of  the  vagus.  The  pathway  along  which 
the  fibers  of  this  nerve  travel  to  the  heart  is  more  or  less  a  devious  one. 
They  arise  in  the  mammal  from  nerve  cells  in  the  gray  matter  in  the 
upper  thoracic  portion  of  the  spinal  cord.  The  fibers  leave  by  the  cor- 
responding spinal  roots  and  pass  by  the  white  rami  communicantes  into 
the  sympathetic  chain,  up  which  they  travel  to  the  stellate  and  inferior 


Medulla 

oblongata 


Cervical  1- 


Accessory  n.~ 
+o  trapezi 


Spinal 
medulla- 
(cord) 


Kami 

communican- 
tes  going  to 
Symp.  gang, 
(preganglionic) 
Ansa 

subclavia- 
(Annulus  of 
Vieussens)r 

"Thoracic— 3 
nerves ^ 


N.I 

Postgsnglionic  fibers 

are  dotted  thus 


N.IX 


^j-Jugular  ganglion  (dang,  of  the  root) 
A  iX- Depressor  (Fall  in  pressure  or  slowing  of  heart.) 
(Sensory)   Separate  nerve  in  rabbit  and  opossum. 

Nodosum  ganglion  (Gang,  of  the  trunk)     ( Hunf  * 
^Inhibitory  cranial  autonomic  fibers 


Harrington) 


-Superior  cervical  ganglion 
-Descending  sympathetic  fibers  in  cord 


^Electrodes   (slowing  or  stoppage  of 
Subclavian      heart.  Augmentation  in  some 

animals.) 
Aortic  arch 


-Cervical  va<?o- sympathetic  trunk 


First  thoracic  qanqlion 
(Stellate) 


Electrodes 
(Acceleration,  or 

augmentation  of  heart.) 

Fig.  70. — Schematic  representation  of  the  innervation  of  the  heart  of  the  mammal.  The  red 
continuous  lines  represent  the  sympathetic  (accelerator)  preganglionic  fibers,  and  the  broken  red 
lines,  their  postganglionic  fibers.  The  cell  stations  are  in  the  inferior  cervical  and  stellate  ganglia, 
some  extending  up  to  the  superior  cervical  ganglion.  The  green  continuous  lines  represent  the 
vagus  preganglionic  fibers,  and  the  broken  green  lines,  their  potstganglionic  fibers.  The  cell  stations 
in  this  case  are  located  in  the  heart  itself.  It  will  be  observed  that  electrodes  applied  to  the  so- 
called  vagus  low  down  in  the  neck  may  stimulate  some  sympathetic  fibers.  (From  Jackson.) 


THE   CONTROL   OF    THE   CIRCULATION 


233 


cervical  ganglia.  Around  the  nerve  cells  of  the  stellate  ganglion  the 
fibers  end  by  synapsis,  and  the  axons  of  the  cells  are  then  continued  on 
as  postganglionic  fibers,  proceeding  to  the  heart  through  branches  com- 
ing off  from  the  stellate  ganglion  itself,  or  from  the  ansa  subclavii  or 
inferior  cervical  ganglion.  (Fig.  70.)  In  cold-blooded  animals,  such  as 
the  frog,  the  sympathetic  fibers  run  up  to  the  upper  end  of  the  cervical 
sympathetic  and  join  the  vagus  immediately  after  it  leaves  the  cranial 
cavity.  They  then  proceed  along  with  this  nerve — forming  the  vago- 
sympathetic — to  the  heart.  The  effect  of  stimulation  is  shown  in  Fig.  71. 
The  sympathetic  nerve  differs  from  the  vagus  in  that  a  much  longer  la- 
tent period  elapses  before  its  influence  becomes  effective,  and  this  persists 
for  a  much  longer  period  after  the  stimulus  is  withdrawn.  If  the  vagus 


A. 


B. 

Fig.    71. — Tracings   showing   the   effects   on   the   heartbeat   of   the   frog   resulting   from    stimulation    of 
the    sympathetic    nerves    prior    to    their    union    with    the    vagus    nerve.      (From    Brodie.) 

and  sympathetic  are  stimulated  at  the  same  time,  as  by  exciting  the  vago- 
sympathetic  in  the  frog,  the  first  effect  observed  is  that  of  the  vagus 
usually  followed,  after  removal  of  the  stimulus,  by  the  sympathetic  ef- 
fect. If  the  stimulus  is  maintained  for  a  long  time,  so  that  the  vagus 
becomes  fatigued,  escapement  will  occur  earlier  than  with  pure  vagus 
stimulation,  and  augmentation  may  become  apparent.  The  sympathetic 
influence  is,  however,  never  so  strong  as  that  of  the  vagus.  The  two 
nerves  are  therefore  not  antagonistic  in  the  sense  that  the  one  neutralizes 
the  effect  of  the  other;  but  when  both  are  stimulated,  the  heart  responds 
first  to  the  vagus  and  later  to  the  sympathetic. 


CHAPTER  XXVII 
THE  CONTROL  OF  THE  CIRCULATION  (Cont'd) 

THE  NERVE  CONTROL  OF  THE  PERIPHERAL  RESISTANCE 

As  already  explained,  the  nerve  control  of  the  peripheral  resistance 
takes  place  through  the  action  of  vasoconstrictor  and  vasodilator  nerve 
fibers  on  the  musculature  of  the  arteriole  walls.  The  vasoconstrictor 
impulses  like  those  in  the  vagus  of  the  heart  are  tonic,  so  that  when  a 
nerve  containing  such  fibers  is  cut,  the  corresponding  blood  vessels  un- 
dergo dilatation  (see  page  135),  and  when  their  peripheral  ends  are  stim- 
ulated artificially,  constriction  occurs.  On  the  other  hand,  the  vasodi- 
lator impulses  do  not  appear,  at  least  under  ordinary  circumstances,  to 
be  tonic,  so  that  the  cutting  of  such  fibers  does  not  cause  vasoconstriction ; 
their  stimulation,  however,  causes  marked  dilatation.  Vasomotor  fibers 
are  contained  in  most  of  the  efferent  (motor)  nerve  trunks,  and  to 
detect  their  presence  the  nerve  must  be  either  cut  or  stimulated  and  the 
condition  of  the  blood  vessels  of  the  innervated  area  observed. 

Methods  for  the  Detection  of  Constriction  or  Dilatation 

Several  methods,  varying  with  the  exact  area  under  observation,  can 
be  used  for  the  detection  of  vasoconstriction  or  dilatation.  In  many  cases 
visual  inspection  is  sufficient,  as  in  the  well-known  experiment  of  Claude 
Bernard  on  the  blood  vessels  in  the  ear  of  the  rabbit  (see  Fig.  106) .  When 
this  is  held  with  a  light  behind  it,  and  the  cervical  sympathetic  of  the 
corresponding  side  is  cut,  marked  dilatation  will  become  evident  and 
vessels  will  spring  into  view  where  previously  there  were  none  visible. 
Visual  inspection  is  usually  also  a  satisfactory  method  of  demonstrat- 
ing vasodilatation  or  constriction  in  exposed  glands,  in  mucous  pas- 
sages and  in  the  vessels  of  the  skin. 

Another  comparatively  simple  method  is  the  observation  of  the  tem- 
perature of  the  part,  this  being  particularly  useful  when  the  vascular 
area  is  one  situated  in  the  peripheral  part  of  the  body,  such  as  the  hand 
or  foot  (see  page  209).  When  dilatation  occurs  the  temperature  of  the 
part  rises,  because  the  warmer  blood  from  the  viscera  flows  with  greater 
freedom  through  the  peripheral  regions,  where  it  is  cooled  off  by  radia- 
tion. When  a  thermometer  is  placed  between  the  toes  of  a  dog  or  cat,  a 

234 


THE   CONTROL   OF    THE    CIRCULATION  235 

distinct  rise  in  temperature  will  be  observed  when  the  sciatic  nerve  of  the 
corresponding  limb  is  cut.  The  application  of  this  principle  in  deter- 
mining the  mass  movement  of  blood  by  the  amount  of  heat  given  off  from 
the  hands  or  feet  has  already  been  explained. 

Other  methods  depend  upon  observation  of  the  outflow  of  Hood  from 
the  veins  of  the  part.  A  simple  application  of  this  method  can  be  used  in 
the  case  of  the  ear  of  the  rabbit.  If  the  tip  of  the  ear  is  cut  off,  bleeding 
under  ordinary  circumstances  is  only  very  slight,  but  if  the  cervical 
sympathetic  is  cut,  it  becomes  quite  marked,  slowing  down  again  or 
even  stopping  entirely  when  the  peripheral  end  of  the  nerve  is  stimu- 
lated. By  making  measurements  of  the  volume  of  the  outflow  of  blood 
from  a  vein  by  this  method,  the  extent  of  constriction  or  dilatation  can 


tube  to  recorder 


oil  enclosed 
by  membrane 


Fig.   72. — Roy's  kidney   oncometer.      (From  Jackson.) 

be  followed  quantitatively.  Vasodilatation  also  causes  changes  in  the 
character  of  the  venous  flow,  the  usually  continuous  flow  becoming  pul- 
satile and  the  color  of  the  blood  brightening.  Comparison  of  the  pressures 
in  the  arteries  and  the  veins  of  a  part  is  also  often  of  value  in  the  detec- 
tion of  changes  in  the  caliber  of  the  blood  vessels,  for,  of  course,  the 
greater  the  difference  in  pressure  between  the  two  manometers,  the 
greater  must  be  the  resistance  offered  to  the  flow. 

For  experimental  purposes,  however,  the  standard  method  is  that 
known  as  the  plethysmo graphic.  For  this  purpose  the  organ  or  tissue  is 
enclosed  in  a  so-called  plethysmograph  or  volume  recorder,  the  prin- 
ciple of  which  will  be  clearly  seen  by  consultation  of  the  accompanying 
diagram  of  one  adapted  for  the  kidney  (Fig.  72).  Any  increase  de- 
tected by  this  means  in  the  volume  of  the  part  must  be  due  either  to 


236  THE    CIRCULATION    OF    THE   BLOOD 

an  increase  in  blood  flowing  into  the  vessels  because  of  increased  heart 
action  or  to  a  local  vasodilatation ;  and  vice  versa,  when  shrinkage  oc- 
curs. We  can  not  tell  from  the  volume  tracing  itself  which  of  these 
changes  is  really  responsible  for  the  observed  alteration,  but  we  can  do 
so  by  simultaneously  observing  the  mean  arterial  blood  pressure.  If  this 
falls  when  the  volume  decreases,  it  means  that  the  volume  of  blood  flow- 
ing to  the  part  must  have  become  diminished.  If,  on  the  other  hand,  the 
blood  pressure  remains  constant  or  rises  while  the  volume  decreases,  it 
means  that  the  blood  vessels  have  locally  constricted. 

Methods  for  the  Detection  of  Vasomotor  Fibers  in  Nerve  Trunks 

If  we  wish  to  find  out  through  which  nerve  trunks  a  given  vascular 
area  is  supplied  with  vasoconstrictor  or  vasodilator  impulses,  we  should 
proceed  by  the  use  of  one  of  the  above  described  methods  to  observe  the 
effect  produced  on  the  vessels  by  cutting  the  nerve  and  then  by  stimu- 
lating the  peripheral  end  of  the  cut  nerve.  As  a  result  of  such  observa- 
tions it  has  been  found  that  the  vasomotor  fibers  are  frequently  dis- 
tributed so  that  those  having  a  vasoconstricting  action  are  collected 
mainly  in  one  nerve  trunk  and  those  having  a  dilating  action  in  another; 
in  some  nerve  trunks,  however,  the  relative  numbers  of  the  opposing 
fibers  are  about  equal.  Nerves  containing  a  great  preponderance  of  vaso- 
constrictor fibers  are  the  great  splanchnic  and  the  cervical  sympathetic ; 
and  those  containing  a  great  preponderance  of  vasodilator  are  the  chorda 
tympani  nerve  to  the  submaxillary  gland  and  the  nervi  erigentes  to  the 
external  genitalia. 

It  must  be  clearly  understood  that,  although  one  kind  of  vasomotor 
fiber  may  preponderate  in  one  of  these  nerves,  yet  the  opposite  kind  is 
also  present.  In  the  cervical  sympathetic,  for  example,  some  vasodila- 
tor fibers  extending  to  the  blood  vessels  of  the  mucous  membrane  of  the 
nose  and  cheeks  can  readily  be  demonstrated,  as  shown  by  the  flushing 
of  these  parts  when  the  peripheral  end  of  the  nerve  is  stimulated;  and 
similarly,  even  in  the  great  splanchnic  nerve  itself,  vasodilator  fibers 
supplying  the  suprarenal  capsule  can  quite  readily  be  made  out.  When 
the  vasoconstrictor  fibers  greatly  preponderate  over  the  vasodilator,  the 
effect  of  the  latter  may  be  demonstrated  by  taking  advantage  of  the  fact 
that  ergotoxine  paralyzes  the  vasoconstrictor  but  not  the  vasodilator 
fibers,  so  that  after  its  administration  stimulation  of  the  great  splanch- 
nic nerve  gives  rise  to  a  vasodilatation  instead  of  a  vasoconstriction. 
The  presence  of  vasoconstrictor  fibers  in  the  so-called  vasodilator  nerves 
(chorda  tympani  and  nervi  erigentes)  has  not  however,  been  demon- 
strated. 

A  good  example  of  a  nerve  trunk  containing  about  an  equal  admix- 


THE    CONTROL    OP    THE    CIRCULATION  237 

ture  of  both  kinds  of  vasomotor  fibers  is  the  sciatic.  If  the  hind  limb  of 
a  dog  is  placed  in  a  plethysmo graph  and  simultaneously  a  record  of  the 
mean  arterial  blood  pressure  taken,  it  will  be  found  on  cutting  the  sciatic 
nerve  that  the  volume  of  the  limb  increases,  whereas  the  blood  pressure 
remains  practically  constant.  Before  placing  the  limb  in  the  plethysmo- 
graph,  the  muscles  must  of  course  be  paralyzed  by  means  of  curare; 
otherwise  muscular  contractions  would  confuse  the  result.  If  the 
peripheral  end  of  the  cut  nerve  is  now  stimulated,  vasoconstriction  will 
readily  be  observed.  So  far,  then,  the  results  demonstrate  the  presence 
of  vasoconstrictor  nerve  fibers  alone. 

To  demonstrate  the  presence  of  vasodilators  a  different  procedure  is 
necessary.  This  is  based  on  the  following  facts:  (1)  The  vasodilator 
nerve  fibers  degenerate  more  slowly  than  the  vasoconstrictor;  (2)  they 
are  less  depressed  in  their  excitability  by  cooling  the  nerve;  and  (3)  they 
are  more  sensitive  to  weak  slow  faradic  stimulation  than  the  vasocon- 
strictor fibers.  Accordingly,  if  we  cut  the  sciatic  nerve  two  or  three 
days  before  the  actual  experiment,  and  then,  while  observing  the  volume 
of  the  limb,  proceed  to  stimulate  the  half-degenerated  nerve  with  feeble 
electric  stimuli  of  slow  frequency  we  shall  usually  observe  a  dilatation 
of  the  limb  instead  of  constriction;  and  even  if  we  cool  a  stretch  of  a 
freshly  cut  .nerve  before '  applying  the  stimulus,  the  same  result  will 
often  be  obtained. 

The  Origin  of  Vasomotor  Nerve  Fibers 

Having  seen  how  the  presence  of  vasomotor  fibers  may  be  detected  in 
peripheral  nerves,  we  must  now  proceed  to  trace  them  back  to  their 
origin  from  the  central  nervous  system.  The  method  for  doing  this  con- 
sists, in  general,  in  observing  the  effect  on  the  blood  vessels  produced  by 
cutting  or  stimulating  the  various  nerve  roots  through  which  the  fibers 
might  pass  on  their  way  to  the  nerve  trunks.  As  a  result  of  such  obser- 
vations it  has  been  found  that  all  of  the  vasoconstrictor  fibers  emanate 
from  the  spinal  cord  in  the  region  between  the  level  of  the  second  thoracic 
and  that  of  the  second  or  third  lumbar  spinal  roots,  but  from  nowhere 
else  in  "the  cerebrospinal  axis.  Section  of  the  spinal  cord  below  the  level 
of  the  second  lumbar  spinal  roots  produces  no  change  in  the  volume  of 
the  hind  limb,  provided  the  muscles  be  thoroughly  curarized,  nor  does 
stimulation  of  the  lower  end  of  the  cut  spinal  cord  have  any  effect.  If 
the  last  two  thoracic  or  the  first  two  lumbar  spinal  roots  are  stimulated, 
however,  evidence  of  vasoconstriction  will  be  obtained. 

The  restriction  of  the  origin  of  vasoconstrictor  fibers  to  the  above- 
mentioned  regions  of  the  spinal  cord  indicates  that  in  proceeding  to 
the  mixed  nerve  trunks  they  must  travel  along  special  nerve  paths. 


238  THE    CIRCULATION    OF    THE    BLOOD 

These  are  provided  by  the  sympathetic  chain  and  its  branches  (Fig.  218). 
The  vasoconstrictor  fibers  in  the  anterior  spinal  roots  leave  the  latter 
by  way  of  the  corresponding  white  rami  communicantes,  and  pass  into 
the  neighboring  sympathetic  chain,  along  which  they  either  ascend  or 
descend,  according  to  their  ultimate  destination.  In  their  course  they 
come  into  contact  with  the  sympathetic  ganglia,  through  one  or  two  of 
which  they  may  pass  without  any  change,  but  ultimately  each  fiber  ar- 
rives at  some  ganglion,  in  which  it  terminates  by  forming  a  synapsis 
around  one  of  the  gangliordc  nerve  cells.  The  axon  of  this  nerve  cell 
then  continues  the  course  by  the  nearest  gray  ramus  communicans  back 
to  the  spinal  nerve  beyond  the  union  of  its  anterior  and  posterior  roots. 
Up  to  the  point  where  the  fiber  forms  a  synapsis  with  a  ganglionic  nerve 
cell,  it  is  medullated  and  is  known  as  the  preganglionic  fiber.  Beyond 
the  nerve  cell,  it  is  nonmedullated  and  is  known  as  postganglionic 
(page  894). 

The  exact  ganglion  in  which  a  given  vasoconstrictor  fiber  becomes  connected  with  a 
nerve  cell  can  be  determined  by  the  nicot  ne  method  of  Langley.  Local  application  to 
the  ganglion  of  a  weak  solution  of  this  drug  (1  per  cent)  paralyzes  the  synaptic  con- 
nection, so  that  a  stimulus  applied  to  the  preganglionic  fiber  no  longer  produces  its 
effect.  Suppose,  for  example,  that  a  vasoconstrictor  fiber  has  been  found  by  the  stimula- 
tion method  to  travel  through  several  ganglia,  and  we  wish  to  determine  in  which  of 
these  the  synapsis  occurs:  we  can  do  so  by  applying  the  stimulus  at  a  point  central  to 
the  ganglia  after  painting  each  of  them  in  turn  with  the  nicotine  solution.  If  the 
application  of  the  drug  to  a  given  ganglion  is  found  to  cause  no  alteration  in  the 
effect  produced  by  stimulation,  then  we  know  that  there  can  not  be  any  synaptic 
connection  in  that  ganglion,  and  we  proceed  in  the  same  way  till  we  have  located 
the  ganglion  in  which  synapsis  occurs.  It  is  important  to  remember  that  the  post- 
ganglionic vasoconstrictor  fibers  in  a  gray  ramus  communicans  do  not  come  from  the 
preganglionic  fibers  of  the  corresponding  spinal  root,  but  from  fibers  coming  through 
white  rami  at  a  higher  or  a  lower  level. 

The  above  description  applies  to  the  vasoconstrictor  fibers  proceeding  to  the  vessels  of 
the  anterior  and  posterior  extremities,  those  for  the  former  arising  (in  the  dog)  from 
about  the  fourth  thoracic  to  the  tenth ;  and  those  for  the  latter,  from  the  lowest  thoracic 
and  the  first  three  lumbar  nerve  roots.  The  cell  station  for  the  fibers  to  the  fore  limbs 
is  in  the  stellate  ganglion,  and  for  the  hind  limbs  in  the  last  two  lumbar  and  first  two 
sacral  ganglia  of  the  abdominal  sympathetic  chain. 

The  vasoconstrictor  fibers  to  the  vessels  of  the  head  and  neck  run  a  somewhat  dif- 
ferent course,  there  being  no  convenient  cerebrospinal  nerve  along  which  the  post- 
ganglionic fibers  may  run.  The  fibers  to  the  blood  vessels  of  the  head  leave  the  cord 
by  the  second  to  the  fourth  or  fifth  thoracic  roots  and  pass  by  the  corresponding  white 
rami  communicantes  into  the  sympathetic  chain,  up  which  they  run,  passing  through  the 
stellate  ganglion,  the  ansa  subclavii,  and  the  inferior  cervical  ganglion,  then  ascending 
in  the  cervical  sympathetic  to  the  superior  cervical  ganglion,  where  their  cell  station 
exists.  The  postganglionic  fibers  on  leaving  this  ganglion  travel  to  their  destination 
mainly  along  the  outer  walls  of  the  blood  vessels. 

The  vasoconstrictors  to  the  abdominal  viscera  are  carried  by  the  splanchnic  nerves, 
the  fibers  of  which  come  off  from  the  lower  seven  thoracic  and  the  uppermost  lumbar 


THE    CONTROL   OF    THE    CIRCULATION  239 

roots.  The  thoracic  fibers  pass  down  the  sympathetic  chain,  which  they  leave  by  the 
great  splanchnic  nerves.  The  lumbar  fibers  form  the  lesser  or  abdominal  splanchnic 
nerves.  As  preganglionic  fibers,  therefore,  these  fibers  are  carried  by  the  greater  and 
lesser  splanchnic  nerves  into  the  abdomen,  where  the  former  comes  into  close  relation- 
ship with  the  suprarenal  glands,  giving  off  a  branch  to  the  suprarenal  ganglion.  The 
main  course  of  the  nerve  is  continued  on  to  the  solar  plexus,  in  the  various  ganglia  of 
which  most  of  the  preganglionic  fibers  end  by  synapsis,  the  postganglionic  fibers  then 
proceeding  along  the  blood  vessels  to  the  vessels  of  the  abdominal  viscera.  (See  also 
page  894). 

Vnsnfl/ilrdnr  fibers  have  a,  rnnrg  varied  origin  than  vasoconstrictor,  and 
they  run  an  entirely  different  course.  Vasodilator  impulses  may  be 
transmitted  by  fibers  arising  from  practically  any  level  of  the  cerebro- 
spinal  axis,  not  only  by  Jbhe  motor  roots,  but  by  the  sensory  as  well. 
Thus,  they  pass  out  of  the  spinal  cord  in  the  posterior  sacral  roots  to 
enter  the  nerves  of  the  hind  limbs,  as  has  been  demonstrated  by  observ- 
ing an  increase  in  the  volume  of  the  curarized  limb  during  electrical 
stimulation  of  the  exposed  rootlets.  The  apparent  inconsistency  of  these 
observations  with  the  well-known  law  concerning  the  direction  of  the 
impulses  contained  in  the  posterior  spinal  roots  is  explained  by  assum- 
ing that  the  dilator  impulses  are  transmitted  along  the  ordinary  sensory 
fibers,  since  there  are  no  efferent  fibers  in  these  roots.  They  are  impul- 
ses which  go  against  the  ordinary  stream  (antidromic).  In  support  of 
this  explanation  it  is  of  importance  to  note  that  at  their  termination 
near  the  skin  many  sensory  fibers  split  into  several  branches,  some  of 
which  run  to  blood  vessels,  and  others  to  receptor  organs  (page  854). 
Stimulation  of  the  latter  branches  may  cause  dilatation  of  the  local  blood 
vessels  nearby,  indicating  that  impulses  must  be  transmitted  up  to  the 
point  at  which  the  branching  occurs  and  then  down  the  vascular  branch, 
this  result  being  obtained  even  after  the  main  trunk  of  the  nerve  has 
been  cut  above  the  division. 

For  the  blood  vessels  of  the  anterior  extremity,  the  vasodilator  impulses  are  similarly 
transmitted  through  the  posterior  spinal  roots  of  the  lower  cervical  region  of  the  spinal 
cord.  The  vasodilator  fibers  to  the  abdominal  viscera  are  transmitted  with  the  splanchnic 
nerves,  but  they  may  also  be  derived  from  the  posterior  spinal  roots,  for  it  has  been 
found  that  stimulation  of  posterior  roots  in  the  splanchnic  area  causes  dilatation  in  the 
intestine  (Bayliss).  Vasodilator  fibers  are  also  contained  in  the  cranial  nerves,  par- 
ticularly the  seventh  and  the  ninth,  being  distributed  in  the  former  nerve  to  the  an- 
terior portion  of  the  tongue  and  the  salivary  glands,  and  in  the  latter  to  the  posterior 
portion  of  the  tongue  and  the  mucous  membrane  of  the  floor  of  the  mouth.  The  vaso- 
dilator fibers  for  the  mucous  membrane  of  the  inside  of  the  cheeks  and  nares  have  their 
course  in  the  cervical  sympathetic,  being  distributed  to  the  buccofacial  region  in  the 
branches  of  the  fifth  cranial  nerve. 

There  is  evidence  to  show  that  the  vasodilator  fibers,  like  the  vasoconstrictor,  become 
connected  by  synapsis  with  nerve  cells  somewhere  in  their  course.  In  the  case  of  the 
vasodilator  fibers  in  the  chorda  tympani  and  nervi  erigentes,  such  cell  stations  have 
been  clearly  demonstrated  in  the  hilus  of  the  submaxillary  gland  in  the  former  nerve 


240  THE    CIRCULATION    OF    THE    BLOOD 

and  in  the  hypogastric  plexus  situated  on  the  neck  of  the  bladder  in  the  latter. 
It  is  therefore  commonly  assumed  that,  although  not  recognizable  by  histological  methods, 
such  terminal  cell  stations  must  also  exist  in  close  association  with  all  blood  vessels 
to  which  the  vasodilator  fibers  run.  Whether  or  not  such  peripheral  cell  stations  exist, 
there  is  a  marked  difference  between  the  course  of  vasodilator  and  of  vasoconstrictor 
fibers. 

The  Vasomotor  Nerve  Centers 

Our  next  problem  is  to  trace  these  fibers  farther  into  the  central 
nervous  system,  and  find  the  location  and  study  the  characteristics  of 
the  nerve  centers  from  which  they  are  derived.  We  must  postulate  the 
existence  of  both  vasoconstrictor  and  vasodilator  centers,  but  since  there 
is  no  adequate  evidence  at  the  present  time  which  enables  us  to  locate 
the  latter,  we  must  confine  our  attention  to  the  vasoconstrictor  centers. 
These  exist  at  two  levels  in  the  cerebrospinal  axis:  (1)  in  .the  gray  mat- 
ter  of  the  jspioal— eord,  and  (2)  in  the  gray  matter  of  the  medulla 
oblongata. 

The  spinal,  or  as  they  are  often  called,  the  subsidiary  vasoconstrictor 
centers,  are  represented  by  certain  cells  of  the  lateral  horn  of  gray  mat- 
ter in  the  thoracic  portion  of  the  spinal  cord,  from  which  the  pregan- 
glionic  vasoconstrictor  fibers  above  described  are  derived.  The  exact 
location  of  the  nerve  cells  composing  the  chief  centers  in  the  medulla  has 
not  as  yet  been  definitely  made  out;  they  undoubtedly  lie  near  those  of 
the  vagus  center  (see  Eanson).  The  axons  of  the  medullary  cells  de- 
scend in  the  lateral  columns  of  the  spinal  cord  to  end  by  synapses 
around  the  cells  of  the  subsidiary  vasoconstrictor  center  in  the  lateral 
horns. 

The  experimental  evidence  which  indicates  the  existence  of  chief  and 
subsidiary  centers  is  quite  definite.  Thus,  if  the  spinal  cord  is  cut  at  the 
lower  cervical  region  (below  the  phrenic  nuclei,  so  as  not  to  interfere 
with  the  movements  of  the  diaphragm),  the  arterial  blood  pressure  falls 
profoundly,  because  the  pathway  connecting  the  two  centers  is  broken. 
After  several  days,  however,  the  blood  pressure  will  gradually  rise  again. 
If  after  this  has  occurred,  the  spinal  cord  is  destroyed  by  pushing  a  wire 
down  the  vertebral  canal,  the  arterial  blood  pressure  will  again  fall, 
indicating  that  the  vascular  tone  which  had  been  reacquired  after  sec- 
tion of  the  pathway  between  the  main  and  the  subsidiary  centers  must 
have  been  brought  about  by  the  development  in  the  subsidiary  centers 
of  an  independent  power  of  reflex  tonic  action.  This  experiment  there- 
fore demonstrates  that  in  the  intact  animal  the  subsidiary  centers  do  not 
by  themselves  discharge  tonic  impulses.  In  other  words,  the  subsidiary 
centers  ordinarily  serve  merely  as  transfer  stations  for  the  tonic  im- 
pulses coming  from  the  chief  center,  but  when  these  impulses  no  longer 


THE   CONTROL   OF    THE   CIRCULATION  241 

arrive,  then  a  hitherto  dormant  power  of  tonic  activity  becomes  devel- 
oped in  the  subsidiary  centers. 

Independent  Tonicity  of  Blood  Vessels 

Even  after  complete  disconnection  of  the  spinal  cord  from  the  blood 
vessels,  as  by  cutting  of  the  splanchnic  nerve  to  the  abdomen  or  abla- 
tion of  that  portion  of  the  lower  spinal  cord  from  which  the  fibers  to 
the  hind  limb  arise,  the  disconnected  blood  vessels,  although  at  first 
completely  dilated,  may  later  acquire  an  independent  tone  of  their 
own,  indicating  therefore,  that  they  must  popgpss  srmnp  ripiirnTTvnso.iilar 
mechanism  which  fia.ria.fit  independently  of  the  nerve  centers,  and  which 
may  be  stimuiTTFeU3a^bettvity-by  the  presence  of  hormones  in  the  blood. 
The  hormone  was  at  one  time  thought  to  be  epinephrine  (see  page  774). 

Epinephrine  control  is  indicated  in  the  effect  produced  upon  arterial 
blood  pressure  by  stimulation  of  the  great  splanchnic  nerve.  Careful 
analysis  of  the  curve,  shown  in  Fig.  29,  shows  that  the  rise  is  both  im- 
mediate and  delayed;  that  is,  the  curve  mounts  immediately,  then  flat- 
tens out  a  little,  and  then  assumes  a  further  rise.  This  delayed  response 
seems  to  depend  upon  the  secretion  of  epinephrine  into  the  blood,  for  it 
does  not  occur  when  the  suprarenal  veins  are  occluded,  and  is  much  de- 
layed by  temporarily  clamping  the  suprarenal  veins  on  the  same  side 
as  that  on  which  the  splanchnic  nerve  is  stimulated.  It  has  been  stated 
by  certain  observers  that,  after  occlusion  of  the  adrenal  veins,  there  is 
a  downward  tendency  of  the  blood  pressure,  which  however  develops 
writh  extreme  slowness;  and  that  a  distinct  elevation  of  blood  pressure 
follows  the  removal  of  a  clamp  temporarily  placed  on  the  adrenal  veins. 
This  rise  is  pronounced  if  the  splanchnic  nerve  is  stimulated  during  the 
occlusion  of  the  veins.  It  must  of  course  be  understood  that  the  imme- 
diate rise  in  blood  pressure  following  splanchnic  stimulation  is  caused  by 
vasoconstriction  in  the  splanchnic  area  itself,  as  is  evidenced  by  the 
fact  that  it  does  not  occur,  or  is  only  very  faint,  when  the  abdominal 
blood  vessels  are  ligated  prior  to  the  stimulation  of  the  splanchnic  nerve. 
Even  after  ligation  of  the  adrenal  veins  and  of  the  blood  vessels  of  the 
splanchnic  area,  stimulation  of  the  splanchnic  nerve  may  still  cause  a 
slight  rise  in  arterial  blood  pressure,  possibly  because  some  fibers  may 
run  from  the  splanchnic  to  vascular  areas  not  situated  within  the  realm 
of  the  splanchnic  nerve — for  example,  the  blood  vessels  of  the  lumbar 
muscles. 


CHAPTER  XXVIII 

THE  CONTROL  OF  THE  CIRCULATION  (Cont'd) 
CONTROL  OF  THE  VASOMOTOR  CENTER 

The  activities  of  the  vasomotor  center  are  controlled  partly  by  hor- 
mones and  partly  by  afferent  impulses. 

The  Hormone  Control 

As  with  the  respiratory  center,  the  chief  hormone  is  the  hvdrogen-ion 
concentration  of  the  blood.  When  this  is  increased,  as  in  asphyxia,  the 
vasoconstrictor  part  of  the  vasomotor  center  becomes  stimulated,  so 
that  the  blood  vessels  are  constricted  and  the  blood  pressure  rises.  Tak- 
ing, as  our  criterion  of  hydrogen-ion  concentration,  the  tension  of  the 
carbon  dioxide  in  the  blood  (see  page  371),  we  may  proceed  to  investi- 
gate the  relationship  by  observing  the  blood  pressure  during  changes 
in  the  carbon-dioxide  tension  brought  about  by  causing  the  animal  to 
breathe  atmospheres  containing  known  percentages  of  the  gas  (Mathi- 
son15).  Thus,  if  a  decerebrate  cat  is  made  to  respire  an  atmosphere 
containing  5  per  cent  or  more  of  carbon  dioxide,  an  immediate  rise 
occurs  in  the  arterial  blood  pressure.  That  the  inhaled  carbon  dioxide 
acts  by  raising  the  hydrogen-ion  concentration  of  the  blood  is  indicated 
by  the  fact  that  a  similar  rise  in  blood  pressure  can  be  obtained  by  intra- 
venous injection  of  a  weak  solution  of  lactic  acid  (2  c.c.  N/15)  in  a  de- 
cerebrate  cat. 

Oxygen  deprivation  also  causes  excitation  of  the  vasoconstrictor  center 
as  can  be  demonstrated  either  by  causing  a  decerebrate  cat  to  breathe  in 
an  atmosphere  of  nearly  pure  nitrogen  or  by  clamping  the  vertebral  ar- 
teries as  they  lie  just  below  the  centers.  The  rise  in  blood  pressure  is  then 
very  prompt  and  is  accompanied  by  hyperpnea. 

The  sensitivity  of  the  medullary  center  towards  the  hydrogen  ion  is  many  times 
greater  than  that  of  the  subsidiary  centers  in  the  spinal  cord.  If  an  animal  is  kept 
alive  by  artificial  respiration  for  some  time  after  cutting  the  cervical  spinal  cord, 
the  subsidiary  vasomotor  centers  will,  as  we  have  seen,  gradually  acquire  a  tonic 
action,  and  the  lowered  blood  pressure  will  gradually  rise  again.  If,  when  this  has 
been  attained,  the  animal  is  made  to  breathe  an  atmosphere  rich  in  carbon  dioxide, 
a  sudden  rise  in  blood  pressure  will  occur,  but  to  produce  it  a  very  much  greater  per- 
centage of  this  gas  must  be  inspired  than  when  the  pathway  between  the  chief  and 

242 


THE   CONTROL   OF   THE   CIRCULATION  243 

subsidiary  centers  is  intact.  Whereas  5  per  cent  carbon  dioxide  is  sufficient  to  cause 
a  rise  of  pressure  in  an  animal  having  its  chief  vasomotor  center,  it  takes  25  per 
cent  and  upward  to  produce  a  like  effect  on  a  spinal  animal;  and  similarly,  although 
2  c.c.  of  N/15  lactic  acid  will  stimulate  the  chief  vasomotor  center,  it  takes  5  c.c.  of 
N/2  to  excite  the  spinal-cord  centers. 

The  Nerve  Control 

HoAvever  important  hormones  may  be  in  maintaining  a  tonic  stimula- 
tion of  the  center,  the  more  sudden  changes  in  activity  are  mainly 
brought  about  by  afferent  nerve  impulses.  The  afferent  impulses  are 
of  two  classes:  (1)  those  causing  a  rise  in  blood  pressure,  called 
pressor,  and  (2)  those  causing  a  fall  in  blood  pressure,  called  depressor. 
The  effect  produced  on  the  arterial  blood  pressure  by  stimulation  of 
either  pressor  or  depressor  fibers  is  usually  more  or  less  evanescent, 
especially  in  the  case  of  the  depressor  fibers;  and  when  the  change  fol- 
lowing stimulation  of  the  nerve  passes  off,  the  blood  pressure  always 
returns  to  its  former  level.  This  indicates  that  the  afferent  impulses  do 
not  affect  the  tonic  control  which  the  vasomotor  center  exercises  on  the 
blood  vessels.  It  has,  therefore,  been  assumed  by  Porter16  that  there  are 
really  two  kinds  of  vasomotor  centers:  one  concerned  merely  in  the 
bringing  about  of  temporary  reflex  changes,  the  other  concerned  in  the 
maintenance  of  the  vascular  tone.  It  may  be  that  the  activities  of  the 
former  are  primarily  dependent  upon  afferent  impulses,  and  the  latter, 
upon  hormones.  Justification  for  this  view  has  been  found  in  observa- 
tions made  on  the  effects  of  stimulation  of  pressor  and  depressor  fibers 
in  animals  under  the  influence  of  curare  or  alcohol.  With  the  former 
drug,  stimulation  of  a  nerve  containing  a  preponderance  of  pressor  or 
depressor  fibers  produces  double  its  usual  effect,  but  the  mean  level  of 
the  blood  pressure  apart  from  this  effect  remains  unchanged.  With  the 
latter  drug  (alcohol),  on  the  other  hand,  the  reflex  response  entirely 
disappears,  although  it  immediately  reappears  when  the  alcohol  effect 
has  passed  off,  and  there  is  no  evidence  of  a  change  in  tone.  The  tonic 
and  the  reflex  mechanisms  of  the  vasomotor  center  can  not  therefore  be 
identical. 

At  the  present  stage  of  our  knowledge,  it  is  only  possible  for  us  to 
study  the  effect  of  stimulation  of  pressor  and  depressor  fibers  on  the 
vasoreflex  center.  Such  fibers  are  contained  in  practically  every  sen- 
sory nerve  of  the  body,  and  it  would  appear  that  a  fairly  equal  mixture 
of  both  kinds  of  fiber  exists  in  most  of  these  nerves. 

Pressor  and  Depressor  Impulses. — Depressor  impulses  alone  are  present 
in  the  cardiac  depressor  nerve.  Sometimes  as  in  the  rabbit,  this  exists 
as  an  independent  nerve  trunk,  originating  by  two  branches,  one  from 
the  superior  laryiigeal,  the  other  from  the  vagus,  and  descending  close  to 


244  THE   CIRCULATION   OF   THE   BLOOD 

the  vagus  trunk,  to  end  around  the  arch  of  the  aorta.  In  other  animals 
the  depressor  is  bound  up  with  the  vagus  trunk  from  which  it  can  some- 
times be  separated  by  careful  dissection.  The  first  prerequisite  in  inves- 
tigating the  cause  of  the  changes  produced  by  stimulation  of  these  nerves 
is  the  elimination  of  any  chance  of  an  alteration  in  heartbeat  as  a  result 
of  simultaneous  stimulation  of  afferent  vagus  fibers.  This  may  be  done 
either  by  cutting  both  vagi  or  by  administering  atropine.  Stimulation 
of  the  central  end  of  the  cardiac  depressor  nerve  after  such  precautions 
causes  an  immediate  fall  in  blood  pressure,  accompanied  by  an  increase 
in  volume  either  in  the  hind  limb  or  in  one  of  the  abdominal  viscera — 
evidence  of  general  vasodilatation  (Fig.  73). 

When  the  central  end  of  a  sensory  nerve,  such  as  the  sciatic,  is  acted 
on  by  a  stimulus  of  moderate  strength,  it  will  usually  be  found  that  the 
arterial  blood  pressure  rises  and  that  the  volume  of  the  limb  or  of  some 


Fig.  73. — Fall  of  blood  pressure  from  excitation  of  the  depressor  nerve.  The  drum  was 
stopped  in  the  middle  of  the  curve  and  the  excitation  maintained  for  seventeen  minutes.  The  line 
of  zero  pressure  should  be  30  mm.  lower  than  here  shown.  (From  Bayliss.) 

abdominal  viscus  becomes  diminished — evidence  of  general  vasoconstric- 
tion.  But  when  the  sensory  nerve  is  stimulated  with  extremely  weak 
f aradic  shocks,  an  entirely  different  result  is  likely  to  be  obtained ; 
namely,  a  fall  of  blood  pressure  and  an  increase  in  volume  of  the  limb 
or  viscus  is  usually  obtained,  indicating  that  we  have  stimulated  depressor 
fibers.  By  careful  experimentation  with  quantitatively  graduated  elec- 
trical stimuli,  it  has  been  found  by  Martin  and  others17  that  on  stimu- 
lating an  afferent  nerve  with  weak  shocks,  a  fall  in  blood  pressure  is 
the  first  effect  to  be  observed,  and  that  this  becomes  more  and  more 
marked  as  the  strength  of  the  stimuli  is  increased,  until  a  certain  opti- 
mum is  reached,  after  which  the  fall  in  blood  pressure  becomes  less  evi- 
dent. When  a  certain  strength  of  stimulation  is  exceeded,  a  rise  instead 
of  a  fall  occurs.  After  this  point  additional  increase  in  stimulation  causes 


THE    CONTROL   OF    THE    CIRCULATION 


245 


more  and  more  marked  elevation  of  blood  pressure  through,  a  very  long 
range  of  stimuli.  Cooling  or  partial  degeneration  of  the  nerve  makes  it 
hyper  excitable  to  depressor  reflexes  so  that  these  occur  whatever  strength 
of  stimulus  is  used.58 

Stimulation  of  two  afferent  nerves  at  the  same  time  usually  produces 
a  greater  reflex  vasomotor  change  than  the  stimulation  with  an  equiva- 
lent strength  of  current  of  either  nerve  alone.  That  is  to  say,  the  effect 
produced  by  stimulating  the  central  end  of  both  sciatics  simultaneously 


fig.  74. — The  effect  of  strong  stimulation  (heat)  of  the  skin  of  the  foot  on  the  arterial  blood 
pressure  and  respiratory  movements.  Upper  tracing,  thoracic  movement;  lower  tracing,  arterial 
blood  pressure. 

will  be  greater  than  that  produced  by  stimulating  either  alone  with  double 
the  strength  of  stimulus. 

As  has  been  stated  above,  the  reflex  change  in  blood  pressure  is  often 
quite  transitory  in  nature,  although  the  stimulation  of  the  pressor  nerve  is 


246 


THE   CIRCULATION   OF   THE    BLOOD 


maintained.  When  this  decline  has  occurred,  the  pressor  reaction  can 
often  be  renewed  by  shifting  the  stimulation  to  a  second  nerve.  These 
facts  concerning  the  greater  efficacy  of  combined  stimulation  of  several 
nerves  are  of  considerable  importance  in  connection  with  the  general 
question  of  reflex  changes  in  blood  pressure.  For  instance,  many  of  the 
pressor  fibers  found  in  the  sciatic  nerve  are  connected  with  the  receptors 
that  mediate  the  sensations  of  the  skin.  Stimulation  of  receptors  for  cold 
and  for  pain  causes  pressor  reflexes  whereas  stimulation  of  those  for  mod- 
erate heat  causes  depressor  reflexes.  It  is  important  to  remember  that 


Fig.    75. — Diagram   showing  the   probable   arrangements   of   the   vasomotur    reflexes. 

A.  Muscle  of  arteriole. 

D.  Vasodilator  nerve  fiber  terminating  on  A  and  inhibiting  its  natural  tonus,  as  indicated  by  - 
sign. 

C.  Vasoconstrictor  fiber  also  ending  in  A,  but  exciting  it  (  +  ).  These  two  kinds  of  fiber  arise 
from  the  dilator  center  (DC)  and  the  constrictor  center  (CC)  respectively.  ' 

F.  Afferent  depressor  fiber,  dividing  into  two  branches,  one  of  which  (-)  inhibits  the  co?i- 
stricter  center,  while  the  other  (+)  excites  the  dilator  center  causing  dilatation  of  the  arteriole  and 
fall  of  blood  pressure. 

R.  Pressor  fiber  exciting  CC  and  inhibiting  DC,  and  therefore  causing  vasoconstriction  and  rise 
of  blood  pressure. 

a,  b,  c,  and  d  represent  the  synapses  of  the  pressor  and  depressor  branches  with  the  efferent 
neurons.  (From  Bayliss.) 

localized  stimulation  of  the  skin  is  less  efficient  in  bringing  about  such 
vascular  changes  than  stimulation  applied  over  large  areas,  even  when 
the  local  stimulus  is  intense  and  the  general  stimulus  mild  in  character. 
Jumping  into  a  moderately  cold  bath  will  cause  a  much  greater  rise  in 
arterial  blood  pressure  than  plunging  the  hand  into  ice  cold  water. 


THE    CONTROL   OF    THE    CIRCULATION  247 

Mechanism  of  Action  of  Pressor  and  Depressor  Impulses. — When  we 
consider  the  exact  mechanism  by  which  these  afferent  impulses  operate, 
we  have  to  bear  in  mind  four  possibilities:  the  reflex  fall  in  blood 
pressure  produced  by  stimulation  of  a  depressor  afferent  fiber  may 
be  due  either  to  a  stimulation  of  the  vasodilator  part  of  the  cen- 
ter or  to  an  inhibition  of  the  tone  of  the  vasoconstrictor  part ;  and,  con- 
versely, a  rise  in  pressure  may  be  dependent  either  on  a  stimulation  of 
the  vasoconstrictor  part  of  the  center  or  on  an  inhibition  of  the  tone  of 
the  vasodilator  part.  All  of  these  changes  have,  as  a  matter  of  fact,  been 
shown  to  occur,  at  least  under  certain  conditions,  although  the  evidence 
for  the  inhibition  of  dilator  tone  is  as  yet  a  little  uncertain  (see  Fig.  75). 

Without  going  into  the  subject  in  detail,  we  may  nevertheless  take 
as  an  example  of  the  methods  by  which  the  information  has  been  ob- 
tained, the  experiment  performed  by  Bayliss,18  showing  that  the  vasodi- 
lation  which  results  from  stimulation  of  the  depressor  nerve  is  owing 
partly  to  removal  of  vasoconstrictor  tone  and  partly  to  vasodilator 
stimulation.  The  volume  of  the  hind  limb  of  a  curarized  and  vagotomized 
rabbit  increases  when  the  central  end  of  the  cardiac  depressor  nerve  is 
stimulated.  In  order  to  determine  whether  this  dilatation  is  due  solely 
to  the  removal  of  vasoconstrictor  tone,  the  above  experiment  was  repeated 
on  a  rabbit  in  which  the  sympathetic  chain  had  been  cut  below  the  level 
of  the  second  lumbar  spinal  roots.  By  such  an  operation  all  the  vaso- 
constrictor fibers  to  the  vessels  of  the  hind  limb  are  severed,  but  the 
vasodilator  fibers,  since  they  emanate  through  the  sacral  sensory  roots, 
are  left  intact.  It  was  nevertheless  found  on  stimulating  the  depressor 
nerve  that  dilatation  of  the  hind  limb  still  occurred,  thus  indicating 
that  stimulation  through  vasodilator  fibers  must  have  taken  place.  Con- 
versely, in  another  experiment,  instead  of  the  sympathetic  chain,  the 
spinal  cord  was  cut  below  the  level  of  the  second  lumbar  segment,  thus 
severing  the  dilator  but  not  the  constrictor  path,  and  again  depressor 
stimulation  caused  the  volume  of  the  limb  to  increase,  indicating  that 
an  inhibition  of  constrictor  tone  must  have  occurred. 

Reciprocal  Innervation  of  Vascular  Areas 

It  must  not  be  imagined  that  changes  in  the  caliber  of  the  blood  ves- 
sels occurring  in  one  vascular  area  are  necessarily  occurring  all  over 
the  body.  On  the  contrary,  a  most  important  reciprocal  relationship 
exists  in  the  blood  supply  to  different  parts.  After  food  is  taken,  for 
example,  more  blood  is  required  by  the  digestive  organs  than  when  they 
are  at  rest,  and  this  is  insured  by  dilatation  of  their  own  vessels  along 
with  reciprocal  constriction  of  those  of  other  parts  of  the  body.  On 
account  of  the  relatively  great  capacity  of  the  abdominal  vessels,  their 


248  THE    CIRCULATION    OF    THE    BLOOD 

dilatation  during  digestive  activity  is  usually  greater  than  the  reciprocal 
constriction  of  the  other  vessels,  so  that  the  diastolic  blood  pressure  falls, 
necessitating  a  more  powerful  cardiac  discharge  in  order  to  maintain 
the  mean  pressure.  After  taking  food,  the  systolic  pressure  does  not 
as  a  rule  fall  so  much  as  the  diastolic,  if  it  falls  at  all;  and  the  pres- 
sure pulse  therefore  becomes  greater  and  causes  a  greater  live  load  to 
be  applied  to  the  vessels  with  each  heartbeat.  During  the  sudden  strain 
that  is  thrown  on  them,  weakened  arteries  may  give  way,  especially  in 
the  brain. 

Another  example  of  reciprocal  action  of  the  vascular  system  is  seen 
in  muscular  exercise.  The  vessels  of  the  acjjj^jnu&el^s—dilate,  while 
those  elsewhere  constrict.  The  local  dilatation  in  this  case  is,  however, 
not  entirely  at  least  a  nervous  phenomenon,  being  caused  in  fact,  as  we 
shall  see,  by  hormone  action  on  account  of  the  local  increase  in  hydro- 
gen-ion concentration  (see  page  431).  Irritants  applied  to  the  surface 
of  the  body,  such  as  liniments,  etc.,  cause  local  dilatation  of  the  super- 
ficial and  perhaps  of  the  immediately  underlying  vessels,  probaTHy  by 
axon  reflexes  (page  898),  and  it  is  believed  reflex  constriction  of  those 
elsewhere  in  the  body.  Hot  applications  (poultices,  etc.,)  have  a  similar 
effect.  Application  of  cold  to  local  areas  of  skin  causes  local  vasocon- 
striction.  This  action  of  cold  is  very  marked  in  some  parts  of  the  body, 
such  as  the  hands,  where  by  Stewart's  method  (page  296)  it  can  be  shown, 
not  only  that  the  bloodflow  of  the  hand  to  which  the  cold  is  applied 
is  greatly  curtailed,  but  also  that  of  the  opposite  side.  In  this  case 
therefore  reciprocal  action  is  not  obtained.  Chilling  of  the  skin  as  by  a 
'[draught  of  air  also  causes  constriction  of  the  vessels  of  the  nasal  mucosa ; 
iiot  dilatation,  as  might  be  expected.  On  the  other  hand,  stimulation  of 
the  central  end  of  the  great  auricular  nerve  of  the  ear  in  a  rabbit,  causes 
dilatation  of  the  vessels  of  the  ear  at  the  same  time  as  a  rise  in  arterial 
blood  pressure  (Loven  reflex).  Similarly,  when  the  central  end  of  one 
of  the  sensory  roots  of  the  leg  of  a  dog  is  stimulated,  there  is  a  rise  in 
arterial  blood  pressure  and  an  increase  in  the  volume  of  the  limb  (Bay- 
liss).  These  last  two  experiments  demonstrated  reciprocal  innervation. 

THE  INFLUENCE  OF  GRAVITY  ON  THE   CIRCULATION 

If  the  arterial  blood  pressure  is  measured  in  the  arm  and  leg  in  a  man 
standing  erect,  a  difference  corresponding  to  the  hydrostatic  effect  of 
gravity  will  be  found  between  the  two  readings.  In  comparison  with 
the  high  pressure  normally  existing  in  the  arteries,  this  difference  is, 
however,  of  little  significance.  On  the  other  hand,  in  the  veins,  where 
the  average  pressure  is  low,  gravity  would  cause  serious  embarrassment 


THE    CONTROL    OF    THE    CIRCULATION  249 


to  the  circulation  of  blood  were  it  not  for  the  yfl]Yefi  ftT)^  *kft  forces 
which  move  the  blood  beyond  them  (page  214). 

In  erect  animals  the  part  of  the  circulation  in  which  blood  might  stag- 
nate as  a  result  of  gravity  is  the  splanchnic  area.  Were  such  stagna- 
tion to  occur,  the  blood  would  not  be  returned  to  the  right  heart,  so 
that  the  arteries  would  not  receive  sufficient  blood  to  maintain  an  ade- 
quate circulation,  particularly  in  the  vessels  of  the  brain. 

Simple  experiments  devised  by  Leonard  Hill19' 2S  illustrate  these  prin- 
ciples. When  a  snake,  for  example,  is  pinned  out  on  a  long  piece  of 
wood  and  an  opening  made  opposite  the  heart,  this  organ  can  be  seen 
to  fill  adequately  with  blood  as  long  as  the  animal  is  maintained  in  the 
horizontal  position.  When  placed  vertically,  however,  the  heart  be- 
comes bloodless.  If  now  the  tail  end  of  the  animal  is  placed  in  a  cylinder 
of  water  so  as  to  overcome  the  effect  of  gravity,  the  heart  will  be  seen 


Fig.    76. — Aortic    blood    pressure    showing    the    effect    of    posture:      A,    vertical,    head-up;    B,    hori- 
zontal;   C,    vertical,    head-down;    D,    horizontal.       (L.H.) 

to  fill  again  with  blood.  Evidently  in  such  an  animal  there  is  no  mechan- 
ism to  compensate  for  gravity. 

If  a  domestic  rabbit  with  a  large  pendulous  abdomen  is  held  in  the 
vertical  tail-down  position,  stagnation  of  blood  in  the  splanchnic  ves- 
sels occurs  to  such  an  extent  that  in  from  fifteen  to  twenty  minutes  the 
animal  dies  from  cerebral  anemia.  If  an  abdominal  binder  is  first  of  all 
applied,  the  vertical  position  will  not  have  the  same  consequences.  This 
experiment  illustrates  clearly  the  possible  evil  effects  that  gravity  may 
produce  in  animals  in  which  no  mechanism  exists  to  compensate  for  it. 

Placing  an  animal  such  as  a  dog  under  light  ether  anesthesia  in  the 
vertical  tail-down  position  produces  an  immediate  fall  in  arterial  blood 


250 


THE    CIRCULATION    OF    THE    BLOOD 


pressure,  as  shown  in  the  tracing  (Fig.  76),  followed  by  a  certain  de- 
gree of  compensation  even  while  the  animal  is  still  in  the  erect  position. 
The  extent  to  which  this  compensation  occurs  varies  with  the  depth  of 
the  anesthesia.  If  the  experiment  is  repeated  after  administering  a  large 
dose  of  chloroform,  not  only  will  the  initial  fall  be  much  greater,  but 
subsequent  compensation  will  be  practically  absent.  The  application  of 
these  facts  in  the  operating  room  will  be  self-evident. 

Leonard  Hill  has  shown  that  three  factors  are  involved  in  the  com- 
pensating mechanism:   (1)   the  tonicity  of  the  abdominal  musculature; 


Fig.  77. — Tracing  to  show  the  effect  of  gravity  on  the  arterial  blood  pressure.  At  A,  the 
animal  was  placed  in  the  vertical  position;  at  B,  the  abdomen  was  compressed;  at  C,  a  crucial 
incision  was  made  in  the  abdomen;  at  D,  the  pleural  cavity  was  opened;  at  F,  the  animal  was 
returned  to  the  horizontal  position.  (From  Leonard  Hill.) 


Fig.  78. — The  effect  of  gravity  on  the  aortic  pressure  after  division  of  the  spinal  cord  in  the 
upper  dorsal  region.  By  placing  the  animal  in  the  vertical  feet-down  posture,  the  pressure  fell 
almost  to  zero,  but  on  returning  it  to  the  horizontal  posture,  the  circulation  was  restored.  (From 
Leonard  Hill.) 

(2)  the  tone  of  the  splanchnic  blood  vessels;  (3)  the  pumping  action  of 
the  respiratory  movements.  The  importance  of  the  first-mentioned  fac- 
tor can  be  readily  shown  by  making  a  crucial  incision  of  the  abdom- 
inal walls  in  an  animal  in  the  erect  position  (Fig.  77),  and  that  of 
the  second  factor  by  cutting  the  great  splanchnic  nerves,  or  the  spinal 
cord.  After  such  an  operation,  even  while  in  the  horizontal  position,  as 
we  have  seen,  the  blood  pressure  falls  to  a  considerable  extent.  If  the 


THE   CONTROL   OP   THE   CIRCULATION  251 

animal  is  now  placed  in  the  vertical  tail-down  position,  however,  it  falls 
to  the  zero  line  and  the  animal  soon  dies  (Fig.  78).  The  influence  of  the 
third  factor  is  not  so  great  as  of  the  other  two,  but  can  be  shown  by  the 
increased  respiratory  activity  which  is  likely  to  develop  in  the  vertical 
tail-down  position,  the  anemic  condition  of  the  respiratory  center  being 
no  doubt  the  cause  of  the  increased  respiration. 

THE  CAPILLARY  CIRCULATION 

It  has  been  the  custom  to  assume  that  the  walls  of  the  capillaries  are 
incapable  of  constricting  or  dilating  independently  of  changes  of  pressure 
in  the  blood  circulating  in  them.  According  to  this  view  the  magnitude 
of  the  capillary  circulation,  the  pumping  action  of  the  heart  being  constant, 
depends  primarily  on  the  state  of  contraction  or  dilatation  of  the  arterioles 
from  which  they  spring  and  secondarily,  on  the  venous  pressure;  when 
the  arterioles  are  dilated,  the  pressure  will  rise  in  the  capillaries,  causing 
them  to  become  passively  dilated,  and  when  the  arterioles  are  constricted, 
the  capillaries  in  virtue  of  their  elasticity  will  contract  again. 

Krogh57  has  recently  brought  forward  unassailable  evidence  to  show  that 
this  conception  is  wrong.  He  has  shown  not  only  that  the  capillaries 
possess  powers  of  constricting  and  dilating  quite  independently  of  the 
arterioles,  but  also  that  their  caliber  when  the  tissue  they  supply  is  at 
rest  is  very  much  less  than  when  the  tissue  is  active,  indicating  therefore 
that  they  exist  in  a  condition  of  constrictor  tone.  These  discoveries  were 
made  by  examining,  chiefly  by  reflected  light,  with  the  binocular 
microscope  thin  muscles  in  living  frogs  and  guinea  pigs  (under  urethane), 
or  by  injecting  intravenously  a  solution  of  india  ink,  then  killing  the 
animals,  and  examining  either  fresh  or  fixed  tissues  by  the  microscope  to 
determine  into  which  capillaries  the  black  particles  of  the  ink  had  pene- 
trated. In  resting  muscles  it  was  found  that  relatively  few  capillaries  are 
visible,  these  being  however  evenly  distributed,  and  forming  an  elongated 
mesh-work  along  the  fibers.  When  the  muscles  contract  (either  spontane- 
ously, or  as  a  result  of  artificial  stimulation)  many  more  capillaries  spring 
into  view,  and  when  the  contraction  is  over  they  disappear  again.  This 
microscopic  evidence  of  extreme  variability  in  open  capillaries  was  con- 
firmed by  noting  the  color  of  the  muscles  after  injections  of  india  ink; 
those  that  had  been  resting  before  the  animal  was  killed  being  stained  only 
a  faint  grey,  whereas  those  that  had  been  active  were  almost  black. 

Another  fact  of  very  great  importance,  which  was  revealed  by  these  in- 
vestigations, was  that  the  blood  corpuscles  often  crowd  themselves  through 
capillaries  having  diameters  that  are  much  less  than  those  of  the  corpus- 
cles. The  average  diameter  of  the  capillaries  in  the  resting  muscles  of 
fm<rs  is  4.5  /*,  whereas  that  of  the  corpuscles  is  22  //,  (long)  and  15  n 


252 


THE    CIRCULATION   OF   THE   BLOOD 


(broad)  ;  in  the  muscles  of  guinea  pigs  the  diameter  of  the  capillaries  is 
3.5  p,  that  of  the  corpuscles  being  7.2  /*.  In  order  that  they  may  pass,  the 
corpuscles  become  folded,  and  the  capillaries  become  deformed  in  shape, 
as  is  shown  in  Fig.  79,  which  depicts  several  capillaries  from  the  abdom- 
inal wall  of  the  guinea  pig,  after  injecting  india  ink.  The  black  particles 
between  the  corpuscles  indicate  that  these  have  been  moving  along  during 
the  life  of  the  animal.  It  will  be  observed  that  the  corpuscles,  in  order  to 
force  their  way  through  the  capillaries,  become  sausage-shaped  as  well  as 
being  rolled  in.  It  could  be  observed  in  living  preparations  in  the  frog 
that  the  bloodflow  is  retarded  when  the  deformation  of  the  corpuscles  is 
great.  These  facts  have  naturally  many  most  important  applications. 

The  great  variability  in  the  number  of  patulous  capillaries  according  to 
the  activity  of  the  tissues  (muscles)  shows  that  the  oxygen  supply  must  be- 


n 


.  7o  L> 


Fig.  79. — Capillaries  from  abdominal  wall  of  guinea  pigs  after  injection  of  india  ink.  The 
black  particles  are  absent  from  the  corpuscles  which  will  be  seen  to  be  distorted  in  shape.  Note 
that  in  a  transverse  section  of  a  capillary  the  corpuscles  may  become  folded.  (Krogh.) 

come  altered  to  meet  the  varying  demands.  Indeed  Krogh  has  shown  by 
mathematical  calculations  based  on:  (1)  the  depth  of  actual  muscle  tissue 
which  each  capillary  supplies,  (2)  the  rate  of  oxygen  consumption  and 
(3)  the  diffusion  rate  of  oxygen  through  tissues  that  the  oxygen  pressure 
necessary  to  supply  the  muscle  fibers  is  remarkably  small,  even  during 
the  heaviest  muscular  work.  This  means  that  the  oxygen  pressure  in  the 
muscular  tissue  must  at  all  times  be  practically  the  same  as  that  of  the 
venous  blood,  and  that  the  call  for  oxygen  by  the  tissues  is  readily  met  by 
diffusion  from  the  capillary  blood.  That  a  measurable  pressure  of  oxygen 
in  the  tissues  is  difficult  to  demonstrate  does  not  contradict  this  conclusion 


THE    CONTROL   OP    THE   CIRCULATION  253 

because  the  oxygen  is  so  rapidly  used  up.  In  lirine,  where  this  is  not  the 
case,  the  pressure  of  02  is  about  the  same  as  in  the  venous  blood,  and  when 
a  neutral  gas  is  placed  in  the  pleural  or  peritoneal  cavities,  it  ultimately 
becomes  mixed  with  oxygen  up  to  3-4  per  cent.  (Tobiesen  cf.  Krogh.) 

Still  more  definite  proofs  of  the  ability  of  capillaries  to  dilate  inde- 
pendently of  changes  in  the  corresponding  arterioles  have  been  obtained 
by  Krogh  and  by  Hooker.co  Krogh  found  that  irritation  of  the  ventral 
aspect  of  the  frog's  tongue,  as  by  punctate  stimulation  with  a  hair,  caused, 
after  a  brief  latent  period,  a  marked  vasodilatation  and  increased  blood- 
flow.  This  dilatation  was  seen  by  the  microscope  sometimes  to  affect  both 
the  capillaries  and  small  arterioles  over  a  considerable  area.  That  the 
former  had  been  actively  dilated,  and  not  merely  passively  distended  by 
greater  inflow  of  blood  from  the  arterioles,  was  shown  by  the  fact  that 
sometimes  it  was  possible  to  restrict  the  irritation  so  that  only  a  capillary, 
or  even  a  short  piece  of  one,  dilated.  In  such  cases  the  dilatation  often 
started  at  the  venous  end  of  the  capillary  and  spread  towards  the  arterial 
end.  This  made  it  appear  as  if  the  blood  were  flowing  towards  the  heart. 
After  clamping  the  lingual  artery  so  as  to  slow  down  the  circulation,  irri- 
tation caused  the  capillaries  to  dilate  without  any  increased  flow  of  blood 
through  them,  this  occurring,  however,  immediately  the  clamp  was  re- 
moved. Urethane  or  epinephrine,  applied  locally,  dilated  the  capillaries, 
but  not  the  arterioles. 

After  cocainization  or  degeneration  of  the  nerves,  the  dilatation  in- 
stead of  being  diffuse  was  then  more  localized;  merely  cutting  the 
nerves,  however,  had  no  effect.  This  indicates  that  a  local  nerve  axon 
reflex,  similar  to  that  described  on  page  898,  is  concerned  in  the  spread. 
There  must  be  sensory  nerve  fibers  on  the  walls  of  the  smallest  vessels 
and  the  impulses  which  are  set  up  by  their  stimulation  must  travel  up 
the  nerve  to  a  collateral,  down  which  they  then  pass  to  neighboring 
parts  of  the  vessel  as  dilator  impulses.  Hooker  has  also  shown  that 
stimulation  of  the  cervical  sympathetic  in  the  cat  causes  the  capillaries 
around  the  hair  follicles  of  the  ear  to  exhibit  movements  which  are  inde- 
pendent of  changes  in  the  arterioles.  These  discoveries  explain  the 
association  of  local  hyperemia  with  cyanosis  (the  blood  is  flow- 
ing so  slowly  in  dilated  capillaries  that  its  oxygen  is  used  up), 
the  pathogenesis  of  shock  (page  307),  the  initial  stages  of  inflamma- 
tion, and  it  is  altogether  likely  that  they  will  before  long  lead  us  to  an 
explanation  of  the  causes  for  clinical  hypertension.  It  is  possible  that 
examination  of  the  capillary  circulation  in  the  skin  at  the  base  of  the 
finger  nails  by  Lombard's  method62*  would  be  of  considerable  value  in 
the  differentiation  of  cases  of  hypertension. 

*A  drop  of  glycerine  is  placed  on  the  skin  at  the  base  of  the  nail,  with  the  hand  firmly 
supported  on  a  rest,  and  a  strong  light  thrown  on  it.  An  objective  magnifying  up  to  35  times 
is  then  focussed  until  the  capillary  loops  are  seen. 


CHAPTER  XXIX 

PECULIARITIES  OF  BLOOD  SUPPLY  IN  CERTAIN  VISCERA 

Up  to  the  present  we  have  been  considering  the  circulation  of  the  blood 
from  a  general  point  of  view.  There  are  certain  organs  and  tissues,  how- 
ever, in  which  the  general  mechanism  is  altered  in  order  to  meet  pecu- 
liar requirements  of  blood  supply.  Thus,  it  is  evident  that  the  brain, 
incased  as  it  is  in  the  rigid  cranium,  will  be  unable  to  contract  and 
expand  as  a  result  of  vasoconstriction  or  vasodilation.  On  the  other 
hand,  we  know  that  the  blood  supply  to  this  organ  does  vary  con- 
siderably from  time  to  time.  What  is  the  nature  of  the  mechanism  by 
which  such  changes  are  brought  about?  In  the  case  of  the  liver  the  cir- 
culation is  peculiar  on  account  of  the  fact  that  blood  is  carried  to  the 
organ  by  two  vessels,  in  one  of  which  it  is  supplied  under  high  pressure 
and  in  the  other,  under  low  pressure.  We  must  investigate  the  rela- 
tionship of  these  two  sources  of  blood  supply.  The  circulation  through 
the  coronary  and  pulmonary  vessels  must  likewise  receive  special  atten- 
tion on  account  of  the  highly  specialized  functions  of  these  organs. 


THE  CIRCULATION  IN  THE  BRAIN 

Anatomical  Peculiarities 

Serious  curtailment  of  the  blood  supply  to  the  brain  is  guarded  against 
by  the  existence  of  the  circle  of  Willis.  Besides  the  four  main  arteries— 
the  vertebrals  and  the  two  carotids — the  spinal  arteries  contribute  to 
the  blood  supply  of  the  circle,  and  consequently  in  certain  animals,  such 
as  the  dog,  the  four  main  arteries  may  be  ligated  without  causing  death. 
In  man,  however,  ligation  of  both  carotids  is  usually  fatal.  The  free 
anastomosis  displayed  in  the  circle  of  Willis  is  not  maintained  in  the 
case  of  the  arteries  which  run  from  it  to  supply  the  brain  structure.  On 
the  contrary,  these  vessels  are  more  or  less  terminal  in  character;  that 
is  to  say,  the  capillary  systems  of  the  different  vessels  do  not  freely  anasto- 
mose, so  that  obstruction  of  one  vessel,  or  an  important  branch,  is  followed 
by  death  of  the  supplied  area.  The  vessels  which  go  to  the  pia  mater,  how- 
ever, break  up  into  numerous  smaller  branches,  which  freely  anastomose 
before  entering  the  brain  tissue. 

254 


PECULIARITIES   OF   BLOOD   SUPPLY   IN    CERTAIN   VISCERA  255 

The  venous  blood  is  collected  by  the  small,  very  thin-walled  and  valve- 
less  cerebral  veins.  These  run  together  to  form  larger  veins  dis- 
charging into  the  sinuses,  the  openings  into  which  are  kept  patent  by 
the  arrangement  of  dura  mater  around  the  orifices.  The  sinuses  exist 
between  the  dura  and  skull  and  are  so  constructed  that  they  can  not 
be  compressed,  particularly  those  at  the  base  of  the  brain.  From  them 
the  blood  is  conveyed  mainly  to  the  internal  jugular  vein,  some  of  it 
however  escaping  by  the  anastomoses  existing  between  the  cavernous 
sinus  and  the  opththalmic  veins,  and  by  the  venous  plexus  of  the  spinal 
cord.  The  most  striking  peculiarities  of  the  veins  are  their  patulous  con- 
dition and  the  absence  of  valves,  so  that  any  change  in  the  blood  pres- 
sure in  the  internal  jugular  vein  must  be  immediately  reflected  in  that  of 
the  venous  sinuses.  This  explains  why  compression  of  the  abdomen 
causes  venous  blood  to  flow  from  an  opening  made  in  the  longitudinal 
sinus. 

In  considering  the  cerebral  circulation,  another  factor  that  must  be 
borne  in  mind  is  the  presence  of  cerebrospinal  fluid.  This  is  contained 
in  the  subarachnoid  spaces  of  the  brain  and  spinal  cord,  these  spaces,  in 
the  case  of  the  brain,  being  often  considerably  enlarged  to  form  the 
cisternae.  The  cerebrospinal  fluid  is  also  present  in  the  ventricles  of  the 
brain,  which  it  will  be  remembered  communicate  with  the  subarachnoid 
spaces  through  the  foramen  of  Magendie,  etc.  There  is  free  communication 
between  the  cerebral  and  spinal  portions  of  the  fluid,  as  is  evidenced  by 
the  fact  that  blood  clots  appear  in  the  spinal  fluid  (collected  by  spinal 
puncture)  when  there  is  hemorrhage  into  the  ventricles  of  the  brain.  It  is 
unlikely  that  the  cerebrospinal  fluid  is  of  much  importance  in  connection 
with  the  control  of  the  blood  supply  to  the  brain  tissue.  It  may  be  merely 
a  lubricating  fluid;  at  least  it  is  so  small  in  amount  (60  to  80  c.c.  in  man) 
as  to  be  apparently  of  little  value  in  bringing  about  an  alteration  in  brain 
volume.  Although  normally  so  scanty,  its  secretion  can  become  re- 
markably stimulated  under  certain  conditions  as  in  fractures  of  the  base 
of  the  skull.  Under  these  conditions  in  man,  it  may  drain  away  at 
the  rate  of  about  J3QO  c.c.  a  day  or  more.  In  cerebrospinal  rhinorrhea  as 
much  as  700  c.c.  of  cerebrospinal  fluid  may  run  away  in  a  day. 

The  fluid  is  apparently  produced  in  the  choroid  plexus,  for  when  the 
pathways  by  which  the  ventricles  communicate  with  the  subarachnoid 
space  are  obstructed  it  collects  in  the  ventricles,  producing  internal  hy- 
drocephalus.  Under  certain  conditions  absorption  is  also  very  rapid,  as 
shown  experimentally  by  the  rate  with  which  physiological  saline  is 
absorbed  when  it  is  injected  into  the  subarachnoid  space.  This  absorp- 
tion is  believed  to  occur  through  various  pathways,  the  most  important 
of  which  is,  directly  into  the  blood  stream,  through  the  capillaries  lining 


256  THE    CIRCULATION   OF    THE   BLOOD 

the  subarachnoid  spaces  of  the  brain  and  cord.  There  is  no  evidence  to 
support  the  view  that  absorption  occurs  through  the  Pacchionian  bodies. 
A  smaller  degree  of  absorption  occurs  by  way  of  the  lymphatics. 

The  cerebrospinal  fluid  is  believed  to  undergo  a  slow  circulation  from 
the  ventricles  through  the  foramen  of  Magendie  into  the  subarachnoid 
spaces  of  the  spinal  cord  down  which  it  travels  on  the  posterior  aspect, 
and  then  ascends  on  the  anterior  aspect  where  the  greater  part  of  its  ab- 
sorption occurs.  The  biochemical  properties  of  this  important  fluid  will 
be  found  described  elsewhere  (page  121).  Important  papers  on  its  pro- 
duction are  those  of  Becht63  who  believes  that  this  depends  solely  on 
alterations  in  venous  and  arterial  pressure  in  the  skull  and  that  none 
is  formed  by  secretion. 

Physical  Conditions  of  the  Intracranial  Circulation 

Considered  from  a  physical  standpoint  the  circulation  through  the 
brain  has  been  recognized  for  long  to  be  unique  in  comparison  with  that 
of  any  other  organ  or  tissue  in  the  body  with  the  exception  of  the  bone 
marrow.  Encased  in  the  rigid  cranium,  the  volume  of  the  brain  can  not, 
like  that  of  other  vascular  areas,  expand  and  contract  in  proportion  to 
changes  in  the  blood  supply;  neither  can  the  caliber  of  its  blood  vessels 
become  altered,  unless  some  special  mechanism  may  exist  whereby  a  part 
of  the  crainal  contents  is  quickly  expelled  from  and  aspirated  into  the 
rigid  case.  In  a  general  way,  the  physical  conditions  of  the  intracra- 
nial  circulation  are  similar  to  those  existing  in  a  flask  full  of  water  and  pro- 
vided with  a  thin-walled  rubber  tube  suspended  in  the  water  with  its  free 
ends  connected  with  glass  tubes  passing  through  the  stopper  of  the  flask. 
If  fluid  be  made  to  circulate  through  the  tubing,  no  change  in  the  caliber 
can  be  produced  by  altering  the  pressure  of  inflow;  but  the  rate  of  dis- 
charge from  the  other  end  of  the  tube  will  be  proportionate  to  the  pres- 
sure. Although  the  tubing  itself  is  readily  distensible  and  elastic,  these 
properties  are  entirely  annulled  by  the  incompressible  fluid  in  which 
the  tube  is  suspended. 

If  any  expansion  or  contraction  of  the  tubing  as  a  whole  is  to  occur, 
provision  must  be  made  for  changes  in  the  volume  of  fluid  in  the  flask, 
by  inserting  in  the  stopper  a  third  tube  connected  with  an  overflow 
flask,  and  in  applying  this  second  model  to  represent  the  circulatory 
conditions  as  they  exist  in  the  brain,  the  question  arises  as  to  whether 
the  cerebrospinal  fluid  which  lies  in  the  large  subarachnoid  spaces  at 
the  base  of  the  brain  and  in  the  ventricles,  by  communicating  through 
the  foramen  of  Magendie  with  the  spaces  surrounding  the  spinal  cord, 
may  not  be  capable  of  functioning  as  the  overflow  fluid.  This  is  at 
least  conceivable,  especially  when  one  bears  in  mind  that  some  outflow 


PECULIARITIES   OF    BLOOD    SUPPLY   IN    CERTAIN   VISCERA  257 

is  also  possible  along  the  sheaths  of  certain  of  the  cranial  nerves.  He- 
cent  investigation  has,  however,  clearly  demonstrated  that  under  nor- 
mal conditions  the  amount  of  cerebrospinal  fluid  is  too  limited  to  make 
it  of  any  significance  in  this  connection.  As  explained  on  page  255  the 
main  function  of  the  fluid  is  to  equalize  the  pressure  between  the  brain 
and  the  cord. 

Although  it  is  therefore  improbable  that  the  vessels  as  a  whole  could 
expand  or  contract,  it  is  still  possible  that  some  provision  might  exist 
by  which  extra  room  could  be  made  to  allow  of  localized  dilatation  of 
certain  parts  of  the  vessels.  The  veins,  for  example,  might  contract 
in  proportion  as  the  arteries  dilated  and  the  possibility  becomes  all  the 
more  likely  when  we  consider  that  because  of  the  great  capacity  of  the 
cerebral  veins,  their  lumina  might  be  considerably  constricted  without 
any  serious  obstruction  being  offered  to  the  bloodflow  through  them. 
Such  a  reciprocal  dilatation  and  constriction  of  the  proximal  and  dis- 
tal halves  of  a  thin-walled  rubber  tube  suspended  in  water  in  a  closed 
flask  can  be  demonstrated  provided  some  resistance  be  inserted  between 
the  two  halves.  This  resistance  would  be  represented  in  the  intracra- 
nial  vessels  by  the  capillary  area.  It  is  impossible  to  say  to  what  extent 
this  reciprocal  mechanism  between  arteries  and  veins  may  prevail,  but 
in  any  case  it  can  not  well  extend  beyond  the  cerebral  veins  to  the 
sinuses,  since  these  are  partly  embedded  in  the  cranium  itself  and  are 
protected  by  relatively  thick  membranes  on  their  free  sides.  The  mech- 
anism may  be  employed  for  permitting  the  arteries  of  a  local  area  to 
expand,  but  it  can  not  obtain  over  any  large  area,  since  otherwise  the 
total  outflow  of  blood  from  the  sinuses  through  the  jugular  foramen 
would  be  curtailed,  which  we  know  to  be  contrary  to  what  actually  oc- 
curs when  the  arterial  pressure  is  raised,  and  which  moreover  would  be 
highly  detrimental,  since  it  would  cause  self-strangulation  of  the  intra- 
cranial  bloodflow. 

These  physical  considerations  lead  us  to  expect  that  there  can  not  be 
any  dilatation  or  constriction  in  the  intracranial  vessels  which  is  com- 
parable with  that  which  occurs  in  other  vascular  areas,  although  it  may 
take  place  to  a  degree  which  is  limited  by  the  extent  to  which  the  cere- 
bral veins  can  be  passively  contracted  or  expanded  without  curtailment 
of  the  bloodflow.  Acting  to  this  extent,  the  dilatation  produced  in  the 
arteries  by  each  cardiac  systole  accounts  for  the  rise  in  pressure  which 
occurs  simultaneously  in  the  venous  sinuses  (as  measured  in  the  torcu- 
lar  Herophili),  but  it  is  unlikely  that  the  amount  of  blood  supplying  the 
brain  will  be  determined  by  local  dilatation  or  constriction  of  the  blood 
vessels,  as  is  the  case,  for  example,  in  a  gland  or  muscle.  Of  this  we 
are  certain,  that  the  total  volume  of  blood  within  the  brain  case  at  any 


258  THE   CIRCULATION   OF   THE   BLOOD 

given  moment  can  undergo  no  considerable  change.  Provision  for  more 
or  less  blood  must  therefore  be  afforded  by  changes  in  the  velocity  of 
now. 

Physiological  Conditions  of  the  Intracranial  Circulation 

We  must  now  proceed  to  test  these  hypotheses  by  physiological  ex- 
periment, for,  if  they  are  found  to  apply  to  the  intracranial  circulation, 
the  conclusion  becomes  inevitable  that  changes  in  the  total  blood  supply 
to  this,  the  most  important  organ  in  the  body,  are  dependent  not  on  any 
local  adjusting  mechanism  in  that  organ  itself,  but  upon  conditions  pre- 
vailing in  other  parts  of  the  body,  with  the  possibility  that  a  local  vaso- 
dilatation  may  be  provided  for  by  a  secondary  compression  of  neigh- 
boring venules,  or  perhaps  even  by  an  active  constriction  of  the  arteri- 
oles  of  neighboring  inactive  centers. 

The  questions  of  greatest  practical  importance  are,  therefore,  as  fol- 
lows: (1)  What  determines  the  intracranial  pressure,  and  how  does  this 
vary  during  each  heart  beat?  (2)  If  there  can  be  no  change  in  the  actual 
volume  of  blood  in  the  vessels  as  a  whole,  what  provision  is  made  to 
cause  changes  in  blood  supply  with  varying  degrees  of  activity  of  the 
brain,  and  how  are  these  changes  brought  about?  (3)  Is  it  possible  with- 
out change  in  the  total  volume  of  blood  in  the  brain  for  certain  vascular 
areas  to  expand  at  the  expense  of  others  that  correspondingly  constrict? 

The  Pulsations  of  the  Brain  and  the  Cause  of  Intracranial  Pressure.— 
Examination  either  of  the  fontanelles  in  an  infant  or  of  the  surface  of 
the  brain  exposed  by  trephining  shows  distinct  pulsations,  but  this  does 
not  prove  that  similar  pulsations  occur  in  the  intact  brain,  for  the  ab- 
se.nce  of  a  part  of  the  cranial  wall  might  be  responsible  for  the  pulsa- 
tion. The  presence  or  absence  of  pulsation  must  be  sought  for  in  the 
still  rigid  brain  case.  This  has  been  done  by  closing  a  trephine  hole  by 
a  glass  window  through  which  the  cranial  contents  can  be  seen  when 
strong  illumination  is  used :  pulsations  of  the  vessels  are  clearly  visible. 
To  determine  the  exact  relationships  of  the  pulsations,  the  trephine  hole 
is  connected  with  a  delicate  recording  tambour  by  screwing  into  it  a 
brass  tube  closed  at  its  inner  end  by  a  thin  rubber  membrane.  It  has 
been  found  that  the  arteries  expand  somewhat  with  each  cardiac  sys- 
tole, and  that  there  are  further  expansions  with  each  expiration,  but  not 
with  inspiration,  as  is  the  case  in  other  vascular  areas.  The  room  for 
the  expansions  is  no  doubt  provided  mainly  by  compression  of  the 
cerebral  veins,  thus  causing  the  blood  within  them  to  exhibit  corres- 
ponding waves  of  pressure.  The  reason  why  expiration  and  not  in- 
spiration causes  the  increase  in  volume  is  that  there  are  no  efficient  valves 
between  the  right  side  of  the  heart  and  the  cerebral  veins.  This  allows 


PECULIARITIES   OF   BLOOD   SUPPLY   IN    CERTAIN   VISCERA  259 

the  expiratory  rise  in  venous  pressure  which  is  well  known  to  occur  in 
the  former  to  be  directly  transmitted  to  the  brain. 

This  brings  us  to  the  second  part  of  our  first  question :  What  determines 
the  intracranial  pressure  ?  To  answer  it  we  must  know  something  of  the 
method  by  which  the  pressure  is  measured.  This  has  been  most  successfully 
done  by  Leonard  Hill,19  who  devised  an  instrument  called  the  cerebral 
pressure  gauge,  consisting  of  a  brass  tube  closed  at  one  end  by  rubber 
membrane  and  screwed  into  a  trephine  hole.  The  outer  end  of  the  tube 
is  joined  to  a  narrow  glass  tube  connected  with  a  pressure  bottle.  The 
whole  system  is  filled  with  fluid  except  for  a  minute  bubble  of  air  in  the 
narrow  glass  tube.  Any  changes  in  pressure  in  the  brain  cause  correspond- 
ing movements  of  the  bubble,  and  the  magnitude  of  the  change  is  meas- 
ured by  readjusting  the  pressure  bottle  so  as  to  bring  the  bubble  back  to 
its  original  level.  It  has  been  found  that  the  pressure  may  vary  from 
zero  to  50  mm.  Hg.  (as  in  strychnine  convulsions),  and  that  these  variations 
depend  entirely  on  circulatory  conditions,  there  being  no  compensatory 
mechanism  by  which  the  pressure  is  kept  constant.  The  average  pressure 
under  physiological  conditions  is  100-130  mm.  H20. 

The  intracranial  pressure  varies  directly  with  the  venous  pressure  within 
the  skull,  and  it  passively  follows  changes  in  the  pressures  in  the  arteries 
and  veins  of  the  systemic  circulation.  This  implies  that  the  efficiency  of 
the  cerebral  circulation  will  be  dependent  very  largely  upon  alterations 
in  the  capacity  of  the  splanchnic  area,  the  greatest  reservoir  of  blood  in 
the  body.  By  actual  measurement  it  has  also  been  found  that: 

1.  The  pressure  within  the  lateral  sinuses  of  the  brain  (measured  by 
connecting  a  tube  and  manometer  with  the  torcular  Herophili)   varies 
absolutely  with  the  intracranial  pressure.     It  therefore  exhibits  pulsa- 
tions which  mirror  precisely  those   observed  in  the  cerebral  pressure 
gauge. 

2.  Both  these  pressures  passively  follow  changes  in  the  pressure  in 
the  right  auricle.     They  also  run  more  or  less  parallel  with  changes  in 
arterial  pressure,  and  there  is  never  any  change  in  either  of  them  which 
can  not  be  traced  to  some  general  circulatory  condition. 

A  few  of  the  many  experiments  performed  by  Leonard  Hill  and  others  will  serve 
to  prove  these  far-reaching  conclusions: 

1.  In  asphyxia  caused  by  cessation  of  the  respiratory  movements  in  a  curarized 
animal,  the  cerebral  venous  pressure  at  first  falls  with  the  fall  in  systemic  pressure 
and  then  rises  as  the  arterial  hypertension   sets  in.     In  the  last   stage,   however,   al- 
though  the   arterial   pressure   is   quickly   falling,   the   venous   pressure   rises   and   with 
it  the  cerebral  venous  pressure.     During  vagus  inhibition  the  fall  in  arterial  pressure  is 
so  marked  that  the  intracranial  pressures  fall  at  first  and  only  rise  later,  correspond- 
ing to  the  rise  in  venous  pressure  (Fig  80). 

2.  During  administration  of  ether,  alterations  in  cerebral  pressure  become  marked 
only  when  there   is  extensive  muscular  movement   or   hyperpnea.     Chloroform,   on  the 


260 


THE    CIRCULATION   OF   THE   BLOOD 


other  hand,  by  acting  more  directly  on  the  heart  so  as  to  produce  a  fall  in  arterial  and 
a  rise  in  venous  pressure,  causes  at  first  a  decided  rise  in  cerebral  pressure  and  later 
a  fall  following  the  development  of  decided  arterial  hypotension. 

3.  Amyl  nitrite,  injected  into  the  jugular  vein,  causes  at  first  a  rise  in  venous 
pressure  and  therefore  in  cerebral  pressure.  Later,  however,  marked  arterial  hypo- 
tension develops,  and  the  intracranial  pressure  declines. 


Fig.  80. — To  show  simultaneous  records  of  the  arterial  blood  pressure  (A),  the  venous  pres- 
sure (B),  the  intracranial  pressure  (C),  the  pressure  in  the  venous  sinuses  (£>).  The  fall  in  ar- 
terial pressure  produced  by  stimulation  of  the  peripheral  end  of  the  vagus  will  be  found  to  cause 
a  fall  of  intracranial  and  cerebral  venous  pressure,  accompanying  that  in  the  arteries,  but  a  rise 
in  that  of  the  venous  system.  (From  Leonard  Hill.) 

4.  During  epileptic  fits  induced  experimentally  by  excitation  of  the  cortex,  there 
is  a  rise  in  venous  pressure  and  correspondingly  in  intracranial  pressure.  In  the  more 
violent  convulsions  produced  by  absinthe,  there  is  very  little  change  in  systemic  venous 
pressure  while  the  arterial  pressure  shows  extreme  variations,  with  which  the  intra- 
cranial pressure  runs  parallel.  With  adrenalin,  where  both  arterial  and  venous  sys- 
temic pressures  rise  enormously,  there  is  of  course  a  great  rise  in  intracranial  pressure 


PECULIARITIES   OF   BLOOD   SUPPLY   IN    CERTAIN   VISCERA  261 

and  there  is  never  any  local  change  in  the  latter  which  would  indicate  that  this  potent 
drug  had  locally  caused  these  vessels  to  constrict. 

5.  The  alterations  in  systemic  pressure  induced  by  the  operation  of  the  force  of 
gravity  and  coming  into  play  when  the  position  of  the  body  is  changed,  if  not  per- 
fectly compensated  for  by  constriction  of  the  splanchnic  area,  will  cause  correspond5 
ing  changes  in  the  intracranial  tensions.  Under  the  influence  of  gravity,  for  example, 
the  intracranial  and  the  intracranial-venous  pressures  may  fall  below  zero. 

The  comparatively  slight  amount  of  extra  room  which  can  be  provided  in  the 
cranial  cavity  by  compression  of  the  venules  and  capillaries  has  suggested  to  some 
writers  that  a  self -strangulation  of  bloodflow  might  occur  when  the  pressure  suddenly 
rises  in  the  basal  and  cerebral  arteries.  The  increased  pressure  would  be  transmitted 
undiminished  through  the  incompressible  brain  substance  to  the  thin-walled  vessels  and 
compress  them  because  of  the  lower  pressure  within.  This  is,  however,  impossible  for 
any  curtailment  in  the  bloodflow  through  the  venules  and  capillaries  could  only  be 
transitory,  since  the  compression  will  be  overcome  by  the  arrival  of  the  pressure  wave 
through  the  blood  stream  itself.  For  it  is  obvious  that  the  arterial  pressure  trans- 
mitted directly  must  be  greater  than  that  pressure  after  it  has  overcome  the  tension 
of  the  arterial  wall  and  is  transmitted  to  the  venules  through  the  brain  substance. 
Whenever  this  readjustment  has  occurred,  the  cerebral  vessels  become  expanded  to 
the  greatest  extent  possible  and  they  become  virtually  rigid  tubes  comparable  with 
the  rubber  tube  suspended  in  water  in  a  closed  flask,  as  in  the  schema  referred  to 
above. 

The  only  variation  in  intracranial  blood  supply  which  can  occur  is 
one  affecting  the  velocity  of  flow  or  if  you  prefer  the  term — the  mass 
movement  of  the  blood;  the  volume  can  not  change.  After  all,  however, 
that  is  what  is  necessary  to  meet  the  demands  for  more  blood,  and  the 
conceptions  which  have  been  formed  by  studies  on  expansible  vascular 
areas,  such  as  the  kidney  and  spleen,  that  increased  blood  supply  runs 
parallel  with  increased  volume,  do  not  apply. 

That  the  mass  movement  of  the  blood  in  the  cranium  increases  when 
the  arterial  pressure  rises  has  been  shown  by  direct  experiment.  Hill 
and  Nabarro  found  it  increased  from  two  to  six  times  during  the  con- 
vulsions produced  by  absinthe. 

Local  Readjustments  of  Blood  Supply  in  Different  Parts  of  the  Brain.— 
Limited  though  any  change  in  caliber  of  the  cerebral  arteries  can  be,  it 
is  nevertheless  sufficient  to  make  it  possible  that  local  variations  in  blood 
supply  might  occur  as  a  result  of  active  constriction  or  dilatation  of  the 
vessels.  Just  as  the  blood  supply  of  a  muscle  or  gland  may  be  varied 
independently  of  any  change  in  general  blood  pressure,  by  local  changes 
in  the  caliber  of  its  blood  vessels,  so  might  that  of  the  brain  be  varied, 
and  this  might  occur  to  a  limited  extent  for  the  supply  as  a  whole,  as 
by  constriction  of  the  circle  of  Willis,  or  to  a  greater  extent  in  one  or 
other  of  the  arteries  which  spring  from  the  circle.  By  the  latter  adjust- 
ment a  greater  blood  supply  might  be  directed  into  an  area  which  had 
become  especially  active,  the  flow  to  other  relatively  quiescent  areas 
being  meanwhile  somewhat  curtailed. 


262  THE    CIRCULATION   OF    THE   BLOOD 

Vasomotor  Nerves, — These  possibilities  raise  the  question  as  to  whether 
there  are  functionally  active  vasomotor  nerves  to  the  cerebral  vessels. 
Histologists  have  definitely  demonstrated  nerve  fibers  running  on  to  the 
cerebral  vessels,  especially  by  the  use  of  the  intra  vitam  methylene  blue 
method  of  staining  (Huber,  Hunter,  etc.),  but  this  does  not  of  course 
necessarily  indicate  that  the  fibers  normally  cause  the  arterial  walls  to 
expand  and  contract.  The  only  basis  upon  which  such  a  claim  could  be 
put  forth  is  an  actual  demonstration  of  changes  in  intracranial  blood- 
flow  occurring  independently  of  changes  in  systemic  arterial  or  venous 
pressures. 

Leonard  Hill  and  Bayliss,  and  later  Leonard  Hill  and  Macleod,20  have 
most  diligently  sought  for  such  evidence,  but  with  entirely  negative 
results.  Ee cords  were  taken  of  the  intracranial  pressure,  the  cerebral 
venous  pressure  and  the  pressure  in  the  circle  of  Willis  (by  a  cannula 
inserted  in  the  peripheral  end  of  the  internal  carotid  artery),  as  well 
as  the  arterial  and  venous  pressures  in  the  systemic  vessels  carotid  and 
jugular).  Since  any  vasomotor  fibers  must  presumably  be  derived  from 
the  vasomotor  centers,  and  since  these  fibers  must  gain  the  cerebral 
vessels  through  the  stellate  ganglion  and  ultimately  travel  into  the 
cranial  cavity  along  the  outer  coats  of  the  arteries,  the  above  pressures 
were  simultaneously  observed  before  and  during  electrical  stimulation 
at  these  places.  It  was  found  that  any  change  that  did  occur  could  in- 
variably be  attributed  to  changes  in  the  circulation  as  a  whole ;  there 
was  never  any  alteration  in  pressure  locally  in  the  brain  for  which  the 
occurrence  of  local  constriction  or  dilatation  of  the  vessels  had  to  be 
assumed. 

Other  observers  have  attempted  to  investigate  the  problem  by  meas- 
urement of  the  volume  of  blood  leaving  the  brain,  but  with  similarly 
negative  results. 

But  an  objection  can  be  raised  to  these  experiments  on  the  ground  that  there 
might  be  feebly  acting  vasomotor  influences,  the  effect  of  which  would  become  entirely 
masked  by  the  much  more  potent  influence  exerted  on  the  bloodflow  by  changes  in  the 
circulation  as  a  whole.  As  pointed  out  by  Wiggers,  the  only  way  by  which  local 
changes  in  the  bloodflow  through  the  intracranial  vessels  can  be  expected  to  reveal 
themselves  is  by  measuring  the  entire  outflow,  a  measurement  which,  however,  it  is  im- 
possible to  make  in  an  intact  animal  on  account  of  the  many  pathways  through  which 
the  venous  blood  can  leave  the  skull.  Measurement  of  the  outflow  by  one  of  them 
does  not  by  any  means  indicate  the  magnitude  of  total  outflow.  To  overcome  these 
difficulties,  Wiggers  proceeded  to  measure  the  outflow  from  all  the  cranial  vessels  of 
oxygenated  Locke's  solution  perfused  into  the  cerebral  artries  under  constant  pressure. 
It  was  found  that  the  otherwise  constant  rate  of  outflow  became  decidedly  curtailed 
when  adrenalin  was  added  to  the  Locke's  solution.  If  we  assume  that  this  drug  acts 
only  on  arterial  muscle  having  functionally  active  vasoconstrictor  nerves,  then  the  result 
would  prove  the  presence  of  such  fibers  to  the  cerebral  vessels,  but  even  granted  this, 


PECULIARITIES   OF   BLOOD   SUPPLY   IN    CERTAIN   VISCERA  263 

the  result  does  not  warrant  the  conclusion  that,  under  normal  conditions  in  the  intact 
snimal,  such  fibers  display  any  activity.  Wiggers  does  not  claim  that  .his  results 
prove  that  a  local  vasomotor  mechanism  is  important,  but  thinks  that  "they  are  favor- 
able to  the  view  that  cerebral  vasoconstrictor  nerves  are  present.*' 

Intracranial  Pressure 

One  word  more  with  regard  to  what  is  known  as  intracranial  pressure, 
that  is,  the  pressure  in  the  space  between  the  skull  and  the  brain. 
Under  ordinary  conditions  it  must  be  equal  to  that  in  the  cerebral  capil- 
laries, and  may  be  measured  by  connecting  a  sensitive  manometer  with 
a  tube  screwed  into  the  cranium  as  described  above.  It  has  been  found 
to  vary  from  0  mm.  Hg  in  a  man  standing  erect  to  50-60  mm.  Hg  in  a 
dog  poisoned  by  strychnine.  It  becomes  increased,  not  only  by  com- 
pression of  the  veins  of  the  neck  and  by  an  increase  in  general  arterial 
pressure,  but  also  in  pathological  conditions,  such  as  hydrocephalus.  A 
new  growth  in  the  brain,  if  it  occupies  more  space  than  the  tissue  which 
is  destroyed,  exerts  pressure  on  all  parts  of  that  region  of  the  cranial 
cavity,  but  this  pressure  may  not  be  transmitted  equally  throughout 
the  cranial  contents,  for  the  falciform  ligaments  and  the  tentorium  sup- 
port a  part  of  it,  thus  directing  the  spread  of  pressure  along  certain 
pathways.  The  structures  at  the  base  of  the  brain,  the  optic  nerves, 
the  veins  of  Galen  and  the  Sylvian  aqueduct  are  most  affected  in  this 
way.  If  the  pressure  is  rapidly  applied,  however,  it  may  rise  through- 
out the  cranial  contents.  In  such  cases  the  pressure  is,  of  course,  cir- 
culatory in  origin,  since  immediately  after  death  from  cerebral  tumor 
the  intracranial  pressure  is  not  found  to  be  raised. 

The  major  symptoms  of  cerebral  compression  are  no  doubt  due  to 
anejnia  of  the  medulla  oblongata,  which  may  be  the  result  either  of 
pressure  applied  locally  in  the  bulbar  region,  where  the  presence  of  a 
very  small  foreign  body  or  only  trivial  tumor  formation  is  sufficient  to 
destroy  life,  or  of  pressure  transmitted  from  the  cerebral  cavity,  in 
which  case,  on  account  of  the  support  offered  by  the  tentorium,  a  much 
larger  growth  is  required  to  affect  the  medulla.  Internal  hydrocephalus 
produced  by  blocking  of  the  aqueduct  of  Sylvius  and  the  veins  of  Galen 
causes  the  greatest  rise  in  intracranial  tension,  and  may  affect  the  me- 
dulla, because  the  brain  is  driven  downwards  so  as  to  pinch  the  bulb 
against  the  occipital  bone.  It  must  be  emphasized  that  it  is  not  the 
pressure  per  se  that  causes  the  symptoms,  but  the  attendant  anemia, 
the  symptoms  of  acute  cerebral  anemia  and  of  compression  being  iden- 
tical (Leonard  Hill19).  To  relieve  the  compression,  trephining  is  the 
common  practice.  The  trephine  hole  should  be  as  large  and  as  near 
to  the  source  of  compression  (tumor,  etc.)  as  possible. 


264  THE   CIRCULATION   OF   THE   BLOOD 

CIRCULATION  THROUGH  THE  LUNGS 

The  pulmonary  or  lesser  circulation,  as  it  is  called,  is  quite  different 
from  the  systemic  circulation.  In  the  first  place,  the  pressure  in  the  pul- 
monary arteries  does  not  amount  to  more  than  about  20  mm.  Hg,  or 
about  one-sixth  of  that  of  the  systemic  arteries,  so  that  the  peripHeTat 
resistance  in  the  blood  vessels  of  the  lungs  is  much  less  than  that  of 
the  body  in  general.  This  lower  resistance  is  owing  partly  to  the  large 
diameter  of  the  arterioles  and  the  small  amount  of  muscular  fibers  in 
their  walls,  and  partly  to  the  fact  that  the  capillaries  are  held  con- 
stantly in  a  somewhat  dilated  condition  on  account  of  the  subatmos- 
pheric  pressure  in  the  thorax  (see  page  323). 

Another  peculiarity  of  the  pulmonary  circulation  is  that  the  caliber 
of  the  vessels  is  to  a  very  large  extent  dependent  upon  the  changes 
that  occur  in  the  iTit.rai.Tim^^jft_jrrfissLUJ!fi  with  eagli  inspiration  and  ex- 
piration. They  become  Dilated  on  inspiration  and  contracted  on  ex- 
piration. The  extent  to  which  these  respiratory  changes  affect  the 
amount  of  blood  contained  in  the  lungs,  is  very  considerable.  At  the 
height  of  inspiration  it  is  computed  that  a  little  more  than  eight  per 
cent  of  the  whole  blood  in  the  body  is  contained  in  the  lungs,  whereas 
on  expiration  it  diminishes  to  between  five  and  seven  per  cent. 

A  third  peculiarity  is  that  although  nerve  fibers  have  been  seen  run- 
ning to  the  wTalls  of  the  pulmonic  blood  vessels  no  changes  in  their  caliber 
can  be  demonstrated,  in  mammals,  by  stimulation  of  the  vagus  or  sympa- 
thetic. In  the  frog,  however,  constriction  of  the  pulmonary  artery  occurs 
when  the  vagus  is  stimulated  (Carlson  and  Luckhardt).  When  the  pul- 
monary vessels  are  perfused  and  the  outflow  measured,  a  diminution 
in  the  latter  is  said  to  occur  when  epinephrine  is  added  to  the  injection 
fluid.  In  short,  the  conclusion  which  we  must  draw  is  much  the  same  as 
that  for  the  blood  vessels  of  the  brain — namely,  that  although  we  must 
admit  that  a  vasomotor  supply  may  be  present,  yet  it  is  one  which  is  so 
feeble  that  it  is  "  readily  overpowered  by  changes  in  the  *  *  *  dis- 
charge of  the  right  heart  or  by  back  pressure  effects  from  the  systemic 
side  of  the  circulation"  (Wiggers57). 

When  the  venous  inflow  to  the  right  heart  is  increased,  the  discharge 

into  the  pulmonary  artery  correspondingly  increases,  in  obedience  to  the 

law  of  the  heart  (page  216)  and  a  certain  degree  of  congestion  of  the 

fpulmonary  vessels  results.    But  when  this  becomes  sufficient  to  cause  an 

[effect  on  the  blood  flow  in  the  pulmonary  veins,  the  left  ventricle  im- 

I  mediately  also  responds  by  augmented  output  so  that  the  engorgement 

I  in  the  pulmonary  circuit  does  not  become  excessive.    It  has  indeed  been 

I  thought  by  some  that  the  left  ventricle  is  so  much  more  sensitive  to 

changes  in  venous  inflow  than  is  the  right  that  it  succeeds  in  preventing 


PECULIARITIES  IN  BLOOD  SUPPLY  IN  CERTAIN  VISCERA         265 

any  pulmonary  congestion  under  the  above  conditions.  When  moderate 
or  slowly  increasing  resistance  is  offered  to  the  systolic  discharge  from 
the  left  ventricle,  no  back  pressure  effects  develop  in  the  pulmonary  veins 
(again  in  obedience  to  "the  law  of  the  heart"),  but  if  the  aortic  resistance 
becomes  so  high  that  the  ventricle  dilates  beyond  its  physiological  capac- 
ity and  fails  to  discharge  its  normal  volume,  then  pulmonary  venous  con- 
gestion develops.  But  it  may  not  be  till  much  later  that  the  "back 
pressure"  shows  itself  in  the  pulmonary  artery  and  this  has  been  ingeni- 
ously explained  as  being  due  to  a  diminution  of  the  capacity  of  the  right 
ventricle,  and  therefore  of  the  discharge  of  blood  from  it,  because  of 
bulging  of  the  intraventricular  septum.  When  the  above  pressure  differ- 
ences become  persistent,  and  especially  when  the  myocardium  begins  to 
break  down,  various  pathological  disturbances  of  the  circulation  (cardiac 
decompensation)  supervene  as  described  in  the  various  textbooks  on 
clinical  medicine. 

CIRCULATION  THROUGH  THE  LIVER 

The  liver  is  the  only  gland  in  the  body  receiving  both  venous  and 
arterial  blood,  the  former  being  supplied  to  it  at  a  very  low  pressure 
by  way  of  the  capacious  portal  vein,  and  the  latter  at  very  high  pressure 
by  the  strikingly  narrow  hepatic  artery.  Except  for  the  relatively 
small  amount  of  blood  which  is  supplied  to  the  walls  of  the  blood  vessels 
and  the  biliary  ducts,  none  of  the  hepatic  artery  blood  mixes  with  that  of 
the  portal  vein  until  the  vessels  enter  the  hepatic  lobules.  Beyond  this 
point  the  two  blood  streams  mix  and  the  combined  stream  is  drained 
away  by  the  sublobular  and  hepatic  veins. 

Methods  of  Investigation 

To  study  the  relative  importance  of  these  tAvo  sources  of  blood  supply,  and  also  to 
.nvestigate  th<?  manner  in  which  the  latter  is  controlled,  the  most  satisfactory  method 
has  consisted  in  measurements  of  changes  in  volume  flow  rather  than  in  those  of 
changes  in  pressure.  The  volume-flow  measurement  has  been  made  either  by  connecting 
stromuhrs  (page  207)  to  the  hepatic  artery  or  portal  vein,  or  by  measuring  the  out- 
flow of  blood  from  the  hepatic  vein  into  the  vena  cava,  first  with  both  inflow  vessels 
intact,  and  then  with  one  of  them  ligated.  An  objection  to  the  first  (the  stromuhr) 
method  is  the  possible  interference  with  bloodflow  or  blood  pressure  produced  by 
inserting  the  stromuhr  into  the  entering  vessels,  and  also  the  fact  that  simultaneous 
measurement  of  the  flow  in  both  vessels  cannot  be  made  satisfactorily. 

To  measure  the  outflow  from  the  hepatic  veins,  the  aorta  is  ligated  below  the  celiac 
axis  and  a  wide  cannula  is  inserted  into  the  central  end  of  the  vena  cava  below  the 
level  of  the  liver,  a  loose  thread  being  placed  around  this  vessel  just  above  the  dia- 
phragm. By  pulling  on  this  thread  the  vena  cava  becomes  obliterated,  and  the  blood 
from  the  hepatic  veins  is  therefore  diverted  into  the  cannula,  through  which  it  flows 
into  one  end  of  a  vessel  shaped  somewhat  like  a  sputum  cup  (the  receiver),  the  other 


266  THE    CIRCULATION   OF   THE   BLOOD 

end  being  connected  by  tubing  with  a  piston  recorder,  from  the  movement  of  which 
the  volume  of  blood  flowing  into  the  receiver  can  readily  be  computed.  To  measure 
the  flow  of  blood,  a  clip  on  the  tube  of  the  receiver  is  removed  at  the  same  moment 
that  the  thread  around  the  vena  cava  above  the  diaphragm  is  tightened,  and  when  the 
receiver  has  filled  with  blood,  this  thread  is  again  loosened  and  the  receiver  tilted  up 
so  that  the  blood  flows  at  low  pressure  back  into  the  circulation.  The  receiver  being 
of  known  capacity,  the  length  of  time  it  takes  the  blood  to  fill  it  as  determined  by  the 
piston  recorder,  furnishes  us  with  the  necessary  data  from  which  to  calculate  the  rate 
of  flow.  The  receiver  is  chosen  of  such  a  size  that  it  takes  only  a  few  seconds  to 
fill,  the  diversion  of  blood  into  it  not  causing  any  material  fall  in  arterial  pressure. 
The  observations  are  repeated  frequently. 

The  Magnitude  of  the  Flow 

By  the  use  of  these  methods  it  has  been  found  that  the  total  mass 
movement  of  blood  to  the  liver  of  the  dog  varies  between  1.46  and 
2.40  c.c.  per  second  for  100  grams  of  liver.  Considerable  changes  may 
occur  in  the  arterial  pressure  without  affecting  the  liver  flow.  When 
the  hepatic  artery  is  occluded,  the  flow  diminishes  by  about  30  per 
cent,  or  conversely,  when  the  portal  vein  is  obstructed  but  the  hepatic 
artery  left  intact,  by  about  60  per  cent,  indicating  that  about  one-third 
of  the  total  bloodflow  through  the  liver  is  contributed  by  the  hepatic 
artery  and  two-thirds  by  the  portal  vein.  Some  blood,  however,  gains 
the  liver  through  anastomotic  channels  between  it  and  the  diaphrag- 
matic veins. 

The  relative  supply  by  the  two  vessels  is  subject  to  various  condi- 
tions. That  through  the  hepatic  artery,  for  example,  may  be  very  con- 
siderably altered  on  account  of  vasoconstriction  in  this  vessel,  for  its 
walls  can  easily  be  shown  to  be  liberally  supplied  with  vasoconstrictor 
fibers  carried  by  the  hepatic  plexus.  This  can  be  demonstrated  by 
the  rise  in  blood  pressure  which  occurs  in  a  branch  of  the  hepatic  artery 
during  stimulation  of  the  plexus.  On  the  other  hand,  alterations  in  the 
bloodflow  in  the  portal  vein  can  not  be  brought  about  by  active  con- 
striction or  dilatation  of  the  intrahepatic  branches  of  this  vessel,  no 
active  vasomotor  fibers  having  been  demonstrated  by  stimulation  of 
the  hepatic  nerves,  although,  as  in  the  case  of  the  vessels  of  the  brain 
and  lung,  a  certain  amount  of  constriction  may  occur  under  the  influence 
of  epinephrine. 

The  bloodflow  through  the  portal  vein  is  dependent  on  changes  oc- 
curring at  either  end  of  the  distribution  of  the  vessel,  that  is,  changes 
occurring  in  the  liver  itself  or  in  the  intestine.  Of  these  factors  the  lat- 
ter is  no  doubt  the  more  important,  an  increase  not  only  in  portal  blood 
pressure  but  also  in  portal  bloodflow  being  readily  produced  by  dila- 
tation of  the  splanchnic  blood  vessels;  for  example,  as  the  result  of  sec- 
tion of  the  splanchnic  nerve.  Alterations  in  portal  bloodflow  brought 


PECULIARITIES    IN    BLOOD    SUPPLY    IN    CERTAIN   VISCERA  267 

about  by  changes  in  the  caliber  of  the  vessels  in  the  liver  itself  are 
partly  dependent  upon  changes  in  the  branches  of  the  hepatic  artery. 
Let  us  consider  briefly  how  this  may  be  brought  about.  At  the  point 
where  the  portal  and  hepatic  arteries  come  together — that  is,  at  the  in- 
trahepatic  capillaries — the  pressure  of  the  blood  in  them  must  become 
equal,  which  means  that  in  its  course  through  the  interlobular  connec- 
tive tissue,  the  branches  of  the  hepatic  artery  must  offer  much  resistance 
to  the  blood  flowing  through  them.  This  frictional  resistance  resides  in 
the  hepatic  arterioles,  and  since  these  are  richly  supplied  with  constric- 
tor nerves,  great  variation  in  hepatic  inflow  becomes  possible.  These 
changes  will  affect  the  degree  of  tension  of  the  interlobular  connective 
tissue  in  which  the  arterioles  lie.  In  this  tissue,  however,  also  lie  the 
thin-walled  branches  of  the  portal  vein.  When  therefore  the  tension 
of  this  tissue  becomes  greater,  as  a  result,  for  example,  of  vasodilatation 
in  the  hepatic  artery,  the  portal  vein  radicles  will  become  compressed 
and  the  bloodflow  along  them  impeded.  Conversely,  when  vasocon- 
striction  occurs  in  the  hepatic  arteries,  the  congestion  of  the  connective 
tissue  becomes  diminished,  the  veins  dilate,  and  the  blood  flows  through 
them  more  readily  (Macleod  and  R.  G.  Pearce21).  Experimental  evi- 
dence in  support  of  the  above  view  is  furnished  by  observing  the  out- 
flow of  blood  from  the  liver  before  and  during  stimulation  of  the  he- 
patic plexus.  The  first  effect  is  an  increase  in  the  outflow,  which  very 
soon  returns  to  its  original  amount,  even  though  the  stimulation  of  the 
plexus  is  kept  up  during  the  experiment.  This  return  to  the  normal 
flow  must  indicate  either  that  the  constriction  of  the  hepatic  artery  has 
not  been  maintained,  or  that  it  has  been  maintained  but  is  accompanied 
by  a  compensatory  increase  in  the  flow  through  the  portal  vein.  As  a  mat- 
ter of  fact,  we  know  from  other  experiments  that  the  hepatic  artery  remains 
constricted  as  long  as  the  hepatic  plexus  is  stimulated,  indicating  that  the 
congestion  of  the'  connective  tissue  in  which  the  venules  lie  has  become  re- 
duced to  such  an  extent,  as  a  result  of  the  constriction,  that  these  open  up 
and  permit  the  blood  to  flow  through  them  more  readily.  The  initial  in- 
crease in  outflow  immediately  following  upon  stimulation  of  the  hepatic 
plexus,  is  no  doubt  caused  by  the  squeezing  out  of  the  blood  already  in 
the  hepatic  vessels,  and  it  is  a  result  which  is  often  observed  in  other 
organs  during  stimulation  of  vasoconstrictor  nerve  fibers. 

• 
THE  CORONARY  CIRCULATION 

We  have  already  studied  the  effect  produced  on  the  heartbeat  by  in- 
terfering with  the  flow  of  blood  in  the  coronary  vessels,  and  it  remains 
for  us  to  study:  (1)  peculiarities  in  the  bloodflow  through  them,  and 


268  THE    CIRCULATION    OF    THE    BLOOD 

(2)  whether  this  bloodflow  can  be  altered  by  dilatation  or  constriction 
of  the  vessels  brought  about  through  nerves.  With  regard  to  the  pecu- 
liarities of  Hood  flow,  it  may  be  stated  that  there  are  said  to  be  two  periods 
in  each  cardiac  cycle  during  which  an  increase  takes  place  in  the  mass 
movement  of  blood  in  the  coronary  vessels — namely,  at  the  beginning 
of  systole,  and  again  at  the  beginning  of  diastole.  Nevertheless  the 
pressure  pulse  has  the  same  contour  in  the  coronary  as  in  the  systemic 
circulation.  (W.  T.  Porter.22)  During  systole  the  intramural  branches 
of  the  coronary  artery  are  compressed  and  the  blood  pressed  out  of 
them.  This  emptying  of  the  vessels  favors  the  flow  of  blood  through 
the  heart  walls. 

Regarding  the  presence  of  coronary  vasomotor  nerves,  there  is  at  pres- 
ent a  certain  amount  of  doubt.  When  strips  of  the  coronary  artery  are 
suspended  in  a  solution  of  epinephrine,  they  undergo  relaxation  instead 
of  contraction.  On  the  assumption  that  the  action  of  epinephrine  on 
blood  vessels  is  the  same  as  that  of  stimulation  of  the  vasoconstrictor 
fibers,  this  result  has  been  taken  as  evidence  of  the  absence  of  such 
fibers  and  the  possible  presence  of  vasodilator  fibers.  A  somewhat 
similar  type  of  experiment  has  been  performed  by  injecting  epineph- 
rine into  the  fluid  used  to.  perfuse  the  excised  mammalian  heart, 
with  the  result  that,  when  such  injections  are  made  into  a  heart  that 
is  not  beating,  evidence  of  vasoconstriction  is  obtained,  whereas  when 
injected  into  a  beating  heart,  dilatation  occurs.  This  latter  result 
may,  however,  be  owing  to  the  action  of  the  epinephrine  in  stimulating 
the  cardiac  contractions.  Other  observers,  however,  deny  that  the  in- 
jection of  epinephrine  into  the  coronary  circulation  has  any  influence 
upon  the  outflow  of  the  perfusion  fluid.  Taking  the  result  of  these 
observations  as  a  whole,  we  may  at  least  conclude  that  epinephrine 
does  not  produce  the  same  marked  vasoconstriction  that  it  produces  in 
other  blood  vessels — a  fact,  which,  as  already  stated,  may  be  taken 
advantage  of  in  bringing  about  the  rise  in  coronary  pressure  that  is 
necessary  for  successful  resuscitation  of  the  heart. 

Attempts  to  demonstrate  the  presence  of  vasomotor  fibers  by  electrical 
stimulation  of  the  vagus  or  sympathetic  nerve  have  yielded  results  which 
are  quite  inconclusive,  although  some  observers  assert  that  the  vagus 
nerve  carries  vasoconstrictor  fibers  to  the  coronary  vessels,  and  that 
the  sympathetic  carries  vasodilator. 

Whatever  may  be  the  mechanism  involved  it  is  evident  that  adjust- 
ment of  bloodflow  through  the  coronary  arteries  in  order  that  this  may 
correspond  to  the  greatly  varying  activities  of  the  heart  must  be  very 
close.  Evans  and  Starling,  working  on  the  heart-lung  preparations 
(page  163),  have  shown  that  changes  in  coronary  bloodflow  depend  in- 


PECULIARITIES    IN    BLOOD    SUPPLY   IN    CERTAIN   VISCERA  269 

timately  on  changes  in  aortic  blood  pressure;  for  example,  an  increase 
of  fifty  per  cent  in  aortic  pressure  may  cause  the  coronary  flow  to  in- 
crease three  times.  The  tone  of  the  vessels  also  becomes  lowered  when 
more  blood  supply  is  required  and  this  dilatation  is  probably  effected 
by  an  increase  in  Cw  of  the  blood  (due  to  acid  metabolic  products)  and 
possibly  by  the  appearance  in  the  blood  of  substances  like  histamine 
that  cause  dilatation  of  the  capillaries.  It  is  computed  that  the  blood- 
flow  through  the  heart  of  a  man  during  rest  is  140  c.c.  per  minute ;  during 
muscular  exercise  the  flow  may  increase  to  800  c.c.  Under  these  condi- 
tions the  oxygen  consumption  of  the  heart  is  increased  in  greater  pro- 
portion than  the  increase  of  bloodflow,  which  indicates  that  the  02  must 
be  more  thoroughly  utilized,  i.e.,  the  coefficient  utilization  becomes 
greater  (page  410). 


CHAPTER  XXX 

CLINICAL  APPLICATIONS  OF  CERTAIN  PHYSIOLOGICAL 

METHODS* 

(Revised  by  N.  B.  Taylor) 

In  the  following  chapters  a  brief  account  will  be  offered  of  the  clinical 
use  of  the  electrocardiogram,  of  polysphygmograms,  and  of  bloodflow 
measurements.  This  is  done  to  show  how  physiological  technic  is  being 
employed  for  the  accurate  investigation  of  cardiovascular  disease. 

ELECTROCARDIOGRAMS 

To  observe  the  electrical  change  produced  by  the  spread  of  the  excita- 
tion wave  over  the  heart  from  auricles  to  ventricles,  it  is  not  necessary 
to  place  the  electrodes  directly  on  the  heart,  but,  as  already  hinted,  we 
may  follow  the  electrical  change  by  leading  off  from  electrodes  applied 
to  the  surface  of  the  body.  From  such  electrocardiographic  tracings 
extremely  important  facts  concerning  the  propagation  of  the  heartbeat 
may  be  ascertained.  In  order  to  make  an  observation  the  hands  and  the 
left  foot  are  each  placed  in  a  solution  of  sodium  chloride  contained  in 
porous  jars,  immersed  in  larger  vessels  containing  a  saturated  solution  of 
ZnS04  and  zinc  terminals.!  An  arrangement  like  that  in  Fig.  81  may  also 
be  used.  By  manipulation  of  suitable  keys,  the  extremities  may  then  be 
connected  with  the  electrocardiograph  in  the  following  manner :  Lead  I, 
right  arm  and  left  arm;  lead  II,  right  arm  and  left  leg;  lead  III,  left  arm 
and  left  leg. 

When  any  pair  of  leads  is  connected  with  the  galvanometer,  it  is  ob- 
served that  the  string  is  deflected  to  one  side  owing  to  electrical  cur-' 
rents  arising  from  the  skin.  Before  taking  a  record  of  the  cardiac 
movements  of  the  string,  it  is  necessary  to  compensate  for  this  skin  cur- 
rent by  introducing  into  the  circuit  in  the  opposite  direction  the  re- 
quired amount  of  current,  called  the  compensating  current,  to  bring  the 
string  shadow  back  to  the  zero  or  midposition.  In  order  that  the  rec- 
ord obtained  may  be  quantitative  in  character,  it  is  further  necessary 
that  the  movement  of  the  string  be  standardized.  This  is  done  by  as- 


*A  certain  amount  of  repetition  of  matter  previously  discussed  has  been  found  advisable  in  these 
chapters  for  which  the  indulgence  of  the  reader  is  requested. 

tit  is  really  unnecessary  to  use  the  so-called  nonpolarizable  electrodes.  Glass  vessels  containing 
20  per  cent  NaCl  solution  with  the  zinc  plates  dipping  into  them  are  quite  satisfactory. 

270 


ELECTROCARDIOGRAMS 


271 


certaining  to  what  extent  the  string  moves  when  a  current  of  known 
voltage  is  sent  through  it  and  by  altering  the  tension  of  the  string  so  that 
one  millivolt  of  current  causes  an  excursion  of  one  centimeter  of  the 
string  shadow  on  the  photographic  plate.  It  would  take  us  beyond  the 
confines  of  this  volume  to  go  in  any  greater  detail  into  the  technic  in- 
volved in  taking  electrocardiograms,  but  it  may  be  said  that  this  is  by 
no  means  difficult,  provided  the  instructions  which  are  supplied  with 
the  instrument  are  carefully  followed.  In  practice  the  taking  of  elec- 


Fig.   81. — Klectrocardiographic  apparatus  as   made   by   the    Cambridge    Scientific   Materials   Co.      Con- 
tact electrodes  are  shown,  but  the  immersion  electrodes  described  in  the  context  are  preferable. 

tro cardiograms  is  indeed  quite  a  simple  matter,  and  the  extremely  im- 
portant information  which  they  give  us  concerning  the  mechanism  of 
the  heartbeat  and  the  evidence  of  myocardial  disease  should  make  their 
employment  a  universal  practice  in  all  cardiac  clinics.  Some  of  these 
clinical  applications  are  described  elsewhere  (page  278). 

Interpretation  of  Electrocardiograms  by  the  Triangle  Method 

In  the  analysis  of  the  electrocardiographic  tracing,  much  information  has  been 
gained  with  regard  to  the  relation  which  the  various  deflections  bear  to  the  electrical 
changes  occurring  within  the  heart,  by  determining  the  average  direction  along 


272  THE   CIRCULATION   OF   THE   BLOOD 

which  the  electromotive  force  is  flowing  at  the  instant  a  particular  deflection  occurs. 
The  resultant  direction  of  the  electromotive  changes — the  electrical  axis  as  it  is 
termed — is  not  constant,  but  varies  from  instant  to  instant  throughout  the  cardiac 
cycle  and  may  be  determined  mathematically  by  employing  as  a  basis  the  triangle 
of  Einthoven.  This  is  a  geometrical  representation  of  the  comparative  potential 
values  in  the  three  leads  and  their  relation  to  the  potential  changes  created  within 
the  heart. 

An  imaginary  equilateral  triangle  is  constructed,  embracing  the  heart,  having 
its  base  in  a  horizontal  plane  and  directed  upwards  and  its  vertex  directed  down- 
wards. (Fig.  84-J5.)  The  sides  of  such  a  triangle  lie  approximately  in  alignment  with 
the  three  leads,  and  represent  the  direction  of  the  circuits  in  these  leads.  An 
electromotive  force  produced  within  the  heart  will  cause  a  deflection  of  the  gal- 
vanometer string,  the  magnitude  and  direction  of  the  deflection  being  dependent 
upon  the  angle  which  the  electrical  axis  makes  with  the  side  of  the  triangle  repre- 
sentative of  the  particular  lead  taken  at  the  time.  When  the  axis  is  precisely  at 
right  angles  to  the  line  of  the  lead  the  string  is  undeflected  in  that  lead,  and  the 
tracing  follows  the  line  of  zero  potential.  When  it  forms  an  angle  other  than  a 
right  angle,  a  movement  of  the  string  occurs  in  one  or  other  direction.  The  more 
nearly  parallel  the  electrical  axis  comes  to  lie  to  the  side  of  the  triangle  corre- 
sponding to  the  respective  lead,  the  greater  will  be  the  electromotive  force  flowing 
along  that  lead,  and  consequently  the  greater  will  be  the  magnitude  of  the  recorded 
deflection.  The  direction  of  the  wave  in  the  tracing  (above  or  below  the  zero  line) 
with  a  given  electrical  axis,  will,  of  course,  depend  upon  the  manner  in  which  the 
electrodes  are  connected  to  the  galvanometer  as  regards  polarity.  When  the  elec- 
trodes are  connected  in  the  standard  way,  an  upward  deflection  occurs  in  lead  I  if  the 
general  direction  of  the  electromotive  force  is  from  right  to  left,  and  in  leads  II 
and  III  when  its  general  direction  is  downwards.  A  downward  deflection  occurs  in 
the  tracing  when  these  directions  are  reversed. 

If  a  line  be  drawn  through  the  centre  of  the  triangle,  then  its  projection  upon 
the  side  of  the  latter  representing  lead  II  will  be  found  to  equal  (according  to  the 
direction  of  the  line)  the  sum  of  or  the  difference  between  its  projections  upon  the 
remaining  sides.  Taking  such  a  line  to  represent  the  electrical  axis  of  the  heart, 
Einthoven  has  formulated  the  rule  that  e1  +  e3  =.  e2  where  e1  e2  and  e3  represent  the 
potential  values  respectively  in  the  three  leads.  For  example,  if,  after  synchronous 
points  in  the  records  from  the  three  leads  have  been  superimposed,  and  the  heights  of 
the  R  waves  measured,  it  will  be  found  that  Rn  (R  wave  in  lead  II)  equals 
B±  +  Rm.  The  same  will  be  true  whatever  deflections  are  compared  in  the  different 
leads  provided  the  sign  of  their  respective  values  be  taken  into  consideration. 
Knowing  the  potential  values  of  a  given  wave  in  the  three  leads,  the  direction  of  the 
electrical  axis  during  the  production  of  that  wave  may  be  calculated  from  a  trigono- 
metrical formula,  which,  however,  need  not  be  detailed  here.  The  following  is  a 
simple  practical  method  for  obtaining  the  direction  of  the  electrical  axis  at  any 
instant.  The  heights  (or  depths)  in  millimeters  equal  to  tenths  of  millivolts  of  the 
particular  deflection  in  leads  I  and  II,  are  laid  off  on  the  corresponding  sides  of  the 
triangle.  (Fig.  84- A.}  Perpendicular  lines  AB,  CD,  EF,  and  GH  are  next  drawn 
from  the  ends  of  these  measurements  toward  the  centre  of  the  triangle,  where  they 
intersect  at  X  and  Y.  The  direction  of  XY  represents  the  electrical  axis,  and  its 
length  the  manifest  value  of  the  electromotive  force  created  within  the  heart.  Since 
the  potential  values  in  the  three  leads  are  as  the  projections  of  the  line  XY  on  to 
the  sides  of  the  triangle,  it  follows  that  the  manifest  value  will  be  the  maximal 


ELECTROCARDIOGRAM 


273 


potential  difference  capable  of  being  recorded  at  any  time,  and  will  be  recorded 
in  full  only  when  the  electrical  axis  lies  parallel  to  the  line  of  the  lead.  The  actual 
potential  difference  set  up  within  the  heart  and  to  which  the  manifest  value  bears  a 
constant  relationship,  is  unable  at  any  time  to  be  recorded. 

Description  of  the  Various  Waves  in  the  Tracing 

It  will  be  observed  (Fig.  82)  that  there  are  three  waves  above  the 
line  of  zero  potential  and  two  waves  below  it.  They  have  been  lettered 
from  before  backward,  P,  Q,  R,  S,  and  T.  The  time  relations  of  each 
wave  have  been  ascertained  by  taking  simultaneously  with  the  electro- 
cardiogram a  record  of  the  mechanical  changes  occurring  in  the  heart 


Fig.  82. — Normal  electrocardiogram.  Leads  I,  II,  III.  Note  that  the  height  of  any  upward 
deflection  or  the  depth  of  any  downward  deflection  in  lead  II  equals  the  sum  of  the  correspond- 
ing deflections  in  leads  I  and  III. 

during  each  cardiac  cycle.  Such  records  have  been  secured  by  taking 
intracardiac  pressure  curves  with  the  results  as  shown  in  Fig.  83.  The 
top  curve  represents  auricular  and  the  second  one  ventricular  pressure, 
whereas  the  lowest  is  an  electrocardiogram.  It  will  be  observed:  (1) 
that  the  P-wave  occurs  just  antecedent  to  contraction  of  the  auricles; 

(2)  that  the  small  positive  wave,  Q,  which  is  absent  in  these  tracings, 
must  occur  just  before  the  beginning  of  the  contraction  of  the  ventricles; 

(3)  that  the  upstroke  of  wave  R  is  inscribed  before  the  commencement 
I  of  ventricular  systole;  and  (4)  that  the  long  upward  wave  T,  culminates 

at  the  moment  the  ventricle  begins  relaxing. 


274 


THE   CIRCULATION   OF   THE   BLOOD 


Although  such  comparisons  give  us  considerable  insight  into  the  cause 
of  several  of  the  waves,  there  yet  remain  certain  peculiarities  of  the 
electrocardiogram  to  be  considered.  These  are:  (1)  the  cause  of  the 
slight  downward  deflection,  Q;  (2)  the  cause  of  S;  (3)  the  cause  for  the 
period  of  equal  potential  during  ventricular  systole  indicated  by  the 
portion  of  the  curve  between  S  and  T;  (4)  the  cause  for  the  wave,  T.  To 
solve  these  problems  it  is  necessary  to  compare  electrocardiograms  taken 
from  the  surface  of  the  body  with  those  from  a  series  of  electrodes  placed 
directly  on  the  ventricle  of  the  exposed  heart. 


I        i        :        : 

Fig.  83. — Electrocardiogram  (dog)  taken  simultaneously  with  curves  from  auricle  and  ven- 
tricle. It  will  be  observed  that  wave  P  slightly  precedes  auricular  systole  and  that  wave  R  occurs 
just  before  the  presphygmic  period  starts  in  the  ventricle.  (From  Lewis.) 

The  Ventricular  Complex 

The  researches  of  Lewis64  have  shown  that  the  spread  of  the  excita- 
tion wave  in  the  ventricles  is  not  primarily  along  muscular  pathways 
but  occurs  through  the  divisions  of  the  auriculo-ventricular  bundle  and 
the  subendocardial  arborizations  of  Purkinje.  Since  there  is  no  con- 
nection between  the  arborization  of  one  ventricle  with  those  of  another, 
the  course  of  the  wave  is  distinct  in  the  two  chambers.  It  travels  at 
first  downwards  over  the  septum  in  each  ventricle  to  the  apex  and  sub- 
sequently ascends  upon  the  endocardial  surface  of  the  free  wall  to  ter- 
minate at  the  basal  attachment  of  the  latter.  The  spread  through  the 
specialized  conducting  tissue  is  very  rapid  (about  5000  mm.  per  sec.) 
the  wave  taking  about  .04  seconds  to  complete  its  journey  over  the  en- 
docardial surface.  The  wave  travels  more  slowly  (400  mm.  per  sec.) 
through  the  ventricular  muscle,  its  spread  being  through  the  muscle 
wall  from  endocardial  to  pericardial  surface  and  at  right  angles  to  its 
course  along  the  subendocardial  network. 


ELECTROCARDIOGRAMS  275 

It  will  be  seen  from  this  that  the  excitation  wave  travels  with  great 
speed  over  a  semicircular  pathway  which  has  a  clockwise  direction  in 
the  right  ventricle  and  an  anti-clockwise  direction  in  the  left  (Fig.  84-5). 
From  this  it  passes  at  a  more  leisurely  rate  through  the  ventricular 
muscle  reaching  points  upon  the  pericardial  surface  at  intervals  which 
to  a  great  extent  are  controlled  directly  by  the  relative  thicknesses  of 
the  heart  wall  at  the  different  points.  It  is  to  be  expected  that  the 
spread  of  negativity  through  the  ventricular  muscle  will  set  up  action 
currents  which  will  vary  in  their  direction  in  accordance  with  the  change 
in  direction  of  the  excitation  wave.  The  alterations  in  the  course  of 
the  electromotive  changes  will  be  in  the  nature  of  a  rotation  which  will 
have  a  clockwise  direction  in  the  right  and  an  anti-clockwise  direction 
in  the  left  chamber.  Lewis,  from  calculations  based  upon  Einthoven's 
triangle  method,  determined  the  direction  of  rotation  of  the  electrical 
axis  separately  in  each  ventricle  after  one  or  other  division  of  the  bundle 
had  been  severed  so  as  to  isolate  that  chamber  effectually,  insofar  as 
the  excitatory  process  was  concerned,  from  its  companion.  It  was 
found  that  the  directions  of  the  electrical  axes  calculated  during  the 
production  of  the  Q.R.S.  complex  were,  at  the  same  instants  of  time, 
closely  in  accord  with  the  direction  of  the  excitation  wave  as  determined 
from  observations  made  with  direct  contacts  placed  upon  the  heart. 
From  this  it  has  been  concluded  that  the  direction  of  the  electrical  axis 
corresponds  to  the  average  direction  in  which  the  excitation  wave  is 
tending  to  move  at  a  given  moment. 

Interruption  of  the  conducting  pathway  in  one  ventricle  does  not  affect 
the  course  of  the  excitation  wave  in  the  contralateral  ventricle  during 
the  time  that  the  initial  deflections  Q.R.S.  of  the  electrocardiogram  are 
being  inscribed  but  since  there  is  no  spread  across  the  septum  from  one 
ventricle  to  the  other,  the  spread  through  the  ventricle  on  the  operated 
side  is  prevented  during  this  period. 

An  electrocardiogram  taken  from  an  animal  of  which  the  right 
or  left  conducting  branch  had  been  severed,  was  therefore  a  rep- 
resentation, insofar  as  the  initial  deflections  were  concerned,  of  the 
electrical  changes  occurring  in  the  contralateral  ventricle.  That  is 
to  say,  a  record  taken  after  division  of  the  right  branch  gave  a 
picture  of  the  electrical  changes  occurring  in  the  left  chamber  alone, 
whilst  one  taken  after  division  of  the  left  branch  was  a  rep- 
resentation of  electrical  changes  in  the  right  chamber.  For  the  sake 
of  convenience  in  the  description  of  his  researches,  Lewis  has  termed 
such  records  of  one  or  other  ventricle  a  levocardiogram  or  a  dextrocardio- 
gram  respectively.  Since  the  physiological  electrocardiogram  is  a  represen- 
tation of  the  potential  differences  occurring  in  the  heart  as  a  whole,  it  has 
been  termed  appropriately  the  "bicar diagram.  In  the  further  study  of 


276  THE   CIRCULATION   OF   THE   BLOOD 

these  curves  and  their  time  relations  to  one  another  and  to  the  normal 
electrocardiogram,  it  is  necessary  to  obtain  a  curve  which  may  serve 
as  a  standard.  This  is  provided  for  by  leading  from  a  series  of  contacts 
placed  directly  upon  the  endocardium  or  the  surface  of  the  heart.  When  a 
levocardiogram,  a  dextrocardiogram  and  a  biocardiogram  are  charted  (Fig. 
84-C)  with  their  voltages  along  the  ordinates  and  their  respective  time 
phases  in  the  same  vertical  line,  it  will  be  found  that  in  lead  I  the  record 
of  the  left  ventricle  shows  a  pronounced  R  wave  and  a  diminutive  S. 
The  dextrocardiogram  on  the  other  hand  shows  a  marked  S  wave  and  a 
stunted  R  deflection.  The  height  and  consequently  the  potential  value  of 
each  wave  of  the  bicardiogram  was  found  to  represent  the  algebraic  sum  of 
the  potential  values  of  the  corresponding  waves  in  the  dextrocardiogram 
and  the  levocardiogram.  When  the  three  records  were  taken  in  the 
other  leads  and  charted  as  described  the  same  relationships  were  found 
to  exist.  The  rotation  of  the  electrical  axes  in  the  two  ventricles  (cf. 
Fig.  84-0)  furnishes  us  with  an  explanation  for  the  variations  in  the 
potential  values  recorded  respectively  from  the  two  chambers  in  a  com- 
mon lead  and  from  a  given  chamber  in  different  leads.  . 

The  right  and  left  ventricles  in  the  other  leads  when  charted  as  de- 
scribed also  show  differences  in  their  potential  values  during  identical 
time  phases.  Thus,  in  the  case  of  the  levocardiogram  taken  in  leads  II 
and  III,  a  well  marked  depression  S  is  seen  but  R  is  of  low  value.  In 
the  case  of  the  dextrocardiogram  R  is  high  in  these  leads  but  S  is  absent. 
The  bicardiogram  in  either  the  second  or  third  lead,  as  in  the  case 
of  the  first  lead  represents  the  algebraic  sum  of  the  records  obtained 
from  the  individual  chambers  in  the  corresponding  lead. 

As  a  result  of  these  researches  it  is  believed  that  the  Q.R.S.  complex  in 
the  physiological  electrocardiogram  is  a  composite  picture  consisting  of 
the  algebraic  summation  of  the  electrical  effects  in  the  two  ventricles. 
The  Q  wave  is  produced  during  the  spread  of  the  excitation  wave  in  the 
septum  and  is  a  left  sided  effect  in  lead  I  and  a  right  sided  effect  in 
leads  II  and  III.  The  beginning  of  the  R  wave  is  produced  by  the  spread 
of  the  excitation  wave  in  both  ventricles.  The  remainder  of  the  R  wave 
is  a  left  sided  effect  in  lead  I  and  a  right  sided  effect  in  leads  II  and  III.  The 
S  wave  is  a  right  sided  effect  in  lead  I  but  a  left  sided  effect  in  the  other 
leads.  Such  a  conception  of  the  manner  of  production  of  the  initial  phase 
(Q.  R.  and  S.  deflections)  of  the  ventricular  complex  renders  the  analysis 
of  certain  clinical  curves,  notably  those  associated  with  the  hypertro- 
phies and  bundle  branch  defects,  a  less  difficult  matter  (see  page  284). 

The  short  period  between  the  S  and  T  waves  during  which  the  electro- 
cardiogram follows  the  base  line  indicates  that  the  whole  heart  is  in  the 
excited  state  and,  in  consequence,  a  condition  of  perfect  potential  bal- 
ance exists  between  its  different  parts. 


LEAD  I 


LEADII 


c. 


DffXtfocsrr 


0123 


Fig.  84. — A.  Schema  to  illustrate  method  of  determining  the  electrical  axis,  and  to  show 
its  projection  on  to  the  three  leads.  The  direction  of  EG  should  also  be  shown  by  an  arrow 
pointing  toward  the  right  in  the  diagram. 

B.  Diagram   showing  direction   of   spread   of   excitation   wave  in   the  heart,   and   the   relations 
of  electrical   axis  to  the    three  leads  at   different   instants.      (Modified   from   Lewis.) 

C.  Curves     illustrating     the    composite     nature     of     the     physiological     electrocardiogram.        The 
two    curves    on    the    right    were    charted    from    the    electrocardiograms    of    a    monkey    before    and 
after  the  right   conducting   branch   had   been  compressed.     Thi    dextrocardiogram    was   subsequent- 
ly  calculated   from    these   curves.     Ordinates    .02    millivolts.     Abscissae    .005    sec.      (Modified    from 
Lewis,    Trans.    Royal.    Soc.,    1916,    B.    Vol.    207.)     Below    diagrams    have    been    constructed    from 
data    published    by    Lewis,    showing    rotation    of    the    electrical    axis    in    each    chamber    during    the 
production   of   the   respective   curves. 


ELECTROCARDIOGRAMS  277 

The  second  phase  of  the  ventricular  complex — the  T  wave — is  ascribed 
to  the  disturbance  of  electrical  balance  which  again  ensues  upon  the 
retreat  of  the  excitation  wave.  The  retreat  of  the  wave  would  be 
expected  to  occur  in  the  same  order  as  the  invasion,  that  is,  the  region 
first  excited  during  the  advance  of  the  wave  would  be  the  first  to  pass 
into  the  unexcited  state  during  the  retreat  and  the  region  at  the  base  of 
each  ventricle  would  remain  excited  longer  than  the  apex.  Such  an  order 
would  cause  a  rotation  of  the  electrical  axes  in  the  reverse  direction  to 
that  described  as  occurring  during  the  invasion  of  the  wave  and  would 
be  expected  to  produce  a  second  phase  in  the  ventricular  complex  iden- 
tical with  the  first  but  with  its  deflections  inverted.  The  T  wave,  how- 
ever, is  a  single  prolonged  upward  deflection  which  indicates  that  the 
retreat  of  the  excitation  wave  is  much  slower  than  the  invasion.  The 
slower  retreat  would  tend  to  cause  the  deflections  to  fuse  with  one  an- 
other, and  to  flatten  out  the  curve.  Again  the  excited  state  probably  does 
not  retire  from  all  portions  of  the  ventricular  muscle  at  the  same  rate 
but  dies  away  more  rapidly  from  apical  regions  than  from  regions  nearer 
the  base.  In  the  latter  region,  consequently,  negativity  would  persist 
for  a  relatively  longer  period  and  the  base  to  apex  direction  of  the  elec- 
trical axis  would  exert  a  greater  influence  upon  the  electrocardiogram. 
A  slower  and  less  uniform  dying  away  of  the  excitation  process  during 
its  retreat  would  in  this  way  account  for  the  differences  in  contour  of 
the  records  inscribed,  during  these  two  periods.  That  the  T  wave  in  the 
human  electrocardiogram  is  probably  dependent  upon  the  longer  con- 
tinuance of  the  excited  state  at  the  base  than  at  the  apex  and  that  dif- 
ferent rates  of  retirement  from  the  two  regions  affect  this  wave  has 
been  demonstrated  by  Mines.  When  the  electrical  changes  at  the  apex  of 
a  frog's  heart,  which  previously  had  shown  no  T  wave,  were  hastened 
by  the  local  application  of  heat,  a  typical  T  wave  appeared.  The  local 
application  of  cold  to  the  region  of  the  base  had  the  same  effect.  It  has 
also  been  shown  by  others  that  vagal  stimulation  or  the  exhibition  of 
drugs  (e.g.,  digitalis)  may  affect  the  form  and  direction  of  the  T  wave. 
These  experiments  indicate  that  the  condition  of  particular  portions  of 
the  cardiac  musculature  may  hasten  or  retard  its  return  to  the  unexcited 
state  and  may  be  a  factor  in  the  production  of  abnormal  T  waves  ap- 
pearing in  clinical  curves. 


CHAPTER  XXXI 

CLINICAL  APPLICATIONS  OF  CERTAIN  PHYSIOLOGICAL 
METHODS  (Cont'd) 

CLINICAL  APPLICATIONS  OF  ELECTROCARDIOGRAPHS 

The  Electrocardiogram  in  the  More  Usual  Forms  of  Cardiac 

Irregularities 

BY  R.  W.  SCOTT  (Revised  by  N.  B.  Taylor) 

The  principle  of  the  application  of  the  string  galvanometer  to  the 
study  of  cardiac  irregularities  has  been  indicated.  It  is  our  object  here 
to  outline  some  of  the  more  common  forms  of  irregular  heart  action, 
with  a  brief  description  of  the  abnormalities  in  the  electrocardiogram 
resulting  therefrom.  For  the  sake  of  comparison  a  normal  electrocar- 
diogram is  shown  in  Fig.  82.  The  cause  and  relationship  of  the  various 
deflections  have  been  explained  (page  272). 

Sinus  Arrhythmia, — This  irregularity  is  seen  commonly  in  children 
and  young  adults,  and  is  without  pathologic  significance.  The  electro- 
cardiogram presents  the  normal  deflections  and  shows  by  the  varying 
spaces  between  the  P  deflections  that  the  cardiac  impulse  has  been  gen- 
erated at  slightly  irregular  intervals. 

Sinus  Bradycardia. — The  electrocardiogram  in  a  simple  case  of  sinus 
bradycardia  is  usually  normal,  except  that  the  deflections  occur  at  an 
unusually  slow  rate  (Fig.  85).  This  indicates  that  the  cardiac  impulse 
is  built  up  at  a  slow  rate,  but  when  generated  it  evokes  a  normal  auric- 
ular and  ventricular  contraction. 

The  Extrasystole. — The  extrasystole  may  be  either  auricular  or  ven- 
tricular in  origin.  Occasionally  a  rare  type  is  seen  in  which  the  im- 
pulse arises  in  the  functional  tissues  between  the  auricle  and  ventricle. 
When  the  focus  of  impulse  production  is  at  or  near  the  sinoauricular 
node,  the  resulting  electrocardiogram  complexes  are  practically  normal. 
If,  however,  the  seat  of  impulse  formation  is  removed  from  the  S-A 
node,  the  P  deflection  may  be  distorted  or  actually  inverted,  followed 
by  a  normal  Q-R-S-T  complex  (Fig.  86). 

In  the  case  of  ventricular  extrasystole,  the  cardiac  impulse  originates 
in  the  muscle  of  either  the  right  or  the  left  ventricle.  From  here  it 

278 


CLINICAL   APPLICATIONS   OF   ELECTRO  CARDIOGRAPH  Y 


279 


t< 


Fig.    85. — Sinus   bradycardia.      Rate    32    per    minute.      Note    the    normal    appearance    of    the    electro- 
cardiogram.     P-R   interval  =  .17   seconds. 


«• 


Fig.    86. — Auricular    extrasystole.      Two    auricular    extrasystoles    following    two    normal    complexes. 
Note   the  ectopic   origin  of  the  extrasystoles   indicated   by   the   inversion  of  P. 


Fig.    87. — Ventricular    extrasystoles    arising    in    the    right    ventricle. 


Fig.    88. — Ventricular    extrasystole    arising    in    the    left   ventricle. 


280 


THE    CIRCULATION   OF   THE   BLOOD 


travels  inwards  to  the  Purkinje  system;  its  subsequent  spread  occurs  in 
both  directions  along  this  pathway  and  subsequently  through  the  ven- 
tricular muscle  from  within  outwards  (see  page  274).  Since  for  the 
instant  the  excitation  wave  is  spreading  in  one  ventricle  alone  the  corn- 


Fig.   89. — Paroxysmal  tachycardia.     Auricular  origin.     Note  that  the   P  deflection   falls  back  on   T. 

Rate   200   per   minute. 

posite  picture  characteristic  of  the  normal  electrocardiogram  is  not  seen, 
but  the  effects  of  one  or  other  ventricle  predominate.  Though  it  is  not 
always  possible  to  accurately  localize  the  site  of  impulse  formation,  it 


Fig.  90. — Auricular  fibrillation.  Leads  1,  2,  3.  Note  the  coarse  fibrillation  waves  between  the 
R  peaks,  and  the  absence  of  any  P  deflections  in  relation  to  R.  Also  the  unequal  spacing  of  the  R 
deflections. 

may  be  taken  as  a  general  rule,  that  when  the  right  ventricle  is  responsi- 
ble, the  record  resembles  the  dextrocardiogram  (see  page  276)  and  when 
the  premature  beat  arises  in  the  left  ventricle  the  characteristics  of  the 


CLINICAL    APPLICATIONS    OF    ELECTROCARDIOGRAPHS  281 

levocardiogram  are  seen  (Figs.  87  and  88).  Any  one  or  several  of  the  general 
types  of  extrasystole  may  occur  in  the  same  patient.  Fig.  88  shows 
an  extrasystole  originating  from  the  left  ventricle. 

Paroxysmal  Tachycardia. — Electrocardiographic  records  taken  in  the 
interval  between  the  paroxysms  may  appear  normal.  During  the  tachy- 
cardia the  records  normally  show  only  two  deflections,  R  and  a  combina- 
tion of  T  and  the  succeeding  P  (Fig.  89).  If  the  paroxysm  is  of  auric- 
ular origin,  the  P  deflection  may  be  inverted,  indicating  that  the  new 
focus  of  impulse  production  is  located  at  some  other  site  than  the  sino- 
auricular  node. 

Auricular  Fibrillation. — The   electrocardiogram   in   auricular   fibrilla- 
tion shows  three  distinctive  features: 
l^.  Absence  of  the  P  deflections  typical  of  auricular  contractions. 

2.  The  ventricular  complexes  (Q-R-S-T  waves)   occur  in  irregular  se- 
/quence  and  may  vary  in  height. 

3.  The  presence  of  small  irregular  oscillations  best  seen,  between  the 
ventricular  complexes.     A  typical  tracing  of  this  condition  is  shown  in 
Fig.  90. 

The  dependence  of  the  P-wave  upon  auricular  contraction  has  been 
indicated  (page  272).  Its  absence  in  auricular  fibrillation  is  accounted 
for  by  the  fact  that  the  individual  muscle  fibers  of  the  auricles  contract 
independently  of  one  another,  so  that  some  fibers  are  in  a  state  of  con- 
traction while  others  are  relaxed.  This  renders  impossible  a  coordinate 
contraction  of  the  auricle  as  a  whole. 

The  multiple  impulses  from  the  fibrillating  auricles  reach  the  ventri- 
cles and  evoke  a  contraction  provided  the  ventricle  is  not  already  in  a 
state  of  contraction  (refractory  period,  page  178).  These  irregular 
ventricular  responses  will  of  course  produce  unequal  spacing  of  the 
ventricular  complexes  in  the  electrocardiogram.  The  variations  in  the 
height  of  the  R  deflections  is  thought  to  be  due  to  the  distortion  caused 
by  the  superimposition  of  the  small  waves  representing  auricular  ac- 
tivity. 

Auricular  Flutter. — Auricular  flutter  was  discovered  by  the  electro- 
cardiograph, and  it  is  practically  impossible  to  make  a  diagnosis  of  this 
condition  without  the  use  of  the  string  galvanometer.  The  auricular 
deflections  are  usually  rhythmic  and  in  the  average  case  vary  in  rate 
from  20QJ&J350  per  minute.  The  initial  deflection  of  P  may  be  di- 
rected either  upwards  or  downwards,  depending  on  the  site  of  the 
origin  of  the  auricular  impulse  (when  arising  from  some  other  source 
than  the  S-A  node  the  impulse  is  said  to  be  ectopic).  Usually  a  regular 
succession  of  P  deflections  can  be  traced  throughout  the  record  (Fig.  91). 


282 


THE   CIRCULATION   OF   THE   BLOOD 


Since  it  is  impossible  for  the  ventricle  to  respond  to  all  the  impulses 
coming  from  the  auricles,  a  condition  of  partial  heart-block  obtains 
(2:1 — 3:1 — 4:1,  etc.).  The  ventricular  complexes  will  occur  regularly 
except  when  a  3:2  rhythm  exists. 

Usually  the  ventricular  complexes  are  such  as  to  indicate  that  the 
stimulus  arose  in  the  auricle  (supraventricular).  The  height  of  the 


Fig.  91.  —  Auricular  flutter.     Auricular  rate  300.     Ventricular  rate  80.     Note  the  inversion  of  the  P 


individual  deflections  Q-R-S-T  may  vary,  depending  on  the  predominance 
of  a  right  or  left  ventricular  hypertrophy. 

Heart-block.  —  There  are  three  degrees  of  severity  in  heart-block:  (1) 
delayed  conduction,  (2)  partial  dissociation,  and  (3)  complete  dissociation. 

DELAYED  CONDUCTION.  —  When  the  conducting  tissues  of  the  heart  are 
so  affected  as  to  cause  an  abnormal  prolongation  of  the  P-R  interval, 


(F-R 


Fig.    92. — Delayed    conduction.      Note    the    normal    appearance    of    the    electrocardiogram    except    for 
the   prolongation   of  the   P-R   interval,   which   measures    .23    seconds. 

the  condition  is  called  delayed  conduction.  The  ventricles  respond  to 
each  stimulus  originating  at  the  sinus  node,  but  the  time  required  for  the 
impulse  to  pass  through  the  conducting  tissues  is  longer  than  normal. 
In  a  simple  case  the  electrocardiogram  may  appear  perfectly  normal,  but 
when  the  P-R  interval  is  measured  accurately,  it  will  be  found  to  be  length- 
ened beyond  the  extreme  limits  of  the  normal  (0.20  seconds)  (Fig.  92). 

PARTIAL  DISSOCIATION. — In  the  typical  case  of  partial  dissociation  the 
ventricles  respond  to  the  impulse  coming  from  the  auricle  most  of  the 
time,  but  occasionally  fail  to  do  so,  when  the  condition  is  called  "  dropped 


CLINICAL    APPLICATIONS    OF    ELECTROCARDIOGRAPHS 


283 


beat."  The  electrocardiogram  records  a  P  deflection  but  no  ventricular 
complex,  showing  that  the  auricles  have  contracted  at  their  usual  rate 
but  that  the  ventricles  failed  to  respond  to  the  stimulus  coming  from 
the  sinoauricular  node  (Fig.  93). 

COMPLETE  DISSOCIATION. — In  a   simple   case   of   complete   dissociation 


t  •/!•  -T 


Fig.    93. — Partial    dissociation.      Note    the    failure    of    ventricular    response    following   the    second    P, 
which   has   been  preceded    by   two   extrasystoles    (x)    of   ventricular   origin. 

the  auricles  beat  independently  of  the  ventricles;  hence  the  P  deflection 
of  the  electrocardiograms  bears  no  relation  to  the  ventricular  complex 
(Q-R-S-T)  (Fig.  94).  The  P  deflections  space  regularly  and  are  easily 
made  out  when  they  fall  during  diastole  of  the  ventricle.  Occasionally 
the  auricle  will  happen  to  contract  during  ventricular  systole,  causing  a 
iistortion  of  the  ventricular  complex  by  the  super-imposition  of  a  P 


Fig.    94. — Complete   dissociation.      Note  that   the   P   wave   spaces   regularly   and   bears   no   definite   re 
lation  to  the  R  wave  of  the  ventricular  complex.     Auricular  rate   72.     Ventricular  rate  40. 

deflection.  Except  when  this  occurs  the  Q-R-S-T  complex  is  the  normal 
supraventricular  type.  The  P  deflections  occur  more  frequently  than 
the  Q-R-S-T  complex,  showing  that  the  auricles  are  beating  more  often 
than  the  ventricles.  The  auricular  rate  in  the  average  case  of  complete 
heart -block  is  about  72,  while  the  ventricular  rate  is  much  slower  (35  to  40). 


284 


THE    CIRCULATION    OF    THE   BLOOD 


Ventricular  Hypertrophies  and  Defects  of  the  Divisions  of  the 

A-V  Bundle 

Hypertrophy  of  the  right  ventricle  on  account  of  the  preponderance 
of  muscle  on  this  side  of  the  heart  produces  an  electrocardiogram,  in 
which  the  right  ventricular  effects  dominate  the  picture.  Such  a  record 
is  characterized  by  a  small  R  wave  in  lead  I  and  a  pronounced  S  deflec- 
tion. In  lead  III  the  reverse  obtains ;  the  R  wave  is  high  and  S  is  dimin- 
utive. In  hypertrophy  of  the  left  ventricle  the  records  are  the  opposite 
of  those  just  described.  R  is  high  in  lead  I  while  S  is  steep  in  lead  III. 

Defects  of  the  right  or  left  branch  of  the  A-V  bundle  give  electrocardio- 
grams which  closely  resemble  those  described  as  characteristic  of  left  and 


Fig.   94-A. 


Fig.   94-B. 


Fig.  94-A. — Electrocardiogram  showing  a  lesion  of  the  right  branch  of  the  conducting 
bundle.  Note  that  the  T  wave  in  this  curve  and  in  the  succeeding  one  is  opposite  in  direction 
to  that  of  the  chief  deflection  (R  or  S)  in  the  initial  phase,  and  that  the  Q-R-S  complex  is 
prolonged.  (From  E.  P.  Carter.) 

Fig.  94-B. — Illustrating  the  effect  upon  the  electrocardiogram  of  a  defect  of  the  left 
division  of  the  bundle.  (From  K.  P.  Carter.) 

right  ventricular  hypertrophy  respectively.  In  the  left  branch  defect 
the  electrical  changes  of  the  right  ventricle  will  impress  themselves  upon 
the  electrocardiogram  whilst  in  right  branch  defects  the  influence  of 
the  left  ventricle  will  prevail.  The  Q-R-S.  complex  which  normally  is 
about  l/w  sec.  in  duration  and  is  but  little  prolonged  in  the  hypertrophies 
is  very  noticeably  lengthened  in  the  bundle  defects.  (Figs.  94-A  and  94-B.) 
The  T  wave  in  the  branch  defects  is  opposite  in  direction  to  the  chief 
deflection  of  the  Q-R-S.  group.  When  R  is  prominent,  T  is  inverted, 
whereas  when  S  is  the  chief  deflection,  T  is  upright. 


CHAPTER  XXXII 

CLINICAL  APPLICATIONS  OF  CERTAIN  PHYSIOLOGICAL 
METHODS  (Cont'd) 

POLYSPHYGMOGRAMS 

(Revised  by  DR.  N.  B.  TAYLOR) 

For  purposes  of  more  precise  study  and  description  of  polysphygmo- 
grams  and  in  order  that  the  events  in  the  different  pulse  tracings  (jug- 
ular, carotid,  apex  beat,  and  radial)  may  be  correlated  accurately  with 
one  another,  in  regard  to  time,  the  following  method  of  standardization 
has  been  employed  (see  Fig.  95).  The  tracings  have  been  superimposed, 
accurately,  so  that  the  commencement  of  each  is  in  the  same  vertical 
line  (i.e.,  all  the  curves  are  made  to  start,  as  it  were,  at  the  same  in- 
stant). Perpendicular  lines  (6  in  number)  have  then  been  drawn  through 
the  tracings  at  certain  important  and  easily  recognizable  points.  Since 
the  tracings  commence  together  and  the  intersecting  lines  are  perpendic- 
ular to  them  it  is  clear  that  the  points  in  the  different  curves  which  are 
cut  by  a  given  line  will  be  synchronous,  for  example,  line  2  cuts  the 
tracing  of  the  apex  beat  at  the  commencement  of  its  upstroke  and  falls 
in  the  case  of  the  venous  tracing  near  the  summit  of  the  "A"  wave. 
These  events  in  the  respective  curves,  consequently,  must  be  of  simul- 
taneous occurrence. 

In  the  taking  of  polysphygmograms  the  following  technique  is  usu- 
ally employed: 

Venous  Pulse  Tracings. — The  subject  is  directed  to  lie  down  with  his 
head  slightly  raised  by  a  cushion  and  turned  toward  the  right  side.  An 
open  tambour  (one  having  no  rubber  membrane)  is  placed  above  the 
inner  end  of  the  clavicle  on  the  right  side  of  the  neck,  that  is,  immedi- 
ately overlying  the  jugular  bulb. 

Though  the  features  of  a  normal  and  typical  venous  pulse  tracing  may  be 
recognized  by  inspection  alone,  it  is  very  often  impossible  in  diseased 
conditions  to  identify  the  different  waves  of  the  curve  without  the  use 
of  a  standard  for  comparison.  For  this  purpose  a  simultaneous  tracing 
is  taken  from  an  artery,  the  features  of  which  (primary  and  dicrotic 

285 


286 


THE   CIRCULATION   OF   THE   BLOOD 


waves)  can  readily  be  defined.     The  receiving  button  of  a  second  tam- 
bour, therefore,  is  applied  to  the  carotid  (or  radial)  artery. 

The  writing  points  of  the  two  tambours  (venous  and  arterial)  are  then  adjusted 
to  the  recording  surface,  their  points  being  so  arranged  that  they  lie  approximately 
in  the  same  perpendicular  line.  Since  it  is  practically  impossible  to  adjust  the  two 
styles  so  that  they  lie  one  precisely  perpendicular  to  the  other,  obviously  one  style 
must  commence  to  describe  its  tracing  a  fraction  of  a  second  before  or  after  the  other 
and  vertical  lines  cutting  the  two  records  will  not  pass  through  synchronous  points. 
In  order  to  correct  for  this  difference  in  the  time  relations  of  the  two  curves,  each 


'/f  Seconds 


Ju  tjul  i 


C  a.  Y  o  C  I  d.  . 


dl  Oi.1 


Fig.  95. — Tracings  of  the  jugular  pulse,  apex  beat,  carotid  and  radial  pulses.  The  perpen- 
dicular lines  represent  the  time  of  the  following  events:  1,  The  beginning  of  the  auricular 
systole;  2,  The  beginning  of  the  ventricular  systole;  3,  The  appearance  of  the  pulse  in  the 
carotid;  4,  The  appearance  of  the  pulse  in  the  radial;  5,  The  closing  of  the  semilunar  valves;  6, 
The  opening  of  the  tricuspid  valves.  (Mackenzie.) 

style  (by  a  gentle  tap  of  the  finger  while  the  paper  is  at  a  standstill)  is  made  to 
describe  an  upright  mark.  The  lines  so  made  are  termed  alignment  marks,  and  by 
their  means  the  relative  positions  of  the  two  writing  points  are  recorded,  thus  enabling 
subsequent  time  measurements  to  be  made  with  accuracy.  After  adjusting  a  time 
marker  (one-fifth  second),  which  should  always  be  employed  simultaneously  with  the 
pulse  tracings,  the  clockwork  mechanism  which  carries  the  paper  is  started  and  al- 
lowed to  revolve  at  a  moderate  speed.  (A  convenient  form  of  apparatus  in  clinical  work 
is  shown  in  Fig.  96.) 

The  interpretation  of  the  venous  pulse  tracing  is  obtained  in  the  fol- 
lowing way:  The  distance  from  the  alignment  mark  of  the  carotid  trac- 
ing to  the  commencement  of  the  upstroke  of  the  latter  (intersection  of 
line  3)  is  measured.  The  same  distance  is  then  laid  off  on  the  venous 
tracing,  commencing  from  the  alignment  mark  of  this  tracing.  If  a 


POLYSPHYGMOGRAMS  287 

stroke  be  made  through  the  point  obtained  by  this  measurement  it 
will  be  found  to  cut  the  venous  curve  at  the  beginning  of  a  small  wave 
(c)  which  is  produced  by  the  bulging  into  the  auricles  of  the  closed  au- 
riculo-ventricular  valves.  Our  measurements  show  that  this  "c"  wave 
of  the  venous  tracing  commences  at  the  same  instant  that  the  upstroke 
appears  in  the  carotid  tracing.  That  these  events  are  simultaneous  in 
the  respective  curves  may  be  shown  in  another  way,  for  example,  should 
two  such  tracings  be  separated  (by  dividing  the  paper  longitudinally 
between  them)  and  superimposed,  so  that  their  respective  alignment 
marks  lay  in  the  same  straight  line,  we  would  find  that  line  3  drawn 
from  the  upstroke  of  the  carotid  tracing  would  when  continued  through 
the  venous  curve  intersect  the  latter  at  .the  commencement  of  the  "c" 
wave.  We  would  then  have  an  arrangement  identical  with  that  of  the 
venous  and  carotid  tracings  in  Fig.  95. 

The  auricular_^ajiZJe-(a)  of  the  venous  pulse,  which  is  due  to  the  sys- 
tole of  the  auricle,  is  determined  by  measuring  approximately  one-fifth 
of  a  second  in  front  of  the  "c"  wave.  Line  1  passes  through  the  com- 
mencement of  this  wave.  In  order  to  identify  other  waves  in  the  venous 
tracing  similar  procedures  are  carried  out  as  in  the  case  of  the  "c" 
wave  determination.  If  the  distance  from  the  alignment  mark  of  the 
carotid  tracing  to  the  commencement  of  the  dicrotic  notch  of  the  latter 
be  measured  and  the  same  distance  marked  off  on  the  venous  tracing,  a 
line  drawn  through  the  point  so  obtained  will  be  found  to  fall  upon 
the  upstroke  of  a  large  wave  "v"  close  to  its  summit.  In  a  similar 
manner  a  measurement  of  the  carotid  curve  from  its  alignment  mark  to 
the  termination  of  its  dicrotic  wave  (intersection  of  line  6)  would, 
when  transposed  to  the  venous  pulse  tracing,  indicate  a  point  on  the 
down  slope  of  "v"  a  short  distance  beyond  its  summit. 

As  the  time  consumed  in  the  propagation  of  the  pulse  to  the  jugular 
and  to  the  carotid  is  approximately  the  same  in  either  case,  the  carotid 
tracing,  in  order  to  avoid  confusion,  has  been  used  as  the  standard  for 
comparison  in  the  foregoing  calculations;  but  the  radial  curve  is  more 
commonly  employed  for  this  purpose.  When  such  is  the  case  the  time 
required  for  the  propagation  of  the  pulse  from  the  neck  to  the  wrist 
must  be  taken  into  our  calculations.  This  is  about  one-tenth  second,  so 
that  when  the  radial  tracing  is  employed  we  must  measure  to  a  point 
one-tenth  second  in  front  of  its  upstroke  (or  dicrotic  wave)  and  apply 
this  distance  to  the  venous  tracing  in  order  to  obtain  synchronous  points 
in  the  two  curves. 

The  respective  factors  responsible  for  the  production  of  the  "c"  and 
"a"  waves  have  already  been  mentioned,  the  production  of  the  other 
features  of  the  venous  pulse  tracing  remains  for  consideration.  The  de- 


288 


THE   CIRCULATION   OF    THE   BLOOD 


pression  x  is  an  indication  of  the  fall  in  intraauricular  pressure,  refer- 
ence to  the  intraauricular  pressure  curve  (Fig.  97- A)  to  which,  as  already 
explained,  the  venous  pulse  tracing  is  qualitatively  similar,  will  make 
this  clear.  The  factors  producing  this  fall  in  pressure  are  as  follows: 
(1)  relaxation  of  the  auricular  wall,  (2)  dragging  down  of  the  auricular 
floor  by  the  contracting  ventricles  (compare  the  jugular  and  apex  curves 
in  Fig.  95),  and  (3)  reduction  of  intrathoracic  pressure  consequent 


Fig.  96. — Polysphygmograph.  This  instrument  records  in  ink  on  glazed  paper  two  simul- 
taneous tracings,  i.  e.,  radial  pulse  and  one  other,  such  as  carotid,  jugular,  apex  beat,  etc.,  in  addi- 
tion to  the  time  tracing.  The  ink  tracings  are  both  more  convenient  and  permanent  than  smoked 
paper  tracings.  The  clockwork  operates  at  variable  speeds,  permitting  the  taking  of  protracted 
records  at  different  speeds. 


Fig.    97. — Normal    jugular    tracing.      The    spacing   below    shows    the    duration    of    the    a-c    interval. 

(From   E.    P.    Carter.) 

upon  the  ejection  of  blood  from  the  ventricle  into  the  arterial  system 
(see  page  215). 

The  slope  from  x  to  y  is  due  to  the  rising  intraauricular  pressure  as  the 
blood,  flowing  into  the  auricle  from  the  great  veins,  is  dammed  back 
by  the  closed  auriculo-ventricular  valves.  A  small  wave,  sometimes,  is 
seen  on  the  upstroke  of  the  "v"  wave  at  the  point  where  the  latter  is 
intersected  by  line  5 ;  this  wave  coincides  with  the  closure  of  the  semi- 
lunar  valves.  At  the  summit  of  the  "v"  wave  the  auriculp^astricular 
valves  open  and  the  fall  in  intraauricular  pressure  which  occurs,  as 


POLYSPHYGMOGRAMS 


289 


the  blood  escapes  into  the  ventricle,  is  responsible  for  the  downward 
slope  in  the  curve  from  v  to  y. 

The  Cardiogram  (tracing  of  the  apex  beat). — In  order  to  record  and 
interpret  the  cardiogram,  tambours  are  applied  to  the  apex  beat  and  the 


SEC 


Fig.  97-A. — Superimposed  pressure  curves  from  aorta,  ventricle  and  auricle,  along  with  elec- 
trocardiogram and  phonocardiogram.  A,  aorta;  V,  ventricle;  Aur,  auricle;  El,  electrocardiogram; 
Ph,  phonocardiogram. 


: 


carotid  pulse  in  similar  manner  to  that  already  described  for  the  venous 
tracing.    An  inspection  of  the  tracings  so  obtained  will  reveal  the  fol- 


290  THE   CIRCULATION   OF   THE   BLOOD 

lowing  features.  A  short  distance  (about  one-tenth  second)  in  front  of 
the  upstroke  of  the  cardiogram  a  small  wave,  sometimes,  appears.  This 
is  due  to  auricular  systole  and  is  termed  the  auricular  (a)  wave  of  the 
apex  curve:  its  commencement  coincides  with  line  1.  The  main  steep 
rise  in  the  curve  is  due  to  ventricular  systole.  Its  commencement,  which 
coincides  with  the  closure  of  the  auriculo-ventricular  valves,  is  inter- 
sected by  line  2.  Turning  now  to  the  carotid  tracing  it  is  found  that 
a  measurement  made  from  its  alignment  mark  to  the  commencement  of  its 
upstroke  when  transferred  to  the  apex  tracing  in  the  usual  way  falls 
near  the  upper  part  of  the  upstroke  of  the  latter  tracing.  This  point 
marks  the  opening  of  the  semilunar  valves  and  is  intersected  by  line  3. 
Measuring  again  on  the  carotid  tracing  from  its  alignment  mark  to  the 


A_/U\_A_/U 


Fig.  98. — Polysphygmograms  including  jugular,  apex  and  radial  tracings.  Line  4  on  the  radial 
tracing  is  first  of  all  located.  It  is  then  transferred  (by  measurement  from  the  alignment  mark  on 
the  right  edge  of  the  tracing)  to  the  jugular  and  1/10  second  subtracted  from  it,  giving  line  3. 
When  this  is  similarly  transferred  to  the  apex  tracing,  it  falls  somewhere  on  the  upstroke  the  be- 
ginning of  which  is  line  2. 

beginning  of  the  dicrotic  wave  and  applying  this  measurement  to  the 
apex  tracing  a  point  is  defined  near  the  beginning  of  the  downstroke 
of  the  latter.  This  marks  the  time  of  closure  of  the  semilunar  valves 
and  is  intersected  by  line  5.  The  termination  of  the  downstroke  in  the 
apex  curve  in  the  same  way  may  be  shown  to  be  synchronous  with  the 
termination  of  the  dicrotic  wave  in  the  carotid  tracing.  This  point  in 
the  cardiogram,  which  is  crossed  by  line  6,  marks  the  time  of  opening  of 
the  auriculo-ventricular  valves. 

The  intervals  between  the  lines  2  and  3,  3  and  5,  and  5  and  6  are 
termed  the  presphygmic,  sphygmic,  and  postsphygmic  periods  respec- 
tively (see  page  150).  The  period  between  lines  6  and  1  coincides 


POLYSPHYGMOGRAMS 


291 


with  that  part  of  the  ventricular  diastole  during  which  the  ventricle  is 
filling  with  blood,  the  auriculoventricular  valves  being  open  and  the 
semilunars  closed. 

Abnormal  Pulses 

The  following  is  a  brief  description  of  the  main  characters  of  abnormal 
pulses : 

The  Ventricular  Form  of  Venous  Pulse. — In  this  no  "a"  waves  ap- 
pear in  the  jugular  tracing,  but  the  "v"  waves  are  unduly  large  and 
dominate  the  curve.  This  type  of  venous  pulse  may  depend  upon  any 
one  of  the  following  circumstances:  (1)  onset  of  auricular  fibrillation, 
in  which  condition  the  pulse  is  usually,  though  not  always,  irregular, 
(2)  great  increase  in  the  rate  of  the  heart,  and  (3)  overfilling  of  the 
right  auricle. 

Delayed  Conduction  and  Heart-block. — This  causes  a  change  in  the 


y^M 


i — r 


X \ X    \ X X X 


Fig.   99. — Delayed   conduction   time.      First  stage   of   heart-block.      The   A-C   intervals   measure   more 
than  0.2  second.      (From  E.   P.   Carter.) 

time  relationship  of  the  "a"  and  "c"  waves  in  the  jugular  curve.  When 
the  heart-block  is  of  the  first  degree,  the  "a-c"  interval  merely  becomes 
lengthened,  but  when  it  is  of  such  degree  that  the  normal  impulse  some- 
times fails  to  be  conveyed  along  the  auriculoventricular  bundle,  isolated 
"a"  waves  can  be  detected.  In  the  higher  degrees  of  heart-block  there 
are  regularly  recurring  "a"  waves  having  no  constant  time  relationship 
to  the  "c"  waves.  For  the  purpose  of  exact  analysis  of  the  curves  in 
suspected  cases  of  delayed  conduction,  it  is  often  advantageous  to  draw 
vertical  lines  below  the  tracing  representing  the  beginning  of  auricular 
and  ventricular  systole.  This  has  been  done  in  the  tracing  reproduced 
in  Fig.  99. 

The  line  joining  these  two  verticals  indicates  the  conduction  time 
or  "a-c"  interval.  When  it  exceeds  one-fifth  of  a  second,  there  is 
delay  in  the  conduction  time. 


292 


THE    CIRCULATION    OF    THE   BLOOD 


A  tracing  showing  a  higher  degree  of  heart-block  is  given  in  Fig.  100. 

Sinus  Arrhythmia. — In  this  disorder,  which  occurs  in  children  and 
young  adults,  the  heart  as  a  whole  is  affected,  so  that  the  "a,"  "c"  and 
"v"  waves  of  the  jugular  tracing  are  in  normal  time  relations  with  one 
another.  The  pulse  is  markedly  irregular,  the  irregularity  very  fre- 
quently bearing  a  direct  relation  to  the  respirations.  A  disturbance  of 


1        T 


r!t 


Fig.    100. — Dropped    beats.      Second    stage    of    heart-block.      (From    E.    P.    Carter.) 

the  vagal  influence  is  believed  to  be  concerned  with  the  production  of 
this  type  of  arrhythmia. 

Sinus  Bradycardia. — The  beat  originates  at  long  intervals  in  the 
sinus;  the  "a-c"  interval  is  normal,  and  the  radial  pulse  very  slow  but 
practically  regular. 

Extrasystoles. — These    may    be    either    ventricular    or    auricular    in 


Fig.    101. — Premature  beats    (extrasystoles)    ventricular   in   origin   at   PB.      Compare   the   duration   of 
the  intervals  marked  A   and  B'  with   those  marked   C  and   D.      (From   E.    P.    Carter.) 

origin.  In  the  former  case  the  "a"  waves  on  the  jugular  tracing  space 
regularly  throughout,  but  the  "c"  waves  at  the  point  of  disturbance 
coincide  with  the  "a"  waves,  giving  therefore  a  more  pronounced  wave. 
This  is  due  to  a  premature  contraction  of  the  ventricle  occurring  about 


POLYSPHYGMOGRAMS 


293 


the  time  of  the  "a"  wave,  so  that  the  latter  finds  the  ventricle  in  a  re- 
fractory state  (see  page  178).  The  premature  contraction  is  therefore 
followed  by  a  compensatory  pause,  which  is  evident  on  the  tracing.  An 
example  of  such  a  case  is  given  in  Fig.  101.  In  doubtful  cases  the  exact 
site  of  origin  of  the  premature  beats  can  be  determined  only  by  careful 
measurement  of  the  distances  between  the  various  beats  of  the  ventricle. 
Whenever  an  irregularity  repeats  itself  and  the  duration  of  one  cycle 
of  the*  arrhythmia  accurately  corresponds  to  another,  the  irregularity 
may  be  due  to:  (1)  premature  auricular  or  ventricular  contractions; 
(2)  the  occasional  occurrence  of  dropped  beats  (a  failure  of  ventricular 
response) ;  or  (3)  a  high  degree  of  heart-block  with  a  wide  variation  in 
the  ventricular  response.  The  important  point  to  note  here  is  that,  no 
matter  how  irregular  such  a  tracing  may  appear,  if  the  irregularity  re- 
peats itself  it  can  not  be  due  to  auricular  fibrillation. 


Fig.    102. — Paroxysmal    tachycardia.      The    paroxysms    start    at    xx    following    normal    beats    and 
lasting  for  seven  beats.      The  clue  to  "a,"  which  falls  with   "v"  after  the   first 


tions,  is  found  in  the  initial  beat  of  the  new  rhythm.      (From  E.   P.   Carter.) 


premature   contrac- 


Paroxysmal  Tachycardia  and  Auricular  Flutter. — These  conditions  are 
characterized  by  a  very  great  increase  in  the  cardiac  rate,  the  auricles 
beating,  in  the  case  of  paroxysmal  tachycardia,  at  the  rate  of  150  to  200 
per  minute.  In  auricular  flutter  the  rate  is  more  rapid  still,  the  auricles 
attaining  a  speed  of  200  to  400  beats  per  minute.  (See  Figs.  102,  103, 
104.)  There  is  no  fundamental  distinction  to  be  made  between  these  two 
conditions;  each  is  dependent  upon  impulses  arising  from  an  unusual 
situation  in  the  auricular  muscle,  the  sinoauricular  node  having  lost  its 
control  over  the  auricular  rate.  The  respective  terms  employed  for  the 
designation  of  the  two  conditions  are  more  or  less  arbitrary  ones  based 
upon  the  extent  to  which  the  auricular  rate  is  increased;  the  term  par- 
oxysmal tachycardia  being  applied  to  cases  with  the  slower  rates  (150 
to  200  per  minute)  whilst  the  term  auricular  flutter  is  employed  in  in- 
stances where  the  higher  rates  of  auricular  contraction  prevail.  In 


294 


THE    CIRCULATION    OF    THE    BLOOD 


auricular  flutter,  however,  on  account  of  the  extreme  degree  to  which 
the  contractions  of  the  auricles  are  increased,  the  ventricles  are  rarely 
able  to  keep  pace  with  the  latter,  so  do  not  respond  to  every  auricular 
impulse.  The  failure  of  the  ventricle  is  due  partly  to  the  refractory 
phase  of  the  conducting  bundle  and  partly  to  the  refractory  phase  of 
the  ventricular  muscle  itself.  In  some  cases  the  ventricular  response 
fails  at  odd  intervals  only,  but  usually  the  missed  beat  recurs  more 
frequently.  Two,  three  or  even  four  auricular  beats  may  occur  before 


ITTTTnTnilllllMMIl'll 


Fig.   103. — Auricular  flutter.     In  this  case  the  ventricular  rate  varied  from  82  to  98  per  minute. 

(From    E.    P.    Carter.) 


Y-\ 


Fig.    104. — Auricular    flutter.      Note   the   relative    rates   of   A    and    V,    and   also    that    the   ventricular 
rate  is  regular.     (From  K.  P.  Carter.) 

one  appears  in  the  ventricle,  so  that  the  ratio  between  the  beats  of  the 
auricles  and  the  ventricles  may  be  2:1,  3:1,  or  4:1.  In  extreme  cases 
the  two  chambers  may  be  completely  dissociated,  the  auricle  beating  at 
a  rate  of  300-400  per  minute  while  the  ventricle  continues  at  its  own 
inherent  rate  of  35-40  beats  per  minute. 

Missed  beats  accompanying  auricular  flutter  must  not  be  confused 
with  true  heart  block ;  in  this  disorder  the  auricular  beats  are  not 
increased. 

Paroxysmal  tachycardia  and  auricular  flutter  are  each  characterized 


POLYSPHYGMOGRAMS 


295 


by  a  sudden  onset  and  an  intermittent  course.  In  the  former  condition 
the  paroxysm  lasts  for  a  period  varying  from  a  few  minutes  to  several 
days;  in  auricular  nutter  the  attack,  though  it  may  be  of  brief  duration, 
more  frequently  lasts  for  months. 

Auricular  Fibrillation. — The  contractions  of  the  auricle,  as  already  ex- 
plained, are  entirely  irregular,  and  the  jugular  tracings  show  an  en- 
waves,  the  radial  tracing  being  characterized  by 


Fig.  105. — Auricular  fibrillation.  Note  the  absence  of  all  "a"  waves  from  the  jugular  tracing,  the 
marked  irregularity  of  the  radial  pulse,  and  the  occurrence  of  "c"  and  "v"  during  the  sphygmic 
period.  (From  E.  P.  Carter.) 

the  complete  absence  of  a  dominant  rhythm  and  by  great  variation  in  the 
length  of  the  individual  beats  from  one  cardiac  cycle  to  the  next.  This 
irregularity  does  not  repeat  itself,  and  the  long  pauses  are  not  simple 
multiples  of  the  shortest  pause.  Tracings  from  a  case  of  auricular 
fibrillation  are  shown  in  Fig.  105. 


CHAPTER  XXXIII 

CLINICAL  APPLICATIONS  OF  CERTAIN  PHYSIOLOGICAL 
METHODS  (Cont'd) 

THE  MEASUREMENT  OF  THE  MASS  MOVEMENT  OF  THE  BLOOD 

Method. — The  apparatus  used  for  this  purpose  consists  essentially  of  a  vessel  con- 
taining a  known  quantity  (3,000  c.c.)  of  water  and  a  thermometer  from  which  a  change 
of  temperature  of  a  hundredth  of  a  degree  centigrade  can  be  read.  In  order  to 
diminish  as  much  as  possible  the  loss  of  heat  between  the  vessel  and  the  outside  air,  the 
walls  are  double,  the  space  between  being  stuffed  with  broken  cork.  The  top  of  the 
vessel  is  closed  with  a  thick  cork  plate,  having  suitable  openings  in  it  for  the  hand  or 
foot  and  for  the  thermometer  and  a  stirrer  (feather)  with  which  to  keep  the  water  in 
constant  motion.  The  apparatus  is  called  a  calorimeter. 

After  the  hand  or  foot  has  been  in  the  calorimeter,  with  the  water  a  few  degrees 
below  that  of  the  body,  for  a  certain  time  (ten  minutes)  the  temperature  of  the  water 
will  of  course  become  raised,  and  the  degree  to  which  this  occurs,  multiplied  by  the 
volume  of  water  in  cubic  centimeters,  will  give  in  calories  the  amount  of  heat  dissipated. 
By  the  application  of  a  very  simple  formula  it  is  now  an  easy  matter  to  calculate  how 
much  blood  must  have  passed  through  the  blood  vessels  of  the  part  in  order  to  give  out 
the  observed  amount  of  heat;  for,  if  we  divide  the  calories  by  the  difference  in  tempera- 
ture between  the  inflowing  and  outflowing  blood  of  the  part,  the  result  must  indicate 
the  volume  of  blood,  in  cubic  centimeters,  that  has  passed  through  it  (since  by  defini- 
tion a  calorie  equals  volume  multiplied  by  difference  in  temperature).  It  remains  to 
explain  the  equation  by  which  the  results  are  arrived  at.  If  Q  equals  the  amount  of 
blood,  H  the  calories  of  heat  given  out  to  the  calorimeter,  T  the  temperature  of  the 
arterial  blood  and  T'  the  temperature  of  the  venous  blood,  then  we  have  the  equation: 

H* 
, , _.     It  has  been  shown  by  Stewart  that  T  may  be  taken  as  the  same  as  that 

of  the  mouth,  or  0.5°  C.  below  that  of  the  rectum,  and  T'  as  the  average  temperature 
of  the  water  in  the  calorimeter  during  the  observation.     To  allow  for  the  specific  heat 

of  blood,  the  result  is  multiplied  by  IP,  the  reciprocal  of  the  specific  heat  of  blood. 

y 

Theoretically,  then,  the  method  is  very  simple,  and  there  are  no  un- 
usual technical  difficulties  in  applying  it.  The  main  precaution  is  that 
the  air  surrounding  the  calorimeter  should  be  kept  constant  in  tempera- 
ture, so  that  we  may  be  enabled  to  allow  in  our  calculations  for  the  loss 
of  heat  from  the  calorimeter  itself,  this  value  being  obtained  by  observ- 

*For  the  determination  of  H  we  must  multiply  the  cubic  centimeters  of  water  plus  the  water 
equivalent  of  the  hand  and  calorimeter  (because  both  of  these  will  absorb  some  heat)  by  the  dif- 
ference in  temperature  plus  the  self-cooling  of  the  calorimeter  (because  some  heat  is  lost  to  the 
air  during  the  observation).  The  water  equivalent  of  the  hand  is  equal  to  its  volume  multiplied 
by  0.8;  that  of  the  calorimeter  must  be  determined  for  each  instrument  and  is  usually  about  100  c.c. 
The  self-cooling  of  the  calorimeter  is  determined  by  observing  the  fall  in  temperature  for  a  period 
equal  to  that  of  the  actual  observation  without  the  hand  in  the  calorimeter. 

296 


MEASUREMENT    OF    MASS    MOVEMENT   OF    BLOOD  297 

ing  the  change  of  temperature  in  the  calorimeter  for  a  certain  period 
of  time  after  the  hand  has  been  removed  from  it. 

The  Normal  Flow 

The  results  are  calculated  on  the  basis  of  grams  of  blood  flowing 
through  100  c.c.  of  tissue  in  one  minute.  The  volume  of  the  hand  or  foot 
is  ascertained  by  placing  it  in  water  contained  in  a  small-sized  irrigation 
can,  the  tube  of  which  is  connected  with  a  burette.  The  height  to  which 
the  water  rises  in  the  burette  is  noted,  and  after  withdrawing  the  hand, 
water  is  added  from  a  graduate  to  the  irrigation  can  until  the  same 
height  is  reached  on  the  burette.  The  number  of  cubic  centimeters  re- 
quired gives  the  volume  of  the  hand.  In  a  normal,  healthy  individual 
the  average  flow  in  the  hand  is  from  12  to  13  gm.  for  the  right  hand, 
and  about  half  a  gram  less  for  the  left.  This  difference  between  the  two 
hands  corresponds,  of  course,  with  their  relative  degree  of  development. 
The  average  foot  flow  is  much  less,  and  varies  according  to  whether  the 
patient  is  sitting  up  or  lying  down  while  the  measurement  is  being  made. 
In  a  normal  individual,  while  lying  down,  it  was  5.11  gm.  in  the  right 
foot  and  5.23  gm.  in  the  left,  per  100  c.c.  of  foot;  but  only  2.96  gm.  for 
the  right  and  4.1  gm.  for  the  left  foot,  while  sitting  up.  By  extended  ex- 
perience with  the  method  we  have  found  that  the  bloodflow  is  very 
greatly  influenced  by  the  average  outside  temperature.  Although  the 
outside  influence  may  be  diminished  somewhat  by  spending  some  time 
indoors  before  the  measurement  is  actually  made,  this  does  not  entirely 
remove  the  outside  influence. 

The  Physiological  Causes  for  Variations  in  Bloodflow. — As  above  indi- 
cated, the  most  marked  of  these  is  probably  the  temperature  of  the 
room.  The  temperature  of  the  water  in  the  calorimeter  has  likewise  a 
great  influence,  and  for  the  comparison  of  different  cases  it  is  always 
important  that  the  room  and  calorimeter  temperatures  be  stated  along- 
side the  results.  Muscular  contractions,  produced  by  compressing 
a  dynamometer  by  the  fingers,  cause  a  decided  increase  in  flow.  A 
great  diminution  of  flow  results  from  constriction  of  the  arm  of  sufficient 
degree  to  obstruct  the  venous  circulation;  and  when  the  constriction, 
as  that  caused  by  a  blood  pressure  armlet,  is  increased  to  between  the 
systolic  and  diastolic  pressures,  extremely  little  blood  flows  through  the 
hand. 

By  immersing  the  opposite  hand  or  foot  in  hot  or  cold  water,  the  blood- 
flow  through  the  observed  hand  increases  or  decreases,  respectively. 
The  change  may  be  of  a  temporary  character,  or  it  may  persist  through- 
out the  whole  period  of  immersion  of  the  hand.  These  reactions  are  due 
to  a  vascular  reflex,  and  observations  of  its  sensitiveness  are  of  value  in 


298  THE     CIRCULATION     OF     THE     BLOOD 

the  study  of  the  effects  of  lesions  either  of  the  nerve  or  of  the  nerve 
centers  concerned  in  vascular  reflexes.  Massage  of  the  hand  prior  to 
placing  it  in  the  calorimeter  does  not  affect  the  flow.  Massage  of  the 
opposite  hand,  however,  appears  to  cause  an  increase  in  flow. 

Clinical  Conditions  which  Affect  the  Bloodflow 

Even  in  cases  where  there  is  plenty  of  other  evidence  of  curtailment 
of  flow,  the  measurement  may  be  of  importance  either  for  detecting 
an  alteration  in  the  vascular  reflex  or,  by  comparison  of  the  two 
hands,  for  demonstrating  the  relative  degree  of  alteration  in  flow.  In 
acute  inflammatory  conditions  affecting  one  hand,  there  is  an  increase 
in  flow  on  the  affected  side  accompanied  by  a  marked  curtailment  on 
the  other  side.  This  indicates  that  an  increased  flow  in  the  infected 
area  is  accompanied  by  a  reflex  vasoconstriction  elsewhere,  particu- 
larly in  the  symmetrically  placed  part  of  the  opposite  side  of  the 
body.  In  cases  of  nonbacterial  inflammation  of  the  hand,  as  in  gout. 
no  sign  of  vasoconstriction  may  be  observed. 

There  are  many  clinical  conditions  in  which  Stewart's  method  re- 
veals an  alteration  in  bloodflow  that  would  be  unsuspected  by  the  use 
of  ordinary  clinical  methods.  It  is  for  the  investigation  of  these  that 
the  method  is  of  greatest  value  but  it  must  be  used  with  very  great  care 
that  the  temperature  conditions  are  always  the  same;  otherwise  the  re- 
sults are  apt  to  be  misleading.  The  most  important  findings  are  as 
follows: 

Anemia. — The  bloodflow  in  the  hand  may  be  much  less  than  normal 
in  pernicious  anemia  and  secondary  anemia,  and  distinctly  curtailed 
in  chlorosis.  Since  the  minute  volume  of  the  heart  is  also  increased 
in  extreme  degrees  of  these  conditions,  the  vasoconstriction  at  the  periph- 
ery will  assist  in  compelling  more  blood  to  pass  through  the  lungs,  so  as 
to  make  up  for  deficiency  of  blood. 

Fever. — Since  changes  in  the  cutaneous  circulation  probably  con- 
stitute the  chief  factor  in  the  derangement  of  the  temperature-regu- 
lating mechanism  in  fever  (cf.  page  742),  it  is  evidently  of  great  ad- 
vantage to  be  able  to  measure  such  changes  quantitatively.  This  has 
been  done  by  Stewart  in  several  cases  of  typhoid  fever  and  in  one  case 
of  pneumonia.  In  general  it  was  found  that  the  flow  in  the  feet  never 
exceeded  the  normal  flow,  and  was  usually  much  below  it.  This  ten- 
dency to  vasoconstriction  seems  to  be  carried  into  convalescence.  For 
practical  reasons  the  handflow  has  not  been  so  extensively  studied. 
This  hyperexcitability  of  the  vasoconstrictor  mechanism  at  the  periph- 
ery is  most  naturally  interpreted  as  a  defensive  reaction  of  the  or- 


MEASUREMENT   OF    MASS    MOVEMENT    OF   BLOOD  299 

ganism  by  which  an  increased  supply  of  blood  is  imported  to  those 
internal  organs  which  bear  the  brunt  of  the  infection.  When  we  con- 
sider that  in  spite  of  this  constriction  of  the  periphery  the  blood  pres- 
sure is  low  and  the  pulse  dicrotic,  we  must  conclude  that  there  is  con- 
isiderable  dilatation  of  other  vascular  parts,  especially  the  splanchnic 
irea.  A  very  practical  application  of  these  facts  presents  itself  in  con- 
sidering the  rationale  of  the  cold-bath  treatment  for  fever.  If,  for 
example,  we  conclude  that  the  cutaneous  constriction  is  in  the  inter- 
ests of  an  increase  in  the  bloodflow  to  the  organ  on  which  the  stress 
of  the  infection  falls,  it  will  evidently  be  more  rational  to  lower  the 
temperature  by  methods  which  will  not  diminish,  and  may  even  in- 
crease, the  cutaneous  constriction  than  to  do  so  by  causing  the  vessels 
to  dilate.  In  other  words,  the  use  of  antipyretics  seems  to  be  contra- 
indicated,  since  they~^mimsh  the  body  temperature  by  causing  vaso- 
dilatation  at  the  periphery  with  a  consequent  withdrawal  of  blood 
from  the  seat  of  infection. 

Cardiovascular  Diseases. — In  cardiac  cases  the  handflow  is  far  more 
apt  to  be  markedly  deficient  where  there  is  evidence  of  serious  impair- 
ment of  the  myocardium  than  in  cases  where  a  gross  valvular  lesion 
exists  but  the  heart  action  is  strong  and  orderly.  This  indicates  that 
it  is  more  serious  for  the  force  of  the  heart  pump  to  be  interfered 
with  than  for  its  valves,  particularly  the  mitral,  to  be  leaky.  Even 
where  there  is  considerable  venous  engorgement,  the  flow  may  be  lit- 
tle diminished.  In  untreated  cases  of  auricular  fibrillation  the  blood- 
flow  is  subnormal.  After  the  administration  of  digitalis  the  bloodflow 
in  such  cases  is  often  promptly  and  decidedly  increased. 

As  would  be  expected,  arteriosclerosis  is  associated  with  a  small  blood- 
flow,  and  the  vasomotor  reflexes  are  weaker  than  in  normal  persons. 

In  aortic  aneurism,  when  the  aneurism  is  of  such  a  size  as  to  cause 
pressure  on  the  subclavian  artery  or  vein,  there  is  a  diminution  in  flow 
of  the  corresponding  hand,  but  aortic  aneurism  itself,  although  it  may 
cause  great  changes  in  the  character  of  the  pulse  beat,  does  not  decid- 
edly affect  the  mass  movement  of  the  blood.  In  aneurism  of  the  sub- 
clavian artery,  the  bloodflow  may  be  much  greater  in  the  corresponding 
than  in  the  opposite  hand,  even  though  the  amplitude  of  the  pulse  is 
very  obviously  diminished  and  the  difference  between  the  systolic  and 
diastolic  pressures  (the  pressure  pulse)  is  much  less  on  the  affected 
than  on  the  normal  side.  By  ordinary  clinical  measurements,  there- 
fore, false  estimates  of  bloodflow  are  quite  likely  to  be  made.  These 
results  are  no  doubt  owing  partly  to  vasodilatation  brought  about  by 
pressure  of  the  aneurism  on  the  brachial  plexus  and  partly  to  the 
lower  resistance  to  the  flow  of  blood  into  the  dilated  subclavian. 


300  THE    CIRCULATION    OF    THE    BLOOD 

In  Raynaud's  disease,  as  would  be  expected,  the  flow  is  small,  the 
diminution  being  more  or  less  proportional  to  the  duration  of  the 
disease.  The  contralateral  vasomotor  reaction  to  cold  is  also  pecu- 
liarly intense. 

In  diabetic  gangrene  of  the  feet  there  is  a  very  subnormal  flow  in  both 
the  hands  and  the  feet.  The  vasomotor  reflexes  are  also  feeble. 

It  is  sometimes  difficult  to  tell  whether  an  observed  curtailment  of 
flow  is  a  nervous  (reflex)  effect  or  is  due  to  some  mechanical  interfer- 
ence. There  are  two  ways  by  which  the  exact  cause  may  be  diagnosed: 
(1)  by  observing  the  flow  from  day  to  day;  if  it  remains  unchanged, 
any  alteration  must  be  dependent  on  mechanical  causes;  (2)  by  observ- 
ing the  change  in  flow  brought  about  by  altering  the  temperature  of  the 
room  or  calorimeter  and  seeing  whether  the  ratio  between  the  two  hands 
remains  unchanged  or  becomes  altered.  If  the  latter  occurs,  the  in- 
equality in  flow  must  be  due  to  nervous  causes. 

Diseases  of  the  Nervous  System. — The  effect  of  neuritis  on  the  flow 
varies  with  the  duration  of  the  disease.  In  cases  of  early  peripheral 
unilateral  neuritis  there  may  be  an  increase  of  flow  altering  the  ratio  be- 
tween the  two  hands  with  the  greater  flow  on  the  diseased  side.  In 
neuritis  of  long  standing  the  flow  is  cut  down,  the  greater  flow  occurring 
on  the  healthy  side.  The  changes  here  are  probably  due  to  anatomical 
alterations  in  the  lumen  of  the  tube,  perhaps  a  thickening  of  the  intima. 
In  motor-neuron  disease  without  any  involvement  of  the  sensory  skin 
nerves  the  flow  seems  to  remain  normal  and  the  reflexes  to  be  well- 
marked.  This  indicates  that  involvement  of  the  motor  nerves  does  not 
interfere  with  bloodflow  to  anything  like  the  same  degree  as  involvement 
of  the  skin  nerves. 

Hemiplegia. — A  deficiency  of  bloodflow  of  the  paralyzed  side  is  usually 
observed,  and  the  vasomotor  reflexes  are  altered,  the  most  usual  change 
being  that  vasoconstriction  is  more  easily  produced  than  vasodilatation. 
In  some  cases  an  abnormal  tendency  to  vasoconstriction  is  a  conspicuous 
feature. 

Tabes  Dorsalis. — The  flow  is  distinctly  diminished,  especially  in  the 
feet,  although  also  in  the  hands,  and  the  vasomotor  reflexes  are  feeble. 
Sometimes  there  is  inequality  in  the  flow  of  the  two  hands,  which  how- 
ever need  not  necessarily  indicate  a  unilateral  lesion  of  the  cord  in  the 
cervical  region. 


CHAPTER  XXXIV 
SHOCK 

Shock  may  be  due  to  a  variety  of  causes.  In  general  it  may  be  de- 
scribed as  a  condition  in  which  there  is  more  or  less  paralysis  of  the 
sensory  and  motor  portions  of  the  reflex  arc,  along  with  profound  dis- 
turbances in  the  circulatory  system,  subnormal  temperature,  and  fre- 
quent and  shallow  respiration.  Certain  of  the  symptoms  may  be  consid- 
ered as  primary  and  others  as  secondary,  an  important  step  in  the  in- 
vestigation of  this  difficult  and  important  problem  being  to  distinguish 
between  the  two  groups.  Before  attempting  to  do  this,  however,  it  will 
be  profitable  to  differentiate  as  sharply  as  possible  the  various  conditions 
in  which  one  or  another  of  the  many  varieties  of  shock  is  liable  to  occur. 

Several  varieties  of  shock  have  been  described  but  it  is  particularly 
that  known  as  surgical  or  secondary  shock  that  is  important.  The  less 
important  varieties  are  as  follows: 

1.  Gravity  Shock. — This  is  caused  by  the  stagnation  of  blood  in  the  splanchnic  ves- 
sels and  the  consequent  inadequate  filling  of  the  heart  in  diastole.  It  occurs,  when  the 
erect  position  is  assumed,  in  animals  in  which  the  mechanism  which  ordinarily  compen- 
sates for  the  tendency  of  gravity  to  make  the  blood  flow  to  the  dependent  parts  is 
inadequate.  Thus,  when  a  domesticated  rabbit  with  a  large  pendulous  abdomen  is 
held  in  the  vertical  tail-down  position  for  any  length  of  time,  the  animal  gradually 
passes  into  a  shocked  condition  and  may  die  in  a  short  time  (20  to  30  minutes).  Ob- 
servation of  the  blood  vessels  of  the  ear  or  a  record  of  arterial  blood  pressure  will 
show  that  the  cause  of  shock  in  this  case  has  been  a  great  curtailment  of  the  blood 
supply  to  the  upper  part  of  the  body,  and  therefore  to  the  nerve  centers.  The  shock 
is  entirely  dependent  upon  the  laxity  of  the  abdominal  musculature,  for  if  a  binder 
is  applied  to  the  abdomen,  or  if  the  experiment  is  performed  on  a  rabbit  whose 
abdominal  musculature  is  in  good  condition,  gravity  shock  does  not  develop.  Nor  can 
fatal  gravity  shock  be  produced  in  a  dog,  although  in  a  deeply  anesthetized  animal 
a  marked  fall  in  arterial  blood  pressure  occurs  when  the  vertical  toil-down  position  is 
assumed.  In  man,  in  whom  compensation  for  the  erect  posture  is  highly  developed, 
shock  from  gravity  occurs  only  when  there  has  been  some  other  considerable  upset  in 
the  circulatory  mechanism  (see  also  page  249). 

2.  Hemorrhagic  Shock. — Free  hemorrhage  produces  a  typical  condition  of  shock,  but 
the  extent  to  which  different  individuals  react  to  the  same  degree  of  hemorrhage 
varies  considerably.  The  essential  factor  in  the  production  of  hemorrhagic  shock  is 
of  course  similar  to  that  of  gravity  shock — namely,  a  deficient  diastolic  filling  of  the 
heart  with  blood.  Details  concerning  the  effect  of  hemorrhage  will  be  found  elsewhere 
(page  138). 

In  man  hemorrhagic  shock  is  often  indistinguishable  from  surgical  shock.  This  does 

301 


302  THE   CIRCULATION    OF    THE   BLOOD 

not  mean  that  every  case  of  severe  hemorrhage  is  necessarily  also  suffering  from  the 
condition  usually  understood  as  surgical  shock,  but  hemorrhage  greatly  predisposes  to 
shock,  and  unfortunately  it  is  often  impossible  to  tell  from  the  symptoms  alone  how 
much  of  the  latter  is  present.  The  diagnosis  is  clinched  by  the  effect  of  transfusion; 
the  hemorrhagic  case  quickly  recovers  whereas  that  in  shock  only  slowly,  if  at  all. 

3.  Anesthetic  Shock. — So  far  as  blood-pressure  reflexes  are  concerned,  an  animal  can 
be  kept  in  a  perfect  condition  when  ether  is  administered  in  just  sufficient  amount  to 
produce  light  anesthesia.  When  larger  quantities  of  ether  are  employed,  a  typical  con- 
dition of  shock  may  supervene  after  a  time.  In  such  instances  the  arterial  blood  pres- 
sure remains  low  and  cannot  be  restored  even  after  an  hour  or  two  of  artificial  respira- 
tion. The  danger  of  anesthetic  shock  has  been  considerably  diminished  in  the  clinic 
by  the  more  careful  administration  of  ether  or  by  the  use  of  other  anesthetics,  such 
as  nitrous  oxide  gas.  A  condition  closely  simulating  shock  may  also  be  induced  in 
the  earlier  stages  of  the  administration  of  anesthetics  when  these  are  badly  given,  but 
paralysis  of  the  heart  or  of  the  respiratory  center  is  a  usual  cause. 

In  cases  which  have  recovered  from  the  shock  which  often  follows  immediately  after 
some  severe  accident,  and  which  is  usually  called  primary  shock,  the  administration 
of  an  anesthetic  may  bring  on  secondary  shock.  The  danger  is  least  when  nitrous  oxide 
is  used. 

4.  Spinal  Shock. — Spinal  shock  is  produced  by  section  of  the  spinal  cord,  but  it  is 
to  be  carefully  distinguished  from  all  other  forms  of  shock  because  of  its  local  charac- 
ter, as  it  affects  only  those  parts  of  the  body  which  lie  below  the  level  of  the  lesion 
in  the  cord.  Above  this  level  the  animal  may  be  in  a  perfectly  normal  condition,  except 
in  cases  where  the  section  has  been  at  so  high  a  level  that  it  has  severed  the  vaso- 
constrictor pathway  and  thereby  produced  a  fall  in  blood  pressure  from  vasodilatation. 
Even  when  this  has  happened  the  part  of  the  animal  anterior  to  the  spinal  lesion  is  by 
by  no  means  in  a  condition  of  shock.  Thus,  Sherrington  observed  in  a  monkey  whose 
spinal  cord  had  been  cut  far  forward  that,  although  the  posterior  part  of  the  body  was 
in  profound  spinal  shock  and  the  blood  pressure  very  low,  the  animal  amused  himself 
by  catching  flies  with  his  hands.  A  sufficient  description  of  the  condition  of  spinal 
shock  will  be  given  elsewhere,  but  here  it  may  be  noted  that  it  consists  essentially 
in  a  paralysis  involving  at  first  all  of  the  reflex  mechanisms,  including  the  control  of 
the  sphincters,  in  the  part  of  the  cord  posterior  to  the  section.  In  the  course  of  a  few 
days  or  weeks,  according  to  the  position  of  the  animal  in  the  scale  of  development, 
the  reflexes  gradually  return,  until  ultimately  in  a  couple  of  months — in  a  dog,  for 
example — they  may  all  have  reappeared.  The  cause  of  this  shock  is  no  doubt  the 
sudden  interruption  of  the  nervous  pathways  which  reflex  action  ordinarily  takes  in 
the  higher  animals  (see  page  924). 

5.  Toxic  Shock. — The  condition  known  as  anaphylaxis  and  that  which  follows  the  in- 
jection of  histamine  into   normal  animals   furnish  the  best  known   examples   of  toxic 
shock.     There  is  also  some  strong  evidence  that  a  toxic  factor  is  often  involved  in  the 
causation    of    clinical   shock.     The    toxic    substance    may    be    liberated    from    a    septic 
process,  as  in  septic  peritonitis,  or  from  bruised  and  mutilated  tissue,  as  after  a  com- 
pound fracture.     Experience  has   shown  that   rapid   amputation   of   a  much   mutilated 
limb  in  a  shocked  patient  has  not  infrequently  ushered  in   striking  changes   for  the 
better.     The  shock  which  develops  in  intestinal  obstruction  has  been  shown  by  Whipp 
and  his  coworkers  to  be  due  to  a  proteose  absorbed  from  the  obstructed  loops    (see 
page  538). 

6.  Nervous  Shock;   "Shell  Shock." — Considerable  attention  has  been  paid  to  the 
nervous  shock  that  has  frequently  been  observed  in  men  who  have  been  subjected  to  the 
harrowing  sights  and  the  constant  noise  and  nerve  strain  incurred  in  modern  warfare. 


SHOCK  303 

The  symptoms  may  appear  suddenly  at  the  front  or  they  may  develop  in  men  who 
have  comported  themselves  in  an  apparently  normal  manner  until  removed  to  the  rear, 
when  they  pass  into  a  condition  more  or  less  simulating  that  of  shock.  Severe  con- 
ditions may  also  result  to  soldiers  from  injuries  which  in  normal  individuals  would 
not  in  themselves  be  sufficient  to  produce  surgical  shock.  The  characteristic  symptoms 
in  such  cases  are  frequently  different  from  those  of  other  forms  of  shock,  and,  as 
has  been  shown  by  Elliot-Smith25  and  T.  H.  Pear,2^  the  condition  must  be  treated  from 
the  neurologic  or  psychopathic  point  of  view. 

Sometimes  however  a  profound  condition  of  shock  which  yields  to  no  treatment  sets 
in  without  any  degree  of  injury  that  would  adequately  account  for  it.ss 

7.  Surgical  Shock. — It  is  this  variety  that  is  usually  referred  to  when  one  speaks 
of  shock.  It  may  be  caused  either  by  severe  ^mechanical  injury  to  a  healthy  person 
or  by  extensive  manipulation  and  rough  handling  on  the  operating  table.  It  is  a  com- 
mon sequela  to  war  injuries  and  industrial  accidents,  especially  where  the  destruction 
of  muscular  tissue  has  been  extensive.  -However  produced,  the  symptoms  of  surgi- 
cal shock  are  very  much  the  same.  \yi(e-  patient  is  restless  and  keenly  alert  mentally. 
He  complains  of  great  thirst  but  if  given  water  almost  immediately  vomits  it.  His 
skin  is  a  peculiar  grey  color  and  the  lips  and  gums  are  more  or  less  cyanotie;  the  skin 
feels  cold  and  is  moist  with  sweat;  the  reflexes  are  greatly  diminished,  and  it  is 
usually  only  after  applying  a  very  painful  stimulus  that  any  movement  of  defense  is 
elicited  or  resentment  is  shown  on  the  part  of  the  patient.  The  postural  reflexes  are 
also  abolished,  so  that  if  a  limb  is  lifted  it  falls  back  limp  and  toneless.  The  pulse  at 
the  wrist  is  very  rapid,  thin  and  almost  imperceptible,  and  the  arterial  blood  pressure 
is  usually  abnormally  low.  The  respirations  are  frequent  and  shallow.  The  rectal  tem- 
perature is  1°  C.  or  more  below  normal.  The  pupils  are  dilated  and  react  slowly  to 
light.  The  symptoms  are  thus  not  unlike  those  of  cholera. 

In  shock  observed  in  the  trenches  and  clearing  stations  it  came  to  be 
recognized  that  there  are  two  stages,  primary  and  secondary.  The  con- 
dition described  in  the  preceding  paragraph  is  that  of  secondary  shock. 
The  primary  shock  comes  on  immediately  the  wound  is  received  or 
shortly  after,  when  the  patient  sees  his  wound  or  realizes  the  gravity 
of  his  condition.  It  may  be  analogous  to  the  effect  caused  by  the  re- 
ceipt of  bad  news,  fright,  etc.  By  free  administration  of  fluids  and  by 
keeping  the  body  warm  this  primary  shock  is  likely  to  be  recovered 
from ;  but  if  the  patient  be  left  untreated  it  is  apt  to  pass  on  to  second- 
ary shock,  the  factors  producing  which  are  several. 

Although  the  above  classification  is  convenient  for  descriptive  pur- 
poses it  must  be  remembered  that  the  clinical  condition  of  shock  is 
usually  due  to  the  combined  action  of  several  causes,  e.g.,  hemorrhage, 
toxins,  and  anesthetics.  Any  one  cause  may  be  insufficient  but  if  two 
act  together  the  effect  will  be  greater  than  the  sum  of  the  two  acting 
separately,  and  this  is  particularly  the  case  if  they  be  allowed  to  act  for 
a  long  time.  Since  cold  is  a  factor  in  the  causation  of  shock,  it  is  most 
important  to  keep  the  patient  warm  from  the  moment  at  which  the  onset 
of  shock  is  feared. 


304  THE    CIRCULATION    OF    THE    BLOOD 

Experimental  Investigations  of  Shock 

In  the  investigation  of  a  problem  of  this  nature  little  real  progress 
can  be  made  unless  it  is  possible  to  reproduce  the  condition  by  experi- 
mental means  on  laboratory  animals.  The  various  factors  which  con- 
tribute to  bring  about  the  shock  can  then  be  investigated  under  con- 
trolled conditions  and  a  rational  therapy  evolved.  It  was  only  after 
attacking  the  problem  of  shock  in  this  manner  that  it  became  possible 
to  treat  the  condition  in  man  with  any  measure  of  success.  For  inducing 
shock  experimentally  several  methods  have  been  employed,  of  which  the 
following  are  important;  1,  rough  manipulation  of  the  abdominal  vis- 
cera; 2,  repeated  electrical  stimulation  of  large  afferent  nerves; 
3,  applying  a  clamp,  off  and  on,  for  a  little  over  two  hours  to  the 
inferior  vena  cava  just  above  the  liver,  or  to  the  aorta,  to  such  a  degree 
that  the  arterial  blood  pressure  is  kept  at  about  40  mm.  Hg.31;  4,  mas- 
sive injections  of  adrenaline.  Since  the  experiments  are  usually  per- 
formed on  anesthetized  animals,  the  effect  of  the  anesthetic  is  a  contrib- 
utory factor  in  producing  the  shock. 

Having  induced  a  condition  of  shock,  the  first  step  in  an  investiga- 
tion into  its  cause  consists  in  a  differentiation  of  the  symptoms  into  pri- 
mary and  secondary. 

The  earlier  investigators  were  naturally  attracted  to  the  pronounced 
fall  in  blood  pressure  as  the  most  outstanding  symptom  in  shock;  and 
attention  was  directed  to  its  cause.  These  might  be  either  a  lowering  of 
peripheral  resistance  or  a  diminished  output  of  blood  from  the  left  ventri- 
cle. It  was  believed  by  Crile  that  the  former  was  the  cause,  and  that  it 
developed  because  of  a  universal  dilatation  of  the  arterioles  brought  about 
by  exhaustion  of  the  tone  of  the  vasoconstrictor  center.  It  has  been 
clearly  shown,  however,  that  the  tone  of  this  center  is  practically  normal 
in  shock,  and  that  the  arterioles  are  maintained  not  in  a  dilated  but  in  a 
contracted  state,  indicating  clearly  therefore  that  the  low  blood  pressure 
must  be  dependent  upon  inadequate  output  of  blood  from  the  heart.  The 
evidence  for  this  conclusion  is  as  follows:  (1)  W.  T.  Porter26  and  his  col- 
laborators have  shown  that  both  pressor  and  depressor  reflexes  (page  243) 
are  perfectly  normal  in  a  rabbit  that  is  in  a  condition  of  extreme  shock.  It 
is  particularly  important  that  depressor  effects  are  still  obtained  in  shock, 
since  this  indicates  that  tonic  activity  of  the  center  must  still  be  present. 
(2)  Morrison  and  Hooker  29  found  that  the  outflow  of  blood  from  the  or- 
gans of  a  shocked  animal,  when  these  are  perfused  through  their  blood 
vessels  with  the  organ  in  situ,  is  less  than  that  from  the  same  organs  under 
normal  conditions.  Furthermore,  severing  of  the  nerve  of  such  an  organ 
has  the  usual  effect  of  causing  an  increased  outflow.  (3)  This  same  fact  has 
been  shown  by  Seelig  and  Joseph,27  who  cut  the  vasomotor  nerve  proceeding 


Fig.  106. — Illustration  showing  the  appearance  of  the  blood  vessels  in  the  ears  of  a  rabbit 
"in  a  state  of  deep  shock."  The  marked  vasoconstriction  is  very  plain  in  the  left  ear,  the  ves- 
sels of  the  right  ear  being  dilated  because  the  cervical  sympathetic,  which  carries  the  constrictor 
fibers,  has  been  cut.  (From  Seelig  and  Joseph.) 


SHOCK  305 

to  the  vessels  of  one  ear  of  a  white  rabbit  and  thus  caused  a  local  paralytic 
dilatation  of  the  vessels.  Intense  shock  was  then  induced,  after  which 
the  blood  pressure  in  the  anterior  part  of  the  animal  was  suddenly  raised 
by  applying  a  clamp  to  the  abdominal  aorta  just  below  the  diaphragm. 
This  increased  blood  pressure  caused  the  vessels  of  the  denervated  ear  to 
become  engorged  with  blood,  but  not  those  of  the  opposite  normal  ear, 
which  retained  their  tone  (Fig.  106).  (4)  The  volume  of  blood  expelled 
by  the  ventricles  has  been  shown  by  Henderson28  to  be  distinctly  diminished 
in  the  early  stages  of  shock,  before  there  is  a  pronounced  fall  in  blood 
pressure  indicating  that  there  must  be  a  compensatory  constriction  of  the 
arterioles. 

To  the  foregoing  evidence  of  a  constricted  condition  of  the  arterioles 
in  shock,  may  be  added  the  less  direct  evidence  furnished  by  the  pallor 
of  the  shocked  patient  and  the  indications  that  the  sympathetic  nervous 
system,  instead  of  being  paralyzed,  is  in  an  excited  state,  as  shown  by 
the  sweating  and  the  dilated  pupils. 

Furthermore,  we  know  from  the  experiments  of  Pike,  Guthrie  and 
Stewart30  that  the  vasomotor  center  can  withstand  complete  anemia  with- 
out losing  its  tone  or  reflex  activity,  better  than  any  of  the  other  cardinal 
centers. 

Those  who  have  maintained  that  a  deficiency  in  the  tone  of  the  vaso- 
constrictor and  other  nerve  centers  is  responsible  for  shock  have  based 
their  evidence  partly  on  histological  examination  of  nerve  cells  of  shocked 
animals,  it  being  assumed  that  the  chromatolysis  shown  by  these  cells 
indicates  an  exhausted  condition.  The  assumption  is,  however,  entirely 
unwarranted,  and  no  regard  is  given  to  the  well-established  fact  that 
similar  histological  changes  may  be  produced  by  other  conditions.  It 
is  certainly  safe  to  conclude  that  the  changes  in  the  nerve  cells  in  shock 
are  the  result  and  not  the  cause  of  this  condition.  It  may  be,  as  suggested 
by  Mott,38  that  toxic  substances  liberated  from  damaged  tissues  are  in 
part,  at  least,  responsible  for  the  chromatolysis. 

Since  the  fall  in  arterial  blood  pressure  occurs  with  contracted  ar- 
terioles, it  must  be  dependent  on  a  diminished  discharge  of  blood  from 
the  heart.  Interference  with  the  heart  action  itself  (independently  of 
the  blood  carried  to  this  organ),  or  a  deficiency  in  the  filling  of  the  ven- 
tricles during  diastole,  are  the  possible  causes  for  the  diminished  output. 
The  possibility  that  the  heart  action  itself  has  been  interfered  with,  as  for 
example,  by  paralysis  of  the  vagus  mechanism,  causing  a  rapid  beating 
and  consequent  shortening  of  the  filling  (diastolic)  period  of  the  heart, 
has  been  shown  to  be  untenable  by  various  experiments.  Thus,  when 
the  arterial  blood  pressure  is  artificially  raised,  either  by  epinephrine  in- 
jection or  by  cerebral  compression,  the  heart  promptly  responds  to  the  in- 


306  THE    CIRCULATION   OF   THE   BLOOD 

creased  blood  pressure  by  contracting  more  slowly  and  vigorously.  Neither 
is  there  evidence  that  the  force  of  the  heart  beat  is  in  itself  diminished. 
When  the  organ  is  exposed  it  is  seen  to  beat  vigorously.  Evidently,  there- 
fore, as  the  cardiac  mechanism  itself  is  normal,  the  deficient  discharge  of 
blood  must  be  dependent  upon  improper  diastolic  filling.  After  this  con- 
dition of  oligemia  has  set  in,  it  becomes  progressively  worse  because  of 
weakening  of  the  heart  muscle,  consequent  upon  the  failing  blood  supply 
through  the  coronary  vessels,  and  this  again  upon  a  curtailment  of  the 
amount  of  blood  in  actual  circulation. 

The  Cause  of  the  Oligemia. — In  the  first  place  it  is  important  to  recall 
that  mechanical  obstruction  of  the  inferior  vena  cava  is  followed  ulti- 
mately by  the  usual  signs  of  shock.  Such  interference  with  the  venous 
return  to  the  heart  may  also  possibly  be  caused  by  excessive  movements 
of  the  thorax,  as  during  artificial  respiration.  That  this  in  itself  may  lead 
to  shock  is  known  to  all  experimental  investigators  on  the  subject,  although 
the  interpretation  has  not  always  been  that  which  is  given  above.  Yan- 
dell  Henderson,32  for  example^  thought  the  excessive  ventilation  to  be 
the  factor  responsible  for  the  shock,  by  causing  a  blowing  off  of  carbon 
dioxide  from  the  blood  (see  page  382)  and  a  consequent  low  tension  of 
this  gas  in  the  blood  (acapnia). 

As  in  gravity  shock,  so  in  surgical  shock,  stagnation  of  Hood  in  the 
splanchnic  area  is  common;  the  animal  bleeds  into  his  own  (splanchnic) 
blood  vessels  (capillaries  and  venules),  because  these  have  lost  their  tone. 
As  we  have  noted  above,  one  of  the  most  certain  ways  of  producing 
shock  is  by  exposure  and  rough  handling  of  the  abdominal  viscera.  It 
is  therefore  of  importance  to  study  the  effects  that  can  be  noted  on 
the  blood  vessels  of  this  area  under  such  conditions.  When  the  viscera 
are  first  exposed  to  air,  there  may  be  a  short  period  during  which  vaso- 
constriction  is  evident.  This  is  soon  followed  by  a  dilatation  of  the  capil- 
laries and  veins  as  during  the  first  stage  of  inflammation.  The  resulting 
accumulation  of  blood  in  the  mesenteric  veins  has  been  shown  by  Mor- 
rison and  Hooker  to  cause  an  increase  in  the  weight  of  an  isolated  loop 
of  intestine  as  an  animal  passes  into  a  state  of  shock.  Erlanger  and  his 
coworkers  insist  also  on  the  constant  appearance  in  shocked  animals  of 
marked  dilatation  of  the  capillaries  and  venules  of  the  intestinal  villi. 
In  the  milder  forms,  the  congestion  may  be  confined  to  the  duodenum.31 

Engorgement  of  the  abdominal  vessels  alone  does  not,  however,  suffice 
to  explain  all  the  curtailment  of  blood,  and  we  are  driven  to  the  con- 
clusion that  much  is  lost  in  the  capillaries  of  the  tissues  outside  the  abdo- 
men. As  a  matter  of  fact,  Cannon  and  others  have  found  that  concentra- 
tion of  the  blood  occurs  in  these  capillaries,  as  indicated  by  comparisons 
of  the  percentage  of  corpuscles  and  hemoglobin  in  blood  drawn  from  veins 


SHOCK  307 

and  from  capillaries  respectively.  Normally  the  values  are  equal;  in 
shock  on  the  other  hand  the  venous  blood  is  much  concentrated,  which 
indicates  that  plasma  must  have  left  the  blood  in  the  capillaries. 

To  understand  the  nature  of  the  process  by  which  this  loss  of  blood  occurs 
in  the  capillaries,  it  is  important  to  digress  here  to  consider  the  results 
obtained  by  H.  H.  Dale  and  A.  N.  Richards53  on  the  effects  of  histamine  on 
the  circulation.  It  is  by  an  application  of  the  work  of  these  investigators 
that  much  light  has  been  thrown  on  the  shock  problem  in  recent  years. 

Evidence  Obtained  by  a  Study  of  the  Shock  Produced  by  Histamine.— 
Histamine  is  derived  by  removal  of  the  carboxyl  group,  as  C02,  from 
histidine,  one  of  the  most  important  of  the  building  stones  of  the  pro- 
tein molecule.  Injected  quickly  into  etherized  animals  in  very  minute 
dosage  (1  mg.  per  kg.  body  weight)  histamine  soon  causes  the  arte- 
rial blood  pressure  to  fall  to  the  shock  level  of  30-40  mm.  Hg.  For  a  brief 
period  preceding  the  fall  there  is  a  rise  in  pressure  due  to  constriction  of  the 
arterioles,  and  this  constriction  persists  while  the  pressure  is  falling.  So  far 
as  the  obvious  vascular  changes  are  concerned,  therefore,  the  condition -is 
strictly  comparable  with  those  found  in  shock — low  blood  pressure  and  con- 
stricted arterioles.  By  the  time  the  pressure  has  fallen  to  near  the  shock 
level  the  cardiac  pulsations  disappear  from  the  tracing.  The  respirations 
also  cease,  but  if  the  animal  be  kept  alive  by  artificial  respiration  and  the 
thorax  opened  for  inspection  of  the  heart  this  organ  will  be  observed  to  be 
beating  quite  vigorously,  with,  however,  a  pronounced  deficiency  of  blood 
in  the  auricles  and  in  the  large  veins  both  of  the  thorax  and  abdomen. 
This  observation  affords  positive  proof  that  in  this  form  of  shock  at  least 
the  fundamental  cause  for  the  condition  is  inadequate  blood  flow  to  the 
heart.  The  question  is,  what  becomes  of  the  blood?  Either  it  must  pass 
out  of  the  blood  vessels  into  the  tissues,  or  the  capacity  of  the  former  must 
be  increased.  Loss  of  blood  itself  could  scarcely  occur  short  of  hemorrhage 
— of  which  there  is  no  evidence  in  histamine  shock — but  the  water  with  some 
of  the  soluble  constituents  (plasma)  might  become  extravasated,  leaving  in 
the  vessels  blood  excessively  rich  in  corpuscles.  Such  extravasation  ac- 
tually occurs  in  acute  histamine  shock,  as  revealed  by  measurement  either 
of  the  concentration  of  hemoglobin  or  of  the  corpuscles,  but  this  in  itself 
cannot  explain  all  of  the  loss  in  circulating  blood,  for  if  the  histamine  be 
given  slowly  (over  a  period  of  20-30  min.)  it  takes  much  longer  for  the 
shock  to  become  established,  and  the  blood  does  not  show  any  increase  in 
the  percentage  of  hemoglobin  or  in  the  number  of  corpuscles.  In  these 
cases  we  are  driven  to  conclude  that  much  of  the  blood  must  be  withdrawn 
from  currency  by  stagnation  in  dilated  vessels.  Direct  evidence  for  this 
important  conclusion  has  been  secured  by  determination  of  the  volume  of 


308  THE    CIRCULATION    OF    THE    BLOOD 

circulating  blood,  by  means  of  the  vital  red  method  of  Keith,  Rowntree  and 
Geraghty,52  described  elsewhere  (page  86). 

Although  the  oligemia  is  due  in  great  part  to  dilatation  of  the  capillaries 
and  venules  of  the  intestine,  as  can  be  shown  by  inspection,  it  is  also  partly 
dependent  upon  dilatation  of  vessels  elsewhere,  since  histamine  shock  can 
be  induced  in  animals  from  which  all  of  the  intestines  have  been  removed. 
The  vessels  of  the  skeletal  muscles  are  probably  the  chief  extraabdominal 
vessels  affected,  for  although  no  dilatation  of  these  can  ordinarily  be  seen 
in  histamine  shock,  it  becomes  quite  evident  in  animals  which  have  been 
transfused  before  being  shocked.  The  capillaries  (and  venules)  in  these 
areas  evidently  lose  their  tone  so  that  they  become  too  roomy  for  the 
available  blood.  As  a  matter  of  fact  Dale  and  Richards53  have  shown  that 
histamine  abolishes  the  tone  of  capillaries  at  the  same  time  that  it  in- 
creases the  permeability  of  the  walls  and  so  permits  the  plasma  to  leak 
through.  It  is  on  account  of  this  latter  action  that  histamine  when  it  is 
rubbed  on  the  scarified  skin  soon  causes  the  formation  of  a  wheal  like  that 
following  the  lash  of  a  whip.54 

When  histamine  is  given  to  unanesthetized  animals  about  ten  times 
as  much  can  be  withstood  as  in  those  that  are  anesthetized  with  ether.38 
At  first  sight  this  result  might  seem  to  discount  the  observations  on  ether- 
ized animals,  but  on  the 'contrary  they  greatly  enhance  their  importance. 
They  indicate  that  whereas  the  normal  animal  is  able  to  combat  the  toxic 
action  of  histamine,  ether  greatly  depresses  this  power,  an  observation 
which  agrees  remarkably  with  the  clinical  experience  that  administration 
of  ether  is  most  dangerous  in  persons  who  are  threatened  with  shock.  The 
poisoning  effect  of  ether  persists  for  some  time  after  the  anesthetic  is  re- 
moved, and  it  is  no  doubt  dependent  upon  a  toxic  action  on  the  endothe- 
lium  of  the  capillaries,  for  it  is  particularly  in  such  animals  that  concen- 
tration of  the  blood  is  evident  after  histamine.  It  is  of  great  significance 
that  histamine  did  not  readily  produce  shock  in  nitrous  oxide  anesthesia. 

Hemorrhage  also  greatly  predisposes  to  histamine  shock,  but  in  this  case 
the  blood  is  not  nearly  so  concentrated  as  ordinarily  because  of  the  passage 
of  plasma  from  the  tissue  spaces  into  the  vessels,  which,  it  will  be  remem- 
bered, is  the  natural  reaction  of  an  animal  to  hemorrhage  alone.  The 
cause  of  shock  in  such  animals  is  mainly  the  opening  up  of  the  vessels. 

Many  bacterial  toxins,  both  when  applied  to  scarified  skin  and  when  in- 
jected intravenously,  have  effects  very  like  those  of  histamine.  It  is  also 
well  known  that  shock  is  peculiarly  common  after  injuries  in  which  there 
has  been  extensive  destruction  of  tissue.  The  facts  warrant  the  suggestion 
that  shock  may  be  due  to  liberation  from  damaged  tissues,  particularly 
the  muscles  and  the  viscera,  of  toxic  substances  acting  like  histamine.  This 
conforms  with  the  fact  that  shock  is  most  common  when  there  has  been 


SHOCK  309 

extensive  destruction  of  muscle,  or  when  the  liver  or  intestines  are  roughly 
handled.  It  is  possible  also  that  the  shock  of  intestinal  obstruction  is  fun- 
damentally due  to  absorption  into  the  blood  of  similar  substances  from  the 
closed  loop  of  intestine.  Whipple  and  Hooper's  discoveries  that  absorp- 
tion of  a  proteose  is  responsible  for  the  shock-like  symptoms  of  intestinal 
obstruction  are  very  suggestive  in  this  connection  (page  538). 

The  Possibility  that  Traumatic  Toxemia  is  a  Factor  in  Surgical  Shock. — 
\\Is  it  possible  that  surgical  shock  is  dependent  upon  intoxication  by  hista- 
mine-like  substances  absorbed  from  greatly  damaged  tissues  ?  To  test  this 
hypothesis  Cannon38  and  others  have  investigated  the  effects  of  crushing 
the  muscles  of  the  hind  limbs,  without  external  hemorrhage,  by  blows 
from  a  heavy  hammer.  It  was  found  that  an  immediate  fall  in  blood  pres- 
sure occurred,  followed  by  a  more  gradual  decline  to  the  shock  level,  with 
a  decrease  in  the  C02-combining  power  and  a  marked  concentration  of 
the  blood.  This  result  was  not  due  to  irritation  of  afferent  nerves,  caus- 
ing excessive  stimulation  of  the  vasomotor  centers,  since  it  persisted  in 
animals  in  which  all  nerves  of  the  limb  had  been  cut;  neither  was  it  caused 
by  any  local  loss  of  circulating  fluid  (by  dilatation  of  vessels  or  extra- 
vasation). It  was  due  to  the  discharge  into  the  circulation  of  some  toxic 
material,  since  no  shock  resulted  when  the  vessels  of  the  damaged  limb 
were  clamped.  Eemoval  of  the  clamp  some  time  after  the  damage  re- 
sulted in  the  immediate  appearance  of  the  symptoms  which  could  again  be 
caused  to  disappear  somewhat  by  its  reapplication.  As  to  the  nature 
of  the  toxic  material,  the  first  possibility  to  be  considered  is  that  it  is 
unoxidized  acid  (lactic),  which,  it  is  well  known,  accumulates  quickly  in 
muscular  tissue  whenever  this  is  destroyed,  or  when  the  circulation 
through  the  tissues  is  greatly  curtailed.  As  a  matter  of  fact  it  was  found 
that  the  C02-carrying  power  of  the  blood  became  greatly  depressed  when- 
ever the  toxic  material  was  permitted  to  enter  the  circulation  by  removal 
of  the  clamp,  and  it  is  well  known  that  there  is  also  a  decided  depres- 
sion in  the  blood  carbonates  in  surgical  shock.  Acid  intoxication  can 
not,  however,  be  the  main  factor,  and  for  the  following  reasons:  (1) 
Injections  of  lactic  acid  intravenously  do  not  cause  shock,  neither  do  they 
predispose  an  animal  to  it.  (2)  Copious  injections  of  bicarbonate  solu- 
tion do  not  prevent  shock.  (3)  Extracts  of  damaged  muscle  made  with 
isotonic  saline  do  have  a  shock-like  effect,  but  this  is  just  as  great  when 
the  lactic  acid  in  the  extracts  is  neutralized  with  bicarbonate,  as  when 
they  are  unneutralized.  Moreover  the  fall  in  the  blood  carbonate  does  not 
coincide  with,  but  rather  precedes,  the  development  of  the  shock  symp- 
toms. An  excess  of  lactic  acid  in  the  blood  has  been  noted  in  the  later 
stages  of  many  cases  of  shock  (Wiggers  and  Macleod),  but  this  is  a  sec- 


310  THE   CIRCULATION   OF   THE   BLOOD 

ondary  effect,  and  it  is  doubtful  whether  it  is  the  only  cause  for  the 
depressed  C02-carrying  power  of  the  blood. 

In  one  or  two  cases  the  muscles  were  crushed  in  unanesthetized  cats, 
with  the  result  that  shock  did  not  invariably  follow,  but  this  does  not 
invalidate  the  observations  on  anesthetized  animals;  it  only  shows  that, 
as  in  histamine  poisoning,  the  anesthetic  weakens  the  resistance.  When 
the  normal  animals  were  bled  before  the  crushing  operation,  shock  super- 
vened with  certainty. 

Taking  the  results  as  a  whole  and  comparing  them  with  clinical  ex- 
perience a  very  strong  case  is  made  for  the  hypothesis  that  surgical  shock 
is  essentially  due  to  intoxication  by  materialls  derived  from  damaged 
tissue.  Shock  is  particularly  common  after  severe  tissue  damage;  rough 
handling  of  the  wound  greatly  aggravates  it,  whereas  rigid  care  to 
render  the  wounded  part  immobile  is  a  valuable  safeguard ;  the  adminis- 
tration of  ordinary  anesthesia,  (ether)  to  a  shock  patient  is  notoriously 
dangerous,  whereas  rapid  amputation  under  nitrous  oxide  often  ushers 
in  a  steady  recovery.  All  these  clinical  facts  conform  admirably  with 
the  experimental  findings.  Examination  of  the  capillaries  of  the  skin  by 
direct  illumination  shows  the  blood  in  them  to  be  almost  in  complete  sta- 
sis. This  is  also  the  case  in  severe  cases  of  septicemia  (Freedlander  and 
Lenhart54). 

With  regard  to  the  diagnostic  value  of  measurement  of  the  blood  vol- 
ume, it  has  been  shown  by  Erlanger,  Gasser  and  Meek40'  41  that  con- 
centration of  the  blood  becomes  evident  before  the  shock  symptoms  are 
pronounced.  This  concentration  is  no  doubt  a  most  important  factor 
in  causing  curtailment  of  the  volume  of  circulating  fluid,  not  only  be- 
cause of  loss  of  plasma,  but  also  because  it  causes  the  corpuscles  to  be- 
come contiguous  so  that  they  have  a  tendency  to  jam  in  the  capillaries 
and  so  lead  to  a  progressively  increasing  under-nutrition  of  the  tissues 
and  the  production  of  more  toxic  material. 

Cause  of  Secondary  Symptoms 

It  remains  to  consider  the  cause  of  some  of  the  secondary  conditions 
developing  in  shock — namely,  the  disturbances  in  sensation  and  motion 
and  the  fall  in  body  temperature.  All  of  these  are  undoubtedly  depend- 
ent upon  the  low  arterial  blood  pressure,  although  some  authors  have 
suggested  that  the  loss  of  sensation  may  be  dependent  upon  an  increased 
resistance  or  block  at  the  synapses  of  the  receptor  neurons  (page  854). 
This  suggestion  depends  on  the  fact,  demonstrated  by  Sherrington,  that 
repeated  stimulation  of  the  receptors  of  a  reflex  arc  produces  fatigue 
of  that  particular  reflex,  and  that  this  fatigue  must  be  resident  in  the 
synapsis  and  not  in  the  motor  neuron,  since  the  same  motor  neuron 


SHOCK  311 

that  participated  in  the  fatigue  can  still  be  called  into  activity  by  afferent 
stimuli  transmitted  to  its  nerve  cell  through  other  sensory  pathways 
(see  page  825).  It  is  thought  that  in  shock  the  frequent  afferent  stimula- 
tion produces  synaptic  fatigue  and  therefore  dulls  the  sensory  responses 
of  the  animal.  The  researches  of  Mann,  in  which  he  shows  that  shock 
may  occur  without  any  demonstrable  afferent  stimuli  in  the  brain  stem, 
would  seem,  however,  to  negative  the  above  hypothesis. 

The  raised  threshold  of  sensory  stimulation  is  no  doubt  an  effect  of  the 
low  blood  pressure.  It  has  been  shown,  for  example,  by  E.  L.  Porter36 
that  when  the  arterial  blood  pressure  is  maintained  at  a  uniform  level, 
the  threshold  stimulus  for  spinal  cord  reflexes  remains  practically  uni- 
form, but  becomes  promptly  increased  when  the  arterial  blood  pressure 
is  made  to  fall.  Why  a  lower  blood  pressure  should  have  this  effect  is, 
however,  difficult  to  understand  in  the  light  of  the  researches  of  Stewart 
and  his  coworkers,  who,  as  remarked  above,  found  that  the  cells  of  the 
central  nervous  system  may  endure  total  anemia  for  many  minutes  and 
still  recover  their  physiological  condition.  It  may  be,  however,  that  the 
low  blood  pressure  affects  the  conductivity  of  the  synapsis. 

The  muscular  weakness  is  probably  also  dependent  on  low  blood 
pressure,  for  it  has  been  found  in  animals  that,  when  the  arterial  blood 
pressure  is  lowered  to  about  90  mm.  Hg,  the  muscles  contract  much  less 
efficiently  than  ordinarily.  The  fall  in  body  temperature  is  dependent 
upon  the  muscular  inefficiency. 

In  conclusion,  it  should  be  pointed  out  that  W.  T.  Porter,  in  the  inves- 
tigation of  acute  shock  met  with  at  the  front,  has  found  that,  in  many 
cases  at  least,  the  circulatory  disturbance  is  due  to  a  condition  of  fat 
embolism.  The  fat  is  derived  from  the  marrow  of  long  bones,  such  as 
the  femur,  by  injuries  which  smash  the  bones.  Porter's  observations 
are  at  least  very  suggestive.  In  any  case  that  fat  embolism  may  be  a  con- 
tributory factor  is  made  probable  by  the  fact  that  fat  emboli  have  been 
observed  by  Mott  in  the  medulla  and  the  cortex  of  the  brain. 

The  Treatment  and  Prognosis  of  Shack 

It  remains  for  us  to  show  that  the  foregoing  conclusions,  drawn  from 
observations  made  on  laboratory  animals,  are  applicable  to  the  clinical 
condition  known  as  surgical  shock.  It  will  then  be  advantageous  to  con- 
sider the  principles  which  determine  successful  treatment.  The  unusual 
opportunity  afforded  at  the  front  to  study  shock  has  led  to  a  furtherance 
of  our  knowledge  of  its  causes,  which  might  have  taken  many  years  of 
investigation  in  time  of  peace,  and  by  far  the  most  important  contribu- 
tions have  come  from  those  who  have  been  intimately  familiar  with  the 
experimental  as  well  as  the  clinical  aspect  of  the  problem.  N.  M.  Keith39 


312  THE    CIRCULATION    OF    THE   BLOOD 

estimated  the  total  volume  of  circulating  blood  by  the  vital  red  method 
and  the  relative  amounts  of  plasma  and  corpuscles  by  measurement  of 
hemoglobin  or  by  means  of  the  hematocrit,  and  as  a  result  of  his  inves- 
tigations has  divided  the  cases  of  secondary  shock  into  three  groups  which 
vary  from  one  another  with  regard  to:  (1)  The  total  volume  of  blood 
in  circulation  and  (2)  the  relative  amounts  of  plasma  and  corpuscles  in 
the  blood.  The  differentiation  is  not  only  of  great  prognostic  value,  but 
also  most  useful  as  a  guide  to  the  proper  plan  of  treatment.  In  group  1  are 
the  compensated  cases,  in  which  the  blood  volume  is  reduced  to  not  more 
than  80  per  cent  of  the  normal,  but  in  which  the  plasma  is  relatively 
greater,  being  reduced  only  to  85  or  90  per  cent  of  the  normal.  In  other 
words  these  cases  have  reacted  like  cases  of  hemorrhage,  i.  e.,  there  has 
been  a  migration  of  fluid  from  the  tissues  into  the  blood.  If  kept  warm  and 
given  fluid  per  rectum,  the  patients  recover.  In  the  second  group,  called 
partially  compensated,  the  blood  volume  is  reduced  to  65-75  per  cent,  with 
little,  if  any,  evidence  of  dilution  of  plasma  (i.  e.,  the  plasma  is  also  re- 
duced to  65-75  per  cent).  Treatment  by  transfusion  either  with  blood 
(citrated  blood  by  Robertson's  method,  or  with  gum  solutions  (vide  infra) 
is  necessary  arid  in  most  cases,  if  the  proper  technic  is  followed  in  the 
transfusion,  recovery  is  likely.  It  is  important,  however,  that  the  plasma 
volume  be  measured  a  few  hours  after  the  transfusion  to  see  whether  the 
desired  reaction,  namely,  a  migration  of  fluid  into  the  plasma,  has  set  in. 
If  not  so,  a  second  transfusion  is  indicated.  In  favorable  cases  the  plasma 
volume  increases  more  rapidly  than  that  of  total  blood,  and  pari  passu  the 
arterial  blood  pressure  rises. 

In  the  third  or  uncompensated  group — the  blood  volume  is  below  65  per 
cent  and  the  blood  is  more  concentrated  than  normal,  i.  e.,  there  is  relatively 
a  greater  decrease  of  plasma.  Treatment  must  be  energetic  in  these  cases, 
but  the  prognosis  is  unfavorable  because  the  transfused  fluid  readily  leaves 
the  vessels,  causing  the  lungs  and  tissues  to  become  edematous. 

With  regard  to  the  rationale  of  the  transfusions,  it  is  clear  that  the 
added  fluid  makes  good  the  blood  that  is  lost  by  stagnation,  etc.,  and  so 
tends  to  maintain  in  the  circulation  a  normal  pressure  for  a  sufficient 
time  to  enable  the  organism  to  destroy  the  toxic  bodies.  If  the  shock  con- 
dition has  existed  for  some  time,  so  that  the  nerve  centers  are  paralyzed, 
the  injections  are  of  no  avail.  Since  many  cases  of  shock  in  man  have 
also  suffered  considerably  from  loss  of  blood,  it  is  often  difficult  to  decide 
whether  the  shock  really  exists  apart  from  the  effects  of  hemorrhage,  the 
cardinal  symptoms  of  the  two  conditions  being  very  much  alike.  The  test 
is  afforded  by  examination  of  the  total  blood  and  plasma  volume,  and  by 
the  reaction  to  transfusion.  After  hemorrhage  alone  there  is  great  migra- 
tion of  plasma  into  the  blood,  making  this  very  dilute,  and  transfusion  has 


SHOCK  313 

immediately  beneficial  results.  In  shock  there  is  no  migration  of  fluid  into 
the  blood,  indeed  the  reverse  is  usually  the  case,  and  transfusion  does  not 
always  succeed  in  reestablishing  normal  conditions. 

Finally,  with  regard  to  the  composition  of  the  transfusion  fluid,  should 
this  be  human  blood,  or  can  a  reliable  substitute  be  found  in  saline  solutions 
containing  gum?  There  is  much  diversity  of  opinion  over  this  question. 
Keith  sums  up  by  stating  that  there  does  not  appear  to  be  any  decided 
advantage  in  blood  over  gum  solutions,  although  the  immediate  restoration 
of  natural  color  to  the  patient,  which  occurs  with  blood  but  not  with  gum 
solutions,  may  make  the  former  appear  to  be  the  more  satisfactory  treat- 
ment. 

Much  painstaking  work  has  been  done  by  Erlanger  and  Gasser41  to  de- 
termine the  exact  conditions  for  success  in  using  gum  solutions.  As  their 
criterion  for  successful  treatment,  they  did  not  merely  see  whether  the 
blood  pressure  was  restored,  but  they  allowed  the  animals  to  recover  from 
the  effects  of  the  anesthetic  and  then  watched  them  to  see  whether  they 
became  restored  to  normal.  Many  animals  might  appear  to  be  recovering, 
but  nevertheless  succumb  within  24  hours.  These  workers  point  out  that 
strong  gum  solutions  owe  their  efficacy  to  the  fact  that  they  slowly  attract 
water  into  the  blood  from  the  tissues,  and  once  attracted  the  water  re- 
mains in  the  vessels.  Hypertonic  solutions  of  crystalloids  on  the  other  hand, 
quickly  attract  water,  but  this  is  not  retained  long.  Erlanger  and  Gasser, 
therefore,  devised  the  scheme  of  combining  the  two  factors,  and  they  found 
that  success  depended  on  how  this  was  attempted.  In  the  shock  produced 
by  partial  clamping  of  the  vena  cava  about  one-half  of  the  animals  died 
within  48  hours.  Neither  weak  gum  (6  per  cent)  and  weak  alkali  (2  per 
cent)  given  in  large  amount  (12  c.c.  per  kg.)  nor  strong  gum  (25  per  cent) 
in  strong  alkali  (5  per  cent)  given  in  smaller  dosage  (5  c.c.  per  kg.)  de- 
creased the  above  mortality;  but  if  strong  gum  (25  per  cent)  were  given 
along  with  strong  glucose  solutions  (18  per  cent)  at  the  rate  of  5  c.c.  per 
kg.  an  hour,  many  more  animals  survived.  The  alkali  was  chosen  to  fur- 
nish the  crystalloid,  in  many  of  the  experiments,  so  that  it  might  inciden- 
tally combat  any  existing  acidosis.  We  have  already  seen,  however,  that 
there  is  no  reason  to  believe  that  acidosis  is  an  important  factor  in  shock. 
Two  precautions  are  necessary  to  success  in  using  the  gum  solutions,  first 
they  must  be  properly  prepared,  and  second  they  must  not  be  injected  so 
rapidly  that  their  high  viscidity  would  slow  the  circulation  and  so  embar- 
ress  the  heart's  action. 

CIRCULATION  REFERENCES 

(Monographs) 

Wiggers,  C.  J.:     The  Circulation  in  Health  and  Disease,  Philadelphia,  1915. 
Mackenzie,  J. :     Diseases  of  the  Heart,  Oxford  Medical  Publishers,  ed.  2,  1910. 


314  THE    CIRCULATION    OF    THE    BLOOD 

Lewis,  Thomas:     The  Mechanism  and  Graphic  Registration  of  the  Heart  Beat,  1920, 

Shaw  &  Son,  Fetter  Lane,  London. 

Lewis,  Thomas:     Harvey  Lectures,  1913-1914,  J.  B.  Lippincott  Co. 
Lewis,  Thomas :     Clinical  Disorders  of  the  Heart  Beat,  P.  B.  Hoeber,  New  York,  1912. 
Hill,    Leonard:     The    Mechanism    of    the    Circulation    of    the    Blood,    in    Schafer's 

Physiology,  ii,  1900.    Young  J.  Pentland. 
Gaskell,   W.    H.:     The   Contraction    of    Cardiac    Muscle,    in    Schafer's   Physiology,   ii, 

1900,  Young  J.  Pentland. 
Flack,  M.:     Further  Advances  in  Physiology,  1909.     Ed.  by  Leonard  Hill,  E.  Arnold, 

London. 

Porter,  W.  T.:     American  Text  Book  of  Physiology,  W.  B.  Saunders  Co.,  1900. 
Bayliss,   Wm. :      Principles   of   General   Physiology,    3rd   ed.,   Longmans,   Green   &   Co. 

(Original  Papers) 

iMac  William,  J.  A.,  et  al.:     Heart,   1913,  iv,  393;   ibid.,   1914,  v,  153;   Brit.  Med. 
Journal,  Nov.,  1914;  VII  Internat.  Congress  of  Medicine,  London,  1913,  Sec. 
II,  Physiology. 
2H111,  Leonard,  F.  E.  S.,  et  al:     Proc.  Eoy.  Soe.,  1914,  B,  Ixxxvii,  344;  ibid.,  1915,  B, 

Ixxxviii,  508  and  516. 

sErlanger,  J.:    Am.  Jour.  Physiol.,  1916,  xxxix,  401;  ibid.,  1916,  xl,  82. 
4Downs,  A.  W.:     Am.  Jour.  Physiol.,  1916,  xl,  522. 
sBayliss,  W.  M.:     Proc.  Roy.  Soc.,  1916,  Ixxxix,  B,  380. 
eKnowlton,  F.  P.:     Jour.  Physiol.,  1911,  xliii,  219. 
7Milroy,  T.  H.:     Jour.  Physiol.,  1917,  Ii,  259. 
sEyster  and  Meek:     Heart,  1914,  v,  119;  ibid.,  194,  v,  137;  Am.  Jour.  Physiol.,  1914, 

xxxiv,  368. 
^Porter,  W.   T. :     Art.   on   Circulation   in   American    Textbook   of   Physiology,   W.   B. 

Saunders  Co.,  1900. 

wBrodie,  T.  G.:    Proc.  Physiol.  Soc.,  1905,  Jour.  Physiol.,  1905,  xxxii. 
"Stewart,  G.  N.:     Heart,  1911,  iii,  33. 
i2Garrey,  W.:    Am.  Jour.  Physiol.,  1912,  xxx,  451. 
"Mines,  G.  R.:     Jour.  Physiol.,  1913,  xlvi,  188. 
i^Cohn,  A.  E.:     Jour.  Exper.  Med.,  1912,  xvi,  732;  Robinson,  G.  Canby:     Ibid.,  1913, 

xvii,  429;  Cohn  and  Lewis,  T.:     Ibid.,  1913,  xviii,  739. 
isMathison,  G.  C.:     Jour.  Physiol.,  1910,  xli,  416. 

isporter,  W.  T.:     Am.  Jour.  Physiol.,  1911,  xxvii,  276;  ibid.,  1915,  xxxvi,  418. 
"Martin,  E.  G.,  and  co-workers:     Am.  Jour.  Physiol.,  1914,  xxxii,  212;  xxxiv,  220; 

1915,  xxxviii,  98;  1916,  xl,  195. 

isBayliss,  W.  M.:     Proc.  Roy.  Soc.,  1908,  Ixxx,  B,  339. 
"Hill,  Leonard:     The  Physiology  and  Pathology  of  the  Cerebral  Circulation,  J.  and 

A.  Churchill,  1896. 

2oHill,  L.,  and  Macleod,  J.  J.  R.:     Jour.  Physiol.,  1900,  xxvi,  394. 
2iMacleod,  and  Pearce,  R.  G.:     Am.  Jour.  Physiol.,  1914,  xxxv,  87. 
22p0rter,  W.  T.:     Am.  Jour.  Physiol.,  1898,  i,  144. 
23ffill,  L.,  and  Barnard,  H.:     Jour.  Physiol.,  1887,  xxi,  323. 
2*Carter,  E.  P.:     Jour.  Lab.  and  Clin.  Med.,  1916,  i,  719. 

25Elliot-Smith,  G.,  and  Pear,  T.  H.:     Shell  Shock,  Longmans,  Green  &  Co.,  1917. 
26p0rter,  W.  T.:    Am.  Jour.  Physiol.,  1907,  xx,  399. 
27Seelig,  M.  G.,  and  Joseph,  D.  R.:     Jour.  Lab.  and  Clin.  Med.,  1916,  i,  283;  also  See- 

lig  and  Lyon,  E.  P.:     Surg.,  Gynec.,  and  Obst.,  1910,  ii,  146. 

28Henderson,  Yandell:  Am.  Jour.  Physiol.,  1908,  xxi,  155;  also  Mann:  Bull.  Johns 
Hopkins  Hosp.,  1914,  p.  210;  Markwald,  J.,  and  Starling,  E.  P.:  Jour.  Physiol., 
1913,  xlvii,  275. 

29Morrison,  R.  A.,  and  Hooker,  D.  R,:     Am.  Jour.  Physiol.,  1915,  xxxvii,  86. 
sopike,  F.  H.,  Stewart,  G.  N.,  and  Guthrie,  C.  C.:     Jour.  Exper.  Med.,  1908,  x,  499; 

see  also  Dolley,  D.  H.:     Jour.  Med.  Research,  1909,  p.  95,  and  1910,  p.  331. 
siJaneway,  H.  H.,  and  Jackson,  H.  C.:     Proc.  Soc.  Exper.  Biol.  and  Med.,  1915,  xii, 
193;  Erlanger,  J.:     Gesell,  Gasser,  Proc.  Am.  Physiol.  Soc.,  Am.  Jour.  Physiol., 
1918,  xlv. 


SHOCK  315 

32Henderson,  Y.,  and  Haggard,  W.  H.:     Jour.  Biol.  Chem.,  1918,  xxxiii,  333,  345-355- 

365  (gives  older  references).    See  also  Macleod,  J.  J.  E.:     Jour.  Lab.  and  Clin. 

Med.,  (editorial),  1918,  iii. 
ssShort,  Eendel:    Lancet,  London,  1914,  p.  131. 
34Mann:     Jour.  Am.  Med.  Assn.,  1918,  Ixx,  611.    Also  Boston  Med.  and  Surg.  Jour., 

1917. 
ssCannon,  W.  B.:    Papers  by  Cannon  and  Collaborators  in  Jour.  Am.  Med.  Assn.,  1918, 

Ixx,  520,  526,  531,  611,  618. 

ssporter,  E.  L.:     Proc.  Am.  Physiol.  Soc.,  Am.  Jour.  Physiol.,  1916,  xlii,  606. 
rf?Wiggers,  C.  J.,  and  Dean,  A.  L.:     Am.  Jour.  Physiol.,  1916,  xlii,  476;  Am.  Jour. 

Med.  Sc.,  1917,  clii,  666. 
ssWallace,   Dale,   Bayliss,   Cannon,   Keith,   and   others:      cf.     Beport   No.   26,   Medical 

Eesearch  Committee,  London. 
ssKeith,  N.  M. :     Blood  Volume  Changes  in  Wound  Shock  and  Primary  Hemorrhage. 

Eeport  27,  Medical  Eesearch  Committee,  London,  1919. 
4oGasser,  H.  S.,  and  Erlanger,  J.:     Am.  Jour.  Physiol.,  1919,  1,  104. 
4iErlanger,  J.,  and  Gasser,  H.  S.:     Ann  Surg.,  1919,  Ixviii,  389. 
42Evans,  C.  L.,  and  Starling,  E.  H. :     Jour  Physiol.,  1913,  xlvi,  413. 
43Boothby,  W.  M.:     Am.  Jour.  Physiol.,    1915,  xxxvii,  383. 
44Krogh,  A.,  and  Lindhard,  J. :     Skand.  Arch.  f.  Physiol.,  1912,  xxvii,  100. 
45Wiggers,  C.  F.:     Arc.  Int.  Med.,    1919,  xxiv,  471. 
"Lewis,  T.:     Quart.  Jour.  Med.,     1913,  iv,  241. 

47Knowlton,  F.  P.,  and  Starling,  E.  H.:     Jour.  Physiol.,  1912,  xlix,  206. 
48Evans,  Lovatt  C.:     Jour.  Physiol.,  1912,  xlv.  214. 

49patterson,  S.  W.,  Piper,  A.,  and  Starling,  E.  H.:     Jour.  Physiol.,  1914,  xlviii,  465. 
soFahr,  G. :     Arch.  Int.  Med.,  1920,  xxiii,  146. 

siKeith,  N.  M.,  Eowntree,  and  Geraghty:     Arch.  Int.  Med.,  1915,  xvi,  547. 
52Dale,  H.  H.,  and  Eichards,  A.  N.:     Jour.  Physiol.,  1918,  Iii,  110. 
ssSollmann,  T.,  and  Pilcher,  J. :     Jour.  Pharm.  and  Exp.  Therap.,  1917,  xix,  309. 
54Turck,  F.B.:     Jour.  Am.  Med.  Assn.,  1897   (June),  p.  1160;  Chicago  Med.  Eecorder, 

May,  1902,  450. 

ssHooker,  D.  E.:     Am.  Jour.  Physiol.,  1911,  xxviii,  235. 
seKrogh,  A.:     Jour.  Physiol.,  1919,  Iii,  409  and  457. 
54Preediauder,  S.  O.,  and  Lenhart,  C.  H.:     Arch.  Int.  Med.,  1922,  xxix. 
snooker,  D.  E.:     Am.  Jour.  Physiol.,  1911,  xxviii,  235. 
seKrogh,  A.:     Jour.  Physiol.,  1919,  Hi,  409  and  457. 
57Wiggers,  C.  J.:     The  Eegulation  of  the  Pulmonary  .Circulation,  Physiol.  Eev.,  1921, 

i,  239. 

ssEanson,  S.  W. :     Afferent  Paths  for  Visceral  Eeflexes,  Physiol.  Eev.,  1921,  i,  477. 
59Garrey,  W.:     Am.  Jour.  Physiol.,  1914,  xxxiii,  397. 
eoHooker,  D.  E.:       Physiol.  Eev.,  1921,  i,  112. 
eiWiggers,  C.  J.:     Arch.  Int.  Med.,  1921,  xxvii,  479. 
^Lombard,  W.  P.:     Am.  Jour.  Physiol.,  1912,  xxix,  335. 
«3Becht,  F.  C.:     Am.  Jour.  Physiol.,  1920,  li,  1  and  120  (with  Matill). 

is,  T.:     Trans.  Eoy.  Soc.,  1915,  B,  vol.  206;  ibid.,  B,  vol.  207. 


PART  IV 
THE   RESPIRATION 


CHAPTER  XXXV 
RESPIRATION 

For  convenience,  the  physiology  of  respiration  may  be  considered  un- 
der its  mechanics,  its  control,  and  its  chemistry. 

THE  MECHANICS  OF  RESPIRATION 

Of  the  many  factors  concerned  in  maintaining  the  normal  functioning 
of  the  animal  body,  the  respiratory  act  is  probably  the  most  important. 
On  this  account  and  also  because  we  are  conscious  of  the  respiratory 
movements,  the  physiology  of  respiration  has  been  studied  from  the 
earliest  times.  Much  of  the  earlier  work  naturally  concerned  itself 
with  the  study  of  the  air  that  enters  and  leaves  the  lungs  at  each  respi- 
ration— the  ventilation  of  the  lungs,  as  it  may  be  called.  Two  obvious 
properties  of  the  respired  air  are:  (1)  its  pressure  and  (2)  its  volume. 

The  Pressure  of  the  Air  in  the  Respiratory  Passages — the  Pulmonary 
or  Intrapulmonic  Pressure 

This  is  readily  measured  by  inserting  a  tube  into  one  nostril  and  con- 
necting the  tube  with  a  manometer;  at  each  normal  inspiration  the 
manometer  registers  a  negative  pressure  of  2  or  3  mm.  Hg,  and  at  each 
expiration,  a  positive  pressure  of  about  the  same  degree.  Although 
normally  of  small  magnitude,  the  intrapulmonic  pressure  may  become 
very  great  when  any  obstruction  is  offered  to  the  free  passage  of  the 
air.  The  greatest  possible  expiratory  pressure  can  be  measured  by  sim- 
ply blowing  into  a  mercury  manometer,  when  it  will  be  equal  to  that 
which  all  the  muscles  of  the  thorax  and  abdomen  can  exert  in  compress- 
ing the  lungs.  In  a  strong  man  it  may  amount  to  more  than  100  mm. 
Hg.  Similarly,  the  greatest  possible  negative  pressure  on  inspiration 
may  be  measured  by  attempting  to  inspire  through  a  tube  connected 
with  a  manometer.  It  represents  the  force  with  which  the  musculature 

316 


RESPIRATION  317 

of  the  thorax  and  abdomen  can  open  up  the  thoracic  cage,  and  may 
equal  -70  mm.  Hg.  These  measurements  in  themselves  are  not  of  much 
importance,  except  as  a  measure  of  muscular  development. 

Intrapulmonic  pressures  that  are  intermediate  between  the  two  ex- 
tremes will  be  acquired  in  the  lower  air  passages  in  cases  in  which  there 
is  partial  obstruction  of  the  upper  respiratory  passages,  as  in  bronchitis, 
spasm  of  the  glottis,  diphtheria,  etc.  During  coughing  also,  the  intra- 
pulmonic  pressure  may  become  very  high.  In  this  act  the  thorax  is  first 
filled  with  air  by  a  deep  inspiration;  the  glottis  is  then  closed,  and  a 
forced  expiration  is  made.  When  a  sufficiently  high  intrapulmonic  pres- 
sure is  attained,  the  glottis  opens  and  the  sudden  change  in  pressure 
causes  so  forcible  a  blast  of  air  that  the  offending  foreign  substance  is 
frequently  carried  with  it  out  of  the  air  passages.  It  is  often  assumed 
that  during  coughing  the  sudden  increase  in  pressure  in  the  alveoli  will 
tend  to  cause  their  walls  to  rupture.  This,  however,  is  not  the  case. 
The  alveoli  do  not  alone  support  the  increase  of  pressure;  they  merely 
act  as  the  inner  layer  of  a  practically  homogeneous  structure  com- 
posed of  lung,  pleura  and  thoracic  cage.  When  the  tissues  of  the  lung 
are  partially  degenerated  or  atrophied,  as  in  old  people,  then  it  is  pos- 
sible that  a  rupture  may  take  place,  but  under  ordinary  conditions  it 
is  not  likely  to  occur. 

Amount  of  Air  in  the  Lungs 

Measurements  of  the  amount  of  respired  air  have  recently  assumed  a 
considerable  interest  on  account  of  the  various  applications  which  can 
be  made  of  them  in  the  study  of  lung  conditions.  The  tidal  air  is  that 
which  enters  and  leaves  the  lungs  with  each  respiration  (about.500  C..C.) ; 
the  complemental  air  is  that  which  we  can  take  in  over  and  above  an 
ordinary  tidal  respiration  (about  1500  c.c.)  ;  and  the  supplemental  air, 
is  that  which  we  can  give  out  after  an  ordinary  tidal  expiration  (about 
15QQ-e.c.).  Taking  these  three  together,  we  have  what  is  known  as  the 
vital  capacity.  It  is  usually  about  3500  c.c.,  and  is  represented  by  the 
amount  of  air  which  we  can  expel  from  the  lungs  after  as  deep  an  inspi- 
ration as  possible.  The  vital  capacity  is  diminished  in  certain  cardiac  and 
pulmonary  diseases,  (page  330).  After  all  the  supplemental  air  has  been 
expelled,  there  still  remains  in  the  lungs  a  large  volume  of  air  which 
can  not  be  voluntarily  expelled.  This  is  known  as  the  residual  air.  To 
measure  it  in  a  dead  animal  it  is  necessary  to  clamp  the  trachea,  open 
the  thorax,  remove  the  lungs  to  a  vessel  of  water,  and  then  allow  the  air 
to  collect  from  the  opened  trachea  in  an  inverted  graduated  cylinder. 
One  part  of  the  residual  air  is  sometimes  called  the  minimal  air;  it  is 
represented  by  that  which  is  not  expelled  from  the  lungs  of  a  dead 


318 


THE   RESPIRATION 


animal  when  the  thorax  is  opened.  In  the  collapse  of  the  lungs  thus 
produced,  the  alveoli  are  not  completely  emptied  of  air,  because  some 
becomes  pocketed  within  them  and  is  expelled  only  when  the  lungs  are 
compressed  under  water. 

The  volume  of  the  residual  air  can  readily  be  measured  during  life 


Maximum  inspiration  —7 — 
Complements  air  _ 

Ordinary  inspiration  -) — 

TIDAL  AIR--C 
Ordinary  expiration — )~— 

Supplemental  air  • 

Maximum  expiration  - 

Residual  air  •• 


Vital  capacity 


Capacity  of  equilibrium 


Fig.    107. — Amounts    of   air   contained   by    the    lungs    in    various    phases    of    ordinary    and    of    forced 

respiration.      (From   Waller.) 


Fig.  108. — Diagram  to  show  manner  of  termination  of  bronchiole  in  the  atria  and  air  sacs. 
I,  Air  sacs  (respiratory  epithelium) ;  II,  atria  (respiratory  epithelium) ;  III,  alveolar  ducts  (res- 
piratory epithelium  and  occasional  muscle  fibers) ;  IV,  respiratory  bronchioles  (partly  respiratory 
and  partly  cuboidal  epithelium  and  continuous  muscle  fibers) ;  V,  bronchiole  (cuboidal  epithelium 
and  muscle  fibers).  It  is  clear  from  this  diagram  that  there  is  no  definite  position  in  the  respira- 
tory passages  where  the  bronchiolar  epithelium  (cuboidal)  ends  and  the  respiratory  epithelium 
starts.  There  can  therefore  be  no  definite  line  of  demarkation  between  the  air  of  the  dead  space 
and  that  of  the  alveoli.  Redrawn  from  Miller  (Journal  of  Morphology,  1913,  XXIV,  p.  459). 


RESPIRATION  319 

by  causing  a  person,  after  a  forced  expiration,  to  take  two  or  three 
breaths  in  and  out  of  a  rubber  bag  containing  a  measured  quantity  of 
an  indifferent  gas  such  as  hydrogen.  Suppose  the  bag  to  contain  at 
the  start  4000  c.c.  of  hydrogen,  and  after  a  few  breaths  3000  c.c.  of 
this  gas  and  1000  c.c.  of  other  gases  (the  total  volume  of  hydrogen  and 
expired  air  in  the  bag  being  still  4000  c.c.);  then  the  residual  air  will 
be  1333  c.c.,  for  it  is  evident  that  after  a  few  breaths  the  composition  of 
the  expired  air  in  the  bag  will  be  the  same  as  that  in  the  lungs.  This 
calculation  is  based  upon  the  assumption  that  no  hydrogen  is  absorbed 
by  the  blood  during  the  experiment,  which  is  not  strictly  the  case. 
The  amount  absorbed  is,  however,  so  small  in  two  or  three  breaths  as  to 
make  it  permissible  to  disregard  it.  The  measurement  can  also  be  made 
by  taking  a  few  breaths  in  and  out  of  a  bag  containing  pure  02.  By 
ascertaining  the  proportion  of  nitrogen  that  collects  in  the  bag,  the 
quantity  of  residual  air  can  be  calculated.  We  shall  see  later  that  the 
measurement  of  the  residual  air  during  life  has  some  practical  impor- 
tance in  connection  with  the  measurement  of  the  bloodflow  through  the 
lungs. 

Alveolar  and  Dead  Space  Air 

In  addition  to  these  moieties  of  respired  air,  we  have  to  consider  the 
division  of  the  air  in  the  lungs  into  what  is  called  alveolar  air  and 
dead  space  air.  The  former  is  the  air  which  comes  in  contact  with  the 
epithelium  through  which  gas  diffusion  between  the  blood  and  the  air 
occurs ;  the  latter  being  the  air  which  fills  the  respiratory  passages.  The 
dead  space  can  not  be  defined  anatomically  with  exactitude ;  it  is  func- 
tional rather  than  morphologic. 

Measurement  of  the  volume  of  the  alveolar  and  dead  space  air  can  be  made 
by  taking  advantage  of  the  fact  that,  while  it  is  in  the  lungs,  the  air  has 
added  to  it  C02  gas,  which  is  present  in  the  inspired  air  only  in  negligible 
traces.  The  necessary  data  are :  (1)  the  volume  of  the  tidal  respiration ;  (2) 
the  percentage  of  C02  in  alveolar  air ;  (3)  the  percentage  of  C02  in  the  tidal 

air.     Suppose  the  values  to  be  500  c.c.,  6  per  cent  and  4  per  cent,  re- 

4 

spectively;  then  the  volume  of  alveolar  air  must  be  500  x  — =  333  c.c., 

b 

and  the  dead  space  167  c.c.  The  measurement  so  made  is  accurate  only 
when  certain  precautions  are  taken.  Because  of  the  practical  impor- 
tance of  this  part  of  our  subject  we  shall,  however,  defer  its  further 
consideration  until  we  have  become  familiar  with  the  general  features 
of  pulmonary  physiology.  Since  the  first  air  to  move  into  the  alveoli 
at  the  beginning  of  inspiration  is  that  present  in  the  dead  space, — the 
last  air  expelled  from  the  alveoli  on  the  previous  expiration, — it  is  of 


320  THE   RESPIRATION 

no  value  in  purifying  the  air  already  present  in  the  alveoli.  If  we  take 
a  tidal  inspiration  as  amounting  to  500  c.c.  and  the  functional  dead  space 
as  150  c.c.,  it  is  plain  that  only  350  c.c.  of  the  outside  air  gains  the 
alveoli,  and  that  the  subsequent  expiration  is  composed  of  150  c.c.  of 
outside  air  that  had  lodged  in  the  dead  space  plus  350  c.c.  of  alveolar  air. 

These  facts  deserve  a  certain  amount  of  emphasis  because  of  their 
practical  importance  in  many  phenomena  connected  with  respiration. 
One  seldom  thinks,  for  example,  that  out  of  the  500  c.c.  of  air  inspired 
with  each  breath,  only  350  c.c.  reaches  the  alveoli,  where  it  comes  in 
contact  with  the  2500-3000  c.c.  of  air  already  present  in  this  part  of  the 
lungs. 

There  must  therefore  be  a  sort  of  interface  somewhere  in  the  alveoli 
between  the  fresh  outside  air  that  comes  in  with  each  breath  through 
the  bronchioles  and  the  air  which  is  more  or  less  stagnant  in  the  alveoli. 
This  interface  must  move  backward  and  forward  somewhat  with  each 
breath,  and  a  rapid  diffusion  of  oxygen  and  of  C02  must  take  place 
across  it  between  the  inspired  air  and  that  in  the  alveoli.  It  is  impossible 
to  fix  any  anatomical  point  at  which  the  interface  occurs. 

The  above  described  mechanism  for  the  ventilation  of  the  alveoli  in- 
sures the  maintenance  of  slight  but  constant  changes  in  the  composition 
of  the  air  next  the  alveolar  epithelium.  It  helps  to  prevent  sudden  varia- 
tions in  the  amount  of  gases  in  the  blood,  particularly  of  C02.  Should 
such  variations  occur,  irregular  stimulation  of  the  respiratory  and  other 
important  centers  that  are  influenced  by  the  amount  of  this  gas  present 
in  simple  solution  in  the  blood,  would  be  the  result.  The  mechanism 
serves  as  a  sort  of  mechanical  buffer  by  diminishing  the  sudden  changes, 
in  gas  concentration  produced  by  inspiration  and  expiration. 

Respiratory  Tracings 

The  measurements  of  air  for  the  determination  of  the  foregoing  val- 
ues are  made  by  the  use  of  meters  of  various  types.  Sometimes,  how- 
ever, it  is  necessary  to  obtain  an  inscribed  record  of  the  respirations. 
This  may  be  either  qualitative  or  quantitative.  A  qualitative  record  is 
taken  by  attaching  some  sort  of  receiving  tambour  to  the  thoracic  wall 
(the  best  type  is  shown  in  Fig.  109),  and  connecting  this  with  a  record- 
ing tambour  arranged  to  write  on  a  blackened  surface.  When  it  is 
desired  merely  to  count  the  respirations  or  to  observe  their  regularity, 
such  a  tracing  is  all  that  is  required,  but  obviously  it  does  not  tell  us 
how  much  air  has  entered  and  left  the  lungs  at  each  respiration.  To 
obtain  a  quantitative  tracing,  we  must  either  connect  a  recording  instru- 
ment with  the  trachea  or  inclose  the  body  of  the  animal  in  what  is 
known  as  a  body  plethysmograph.  In  observations  on  laboratory  an- 


RESPIRATION 


321 


imals  the  best  type  of  recording  instrument  to  connect  with  the  respira- 
tory passages  is  the  Gad  or  Krogh  pneumograph.  All  these  instruments 
must  of  course  be  calibrated,  which  is  done  by  pouring  a  definite  num- 


Fig.    109. — Pneumograph.      The    straps    (b,    b)    are    held    around    the    thorax,    and    the    tube    of    the 
tambour    connected    by    rubber    tubing    with    a    recording    tambour. 

ber  of  c.c.  of  water  from  a  graduate  into  a  bottle  with  which  the  record- 
ing instrument  is  connected  by  tubing.  The  displacement  of  the  writing 
point  gives  us  the  necessary  data  for  standardization. 

The  Intrapleural  Pressure 

The  air  which  we  have  just  been  considering  depends  for  its  move- 
ment in  and  out  of  the  air  passages  upon  changes  occurring  on  the  outer 
aspect  of  the  lungs  in  the  space  between  them  and  the  thoracic  wall. 
This  is  called  the  intrapleural  space.  It  does  not  really  exist  as  an 
actual  space  in  the  living  animal,  for  the  visceral  pleura  which  covers 
the  lungs  is  in  accurate  and  intimate  apposition  with  the  parietal  pleura 
on  the  inner  aspect  of  the  thorax. 

If  the  thoracic  walls  are  punctured  in  a  living  animal  or  in  one  which 
has  recently  died,  the  air  will  enter  the  thorax,  the  two  layers  of 
pleura  separate,  and  the  lungs  collapse,  causing  temporarily  a  space 
to  be  formed  between  the  two  layers  of  pleura  and  indicating  that  a 
certain  subatmospheric  or  negative  pressure  must  exist  in  the  intact 
thorax.  The  degree  of  this  negative  pressure  may  be  measured  by  con- 
necting a  tube  and  a  manometer  with  the  thoracic  cavity.  While  the 
thorax  is  at  rest,  as  in  expiration  or  immediately  after  death,  this  pres- 
sure amounts  to  about  -5  millimeters.*  On  inspiration  it  increases  to  -10 
millimeters.  There  are  therefore  two  problems  to  be  considered:  (1)  the 
cause  of  the  negative  pressure  in  the  quiescent  thorax,  and  (2)  the  cause 
of  the  increase  of  the  negative  pressure  during  inspiration. 


*The  minus  sign  indicates  that  the  pressure  is  negative  or  subatmospheric.     It  is  a  suction  pressure. 


322  THE   RESPIRATION 

The  Permanent  Negative  Pressure. — Let  us  start  with  the  changes 
that  occur  in  the  thorax  when  the  first  breath  is  drawn.  While  the  an- 
imal is  still  in  utero,  the  lungs  completely  fill  the  thorax.  When  the 
first  breath  is  drawn  the  thoracic  cage  expands  and  the  lungs  become 
expanded  to  fill  the  extra  space  so  that  air  is  introduced  into  them  from 
the  outside  through  the  trachea  and  bronchial  tubes.  The  distended 
lungs  fill  the  increased  space  created  in  the  thorax  by  the  expansion  of  the 
thoracic  cage.  This  in  itself,  however,  would  not  explain  the  cause  of  a 
subatmospheric  pressure  in  the  intrapleural  space.  Another  factor  must 
come  into  play,  which  is  the  elastic  tissue  of  the  lungs.  By  the  expan- 
sion of  the  lungs  this  elastic  tissue  becomes  stretched  and,  therefore, 
tends  constantly  to  recoil  and  so  exert  a  pull  on  the  structures  be- 
tween it  and  the  thoracic  wall.  It  is  this  elastic  recoil  which  we  really 
measure  when  we  connect  a  manometer  with  the  intrapleural  space. 
Throughout  life  the  lungs  remain  of  smaller  size  than  the  thoracic  wall, 
and  therefore  to  fill  the  thoracic  cavity  they  are  constantly  more  or 
less  distended  and  the  elastic  tissue  somewhat  stretched.  The  lungs 
are,  however,  not  the  only  structures  in  the  thorax  which  become  ex- 
panded; all  thin-walled  vessels  and  viscera,  like  the  veins,  the  esopha- 
gus, the  auricles,  etc.,  must  also  become  opened  out  a  little. 

When  the  thoracic  wall  is  punctured  and  the  outside  air  allowed  free 
entry  to  the  intrapleural  space,  differences  in  pressure  no  longer  exist 
on  the  inner  and  outer  aspects  of  the  lungs,  so  that  they  collapse  into 
the  postmortem  condition  on  account  of  the  elastic  recoil.  If  a  puncture 
in  the  thoracic  wall  of  a  living  animal  is  immediately  occluded,  the 
lungs  will  expand  again,  because  the  blood  absorbs  the  gases  from  the 
intrapleural  space  and  recreates  the  partial  vacuum  required  to  expand 
the  lungs.  This  absorption  of  gas  in  the  pleural  cavity  is  usually  quite 
rapid;  but  if  the  pneumothorax,  as  the  condition  is  called,  is  allowed  to 
persist  for  any  length  of  time,  the  lungs  will  not  become  properly  ex- 
panded again. 

The  Greater  Negative  Pressure  on  Inspiration. — The  cavity  of  the  tho- 
rax becomes  increased  in  all  diameters  during  inspiration,  with  the  re- 
sult that  a  greater  space  in  the  pleural  cavity  has  to  be  filled.  All  the 
thin-walled  structures  in  the  thorax  therefore  become  still  more  stretched, 
the  lungs  of  course  participating  to  the  greatest  extent  because  of  the 
entrance  of  outside  air.  The  stretching  of  the  elastic  structures  causes 
a  greater  pull,  or  negative  pressure,  to  be  exerted  in  the  pleural  cavity. 
Instead  of  being  -5  mm.  Hg,  as  in  expiration,  the  intrathoracic  pressure 
now  comes  to  be  above  -10  mm.  Hg. 

When  any  obstruction  exists  in  the  air  passages,  the  changes  in  intra- 


RESPIRATION  323 

thoracic  pressure  produced  by  the  movements  of  respiration  become 
more  pronounced  than  under  normal  conditions.  When  the  thorax  ex- 
pands with  the  trachea  blocked,  the  lungs  are  not  able  to  open  up  suffi- 
ciently to  fill  all  the  space  so  that  there  is  excessive  dilatation  of  the 
veins,  auricles  and  esophagus,  as  well  as  drawing  in  of  the  intercostal 
spaces  and  bulging  upwards  of  the  diaphragm.  If  a  manometer  is  con- 
nected with  the  pleural  space  under  these  conditions,  a  very  large 
negative  or  suction  pressure  will  be  observed,  amounting  often  to  -70 
or  -80  mm.  Hg.  In  the  opposite  condition,  in  which  the  respiratory  passages 
are  blocked  and  a  forced  expiration  is  made,  as  for  example  in  the  first  stage 
of  coughing  or  during  such  acts  as  defecation  and  parturition,  the  thoracic 
cage  is  compressed  upon  the  viscera,  with  the  result  that  the  air  in  the  lungs 
assumes  a  positive  pressure,  amounting  often  to  nearly  100  mm.  Hg.  If  a 
puncture  wound  is  made  in  the  thorax  under  these  conditions,  the  lungs  in- 
stead of  collapsing  will  bulge  out  of  the  wound,  for  what  is  really  occurring 
is  that  the  thorax  is  forcibly  contracting  on  occluded  sacs  of  air. 

It  is  the  alternating  changes  in  intrapleural  pressure  that  are  respon- 
sible for  the  changes  in  intrapulmonic  pressure  and  these  for  the  move- 
ment of  air  in  and  out  of  the  lungs  with  each  respiration.  In  other 
words,  the  thorax  does  not  expand  on  inspiration  because  air  rushes 
in,  as  the  uninitiated  imagine,  but  air  rushes  in  because  the  thorax 
expands. 

The  Influence  of  Intrapleural  Pressure  on  the  Blood  Pressure. — The 
movements  of  respiration  produce  effects  on  the  vascular  system  that 
are  of  considerable  importance  in  maintaining  the  circulation  of  the 
blood.  If  an  arterial  blood-pressure  tracing  is  examined,  it  will  be 
observed  that  aside  from  the  cardiac  pulsations  large  waves  exist  on  it  that 
are  approximately  synchronous  with  the  respiratory  movements,  the 
upstroke  of  each  of  these  waves  corresponding  in  general  with  inspira- 
tion, and  the  downstroke  with  expiration  (Fig.  22).  These  respiratory 
variations  in  blood  pressure  might  be  due  either  to  changes  in  heart 
rhythm  or  to  a  purely  mechanical  cause.  Regarding  the  first  possi- 
bility, it  is  indeed  the  case  in  most  animals  that  the  pulse  is  quicker  on 
inspiration  than  on  expiration,  but  that  this  alone  is  not  an  adequate 
explanation  of  the  rise  is  shown  by  the  fact  that  it  still  persists  after 
the  vagus  control  of  the  heart  has  been  eliminated,  either  by  cutting 
the  nerve  or  by  the  action  of  atropine. 

The  cause  must  therefore  be  a  mechanical  one.  Bearing  in  mind  the 
effects  which  we  have  seen  are  produced  on  the  movement  of  air  in  and 
out  of  the  lungs  by  the  changes  in  capacity  of  the  thorax  with  each  res- 
piration, we  naturally  assume  that  the  increase  in  blood  pressure  may 
be  due  to  the  fact  that  on  inspiration  more  blood  is  sucked  out  of  the 


324  THE   RESPIRATION 

systemic  veins  into  those  of  the  thorax,  that  this  excess  when  it  is  pro 
pelled  by  the  heart  into  the  arteries  raises  the  blood  pressure,  and  that 
on  expiration  the  opposite  condition  obtains.  That  the  movements  of 
the  thorax  on  inspiration  do  accelerate  the  speed  with  which  the  venous 
blood  is  traveling  towards  the  heart  can  easily  be  shown  by  measure- 
ments of  bloodflow. 

This  explanation,  however,  does  not  suffice  to  account  for  all  the 
changes  of  blood  pressure  which  occur  in  respiration,  for  if  we  take 
very  accurate  tracings  of  blood  pressure  and  of  the  respiratory  move- 
ments side  by  side,  we  shall  find  that,  although,  in  general,  the  blood 
pressure  rises  with  inspiration,  yet  the  beginning  of  the  rise  is  consid- 
erably delayed;  that  is,  immediately  following  the  beginning  of  the 
inspiratory  act  the  arterial  blood  pressure  continues  for  some  time  to 
fall,  and  at  the  beginning  of  expiration  it  continues  for  some  time  to 
rise  (Fig.  22).  Moreover,  it  will  be  found,  if  tracings  taken  from  dif- 
ferent animals  are  compared,  that  frequently  the  general  effect  of  ex- 
piration is  to  cause  more  rise  than  fall,  and  of  inspiration  more  fall 
than  rise.  It  will  be  found  that  these  differences  are  dependent  largely 
on  the  type  of  respiration,  whether  thoracic  or  abdominal  (Lewis).11 

Let  us  consider  first  of  all  exactly  what  will  happen  in  an  animal 
breathing  entirely  by  the  thorax  (e.g.,  the  rabbit).  The  first  effect  of 
the  inspiration  is  to  cause  the  veins  leading  to  the  auricles,  the  auricles 
themselves  and  the  blood  vessels  of  the  lungs  to  become  suddenly  ex- 
panded. More  blood  therefore  will  flow  into  them.  For  a  moment  or 
two  this  blood  will,  however,  tend  to  stagnate  in  the  more  capacious 
vessels,  and  it  will  be  some  time  until  it  finds  its  way  to  the  left  side 
of  the  heart ;  therefore  the  initial  effect  of  inspiration  is  a  distinct  fall 
in  arterial  blood  pressure.  When  the  extra  space  created  in  the  blood 
vessels  has  been  filled  with  blood, — that  is,  when  inspiration  has  prac- 
tically ceased, — the  blood  will  flow  on  in  increased  volume  to  the  left 
side  of  the  heart,  and,  therefore,  raise  the  arterial  blood  pressure.  On 
expiration  the  first  effect  is  that  the  diminishing  negative  pressure  will 
cause  the  thin-walled  vessels  mentioned  above  to  constrict  and  thus 
squeeze  the  blood  inside  them  into  the  left  side  of  the  heart  and  raise 
the  pressure;  but  the  ultimate  effect  in  the  later  stages  of  expiration 
will  be  that  the  vessels,  being  constricted,  will  allow  less  blood  through 
them  and  the  arterial  blood  pressure  will  fall. 

Take  now  the  case  of  abdominal  respiration.  In  inspiration  the  dia- 
phragm descends  and  crowds  the  viscera  against  the  vena  cava,  with 
the  result  that  at  first  more  blood  is  squeezed  into  the  thorax  and  the 
blood  pressure  tends  slightly  to  rise.  After  this  initial  effect,  how- 
ever, the  compression  of  the  vena  cava  causes  less  blood  to  reach  the 


RESPIRATION 


325 


thorax,  and  the  arterial  blood  pressure  falls.  The  conditions  will  be 
exactly  reversed  on  expiration.  The  initial  effect  of  thoracic  inspira- 
tion is,  therefore,  to  make  the  arterial  blood  pressure  fall,  and  the  in- 
itial effect  of  abdominal  inspiration,  to  make  it  rise.  The  net  effect 
produced  will  be  the  algebraic  sum  of  these  two  opposing  influences 
(see  Fig.  110). 

Another  factor  that  comes  into  play  in  determining  the  effect  of  the 
respiratory  movements  on  the  cardiac  output  acts  through  the  changes 
in  the  pericardial  pressure.  When  this  is  lowered,  as  early  in  inspira- 


IJUUU 

/(.ABDOMEN. 


B.CHE  ST. 


Fig.  110. — Effect  of  abdominal  and  chest  breathing  on  the  pulse  and  blood  pressure  of  man. 
Abdominal  inspiration  raises  the  pressure  and  diminishes  the  amplitude  of  the  pulse  curve.  Thoracic 
inspiration  less  clearly  lowers  the  pressure.  Expiration  has  the  opposite  effects.  (From  Lewis.) 

tion,  it  encourages  diastole,  thus  causing  better  filling  and  therefore 
better  discharge  from  the  heart. 

These  considerations  taken  together  make  it  easy  to  understand  the 
changes  in  blood  pressure,  particularly  in  the  veins,  which  occur  when 
a  forced  inspiratory  or  expiratory  movement  is  made  with  the  glottis 
closed.  A  forced  expiration  of  this  nature  occurs  during  the  acts  of 
defecation  and  parturition,  as  well  as  in  the  first  stages  of  coughing;  it 
is  also  produced  by  blowing  into  a  tube,  or  against  some  resistance. 
On  account  of  the  positive  pressure  that  is  brought  to  bear  on  the  veins 
as  they  enter  the  thorax,  the  venous  pressure  suddenly  rises,  slowing 


326  THE   RESPIRATION 

down  the  flow  of  blood  through  the  capillaries  and  causing  bulging  of 
the  veins  and,  if  the  effect  is  sustained,  cyanosis.  On  the  arterial 
side  of  the  vascular  system,  after  a  momentary  rise  caused  by  the 
squeezing  out  into  the  left  side  of  the  heart  of  the  blood  in  the  capil- 
laries of  the  lungs,  there  is  a  more  permanent  fall  in  pressure  due  to 
the  fact  that  less  blood  is  now  getting  from  the  right  side  to  the  left 
side  of  the  heart.  After  some  time  the  pressure  begins  to  rise  again, 
partly  on  account  of  the  back  pressure  through  the  capillary  vessels 
and  partly  because  of  vasoconstriction  as  a  result  of  asphyxial 
conditions. 

In  the  opposite  condition,  during  a  forced  inspiratory  movement  with 
the  glottis  closed  or  with  the  mouth  attached  to  some  tube  through 
which  the  attempt  is  made  to  suck  air,  the  thoracic  cavities  open  up 
without  the  lungs  being  able  to  occupy  completely  the  extra  space. 
The  dilatation  of  the  veins  and  other  thin-walled  structures  in  the  tho- 
rax thus  causes  an  immediate  fall  in  both  the  venous  and  the  arterial 
pressure — in  the  venous,  because  the  blood  is  sucked  toward  the  large 
vessels  in  the  thorax  and  lungs,  and  in  the  arterial,  because  the  blood  is 
now  delayed  in  its  passage  from  the  right  to  the  left  side  of  the  heart. 
If  this  condition  is  maintained,  the  arterial  pressure  may  recover  some- 
what, but  that  in  the  veins  is  permanently  lowered. 


CHAPTER  XXXVI 
THE  MECHANICS  OF  RESPIRATION   (Cont'd)* 

VARIATIONS  IN  THE  DEAD  SPACE,  THE  RESIDUAL  AIR  AND 
MID-CAPACITY,    AND    THE    VITAL    CAPACITY    IN    VARI- 
OUS PHYSIOLOGICAL  AND  PATHOLOGICAL 
CONDITIONS 

Dead  Space 

Under  ordinary  conditions  of  breathing  the  dead  space  is  fairly  con- 
stant in  volume.  Haldane5  and  Henderson6  believe  that  it  may  be  in- 
creased by  400  per  cent  in  maximal  deep  breathing,  and  that  the  in- 
crease is  due  to  the  passive  stretching  of  the  lower  air  sacs.  Although 
such  large  variations  in  the  capacity  of  the  dead  space  has  not  been  ob- 
served by  Krogh  and  Lindhard7  or  by  R.  G.  Pearce,8  it  is  undoubted 
that  moderate  rhythmic  variations  may  occur.  Even  in  deeper  breath- 
ing (1500  c.c.  or  over),  a  slight  increase,  which  with  maximum  breaths 
may  amount  to  100  c.c.,  can  be  demonstrated.  This  is  not  surprising 
when  we  remember  that  the  walls  of  the  bronchi  and  bronchioles  are 
made  up  largely  of  readily  expansible  tissue  (elastic  and  smooth-muscle 
fibers).  As  the  respirations  become  deeper  and  the  expanding  force  of 
the  inspiratory  movements  of  the  thorax  becomes  more  pronounced,  the 
diameter  of  the  bronchi  and  bronchioles  will  enlarge  proportionately — 
that  is,  the  diameter  or  circumference  will  increase  in  direct  proportion 
to  this  force;  but  the  area  of  the  cross  section  of  the  bronchi  (i.  e.,  the 
capacity)  will  increase  as  the  square  of  the  diameter.  This  depends  on 
the  fact  that  the  area  of  a  circle  is  increased  by  125  per  cent  when  the 
diameter  is  increased  by  50  per  cent,  and  by  about  300  per  cent  when 
the  diameter  is  increased  by  100  per  cent. 

The  capacity  of  the  dead  space  has  a  certain  clinical  significance. 
Siebeck9  has  estimated  that  the  dead  space  may  increase  by  100  c.c.  in 
asthma,  but  others  believe  that  the  increase  may  be  greater.  One  rea- 
son for  the  discordant  results  lies  in  the  fact  that  the  percentage  of 
C02  found  in  the  alveolar  air  obtained  by  the  Haldane-Priestley  method 
has  been  used  as  one  of  the  basic  figures  in  the  determination  of  the 

'Most  of  this  chapter  was  written  by  R.    G.   Pearce,   M.  D. 

327 


328  THE    RESPIRATION 

capacity  of  the  air  passages.  As  explained  elsewhere  (page  361),  the  pro- 
longation of  expiration  required  to  obtain  the  sample  of  alveolar  air  by  this 
method  gives  figures  that  are  too  high  even  under  normal  conditions, 
and  it  is  plain  that  this  error  will  be  exaggerated  in  asthma,  where  the 
expiration  is  greatly  prolonged.  An  increase  in  the  capacity  of  the 
dead  space  must  be  accompanied  by  an  increase  in  the  respiratory  vol- 
ume if  the  alveoli  are  to  be  adequately  ventilated.  It  has  been  thought 
by  some  clinicians  that  the  difficulty  in  asthma,  emphysema  and  car- 
diac decompensation  may  lie  in  part  in  an  increase  in  the  dead  space. 
Careful  estimations  of  the  dead  space  in  these  conditions,  however, 
fail  to  demonstrate  any  great  variation. 

An  explanation  of  the  fact  that  the  dead  space  in  emphysematous  patients  has  been 
found  to  be  generally  large  when  determined  by  the  Haldane-Friestley  method  (see 
page  357),  and  also  for  some  of  the  clinical  phenomena  accompanying  the  condition, 
may  be  as  follows:  In  emphysema  the  walls  of  the  alveoli,  especially  about  the  lateral 
and  lower  borders  of  the  lungs,  have  lost  their  elasticity  and  fail  to  expand  or  relax 
properly  during  the  respiratory  cycle.  As  a  result  the  air  in  these  alveoli  remains 
relatively  unchanged  except  when  forced  respirations  are  made.  When  a  sample  of 
alveolar  air  is  taken  directly,  this  dead  air  is  pushed  out  of  the  distended  and  diseased 
alveoli  by  the  forced  respiration  required  in  the  direct  sampling  of  the  alveolar  air. 
Since  the  air  in  these  alveoli  has  been  in  contact  with  the  blood  entering  the  lungs,  it 
has  a  high  CO2  content,  which  results,  when  compared  with  the  uniformly  low  CO9  content 
found  in  the  tidal  air,  in  giving  a  large  figure  for  the  dead  space.  Since  the  capacity  of 
the  dead  space  is  not  increased,  the  blood  in  the  normal  alveoli  is  probably  being 
superventilated  in  order  to  compensate  for  the  high  CO2  tension  in  the  blood  entering 
the  left  heart  from  the  diseased  alveoli.  However,  the  O2  content  of  the  blood  leaving 
the  sound  alveoli  is  practically  normal  (because  superventilation  can  not  cause  it  to 
take  up  more),  and  can  not  compensate  for  the  low  O2  content  in  the  blood  coming  from 
the  diseased  alveoli,  the  net  effect  being  therefore  a  low  tension  of  O  in  the  blood 
leaving  the  heart,  which  accounts  for  the  cyanosis  often  seen  in  emphysema  (Pearce). 
A  somewhat  similar  explanation  can  be  given  for  the  cyanosis  present  in  pulmonary 
edema,  if  we  assume  that  all  the  alveoli  in  this  condition  do  not  share  alike  in  the 
edema  (Hoover). 

The  Residual  Air  and  Mid-capacity  of  the  Lungs 

During  muscular  exercise  the  residual  air  of  the  lungs  is  increased, 
and  the  vital  capacity  decreased  (Bohr).  This  causes  the  lungs  to  as- 
sume a  more  inflated  condition  between  breaths  or,  as  it  has  been  clum- 
sily styled,  a  greater  mid-capacity.  These  changes  may  serve  as  a 
physiological  method  for  increasing  the  efficiency  of  alveolar  ventilation 
so  as  to  meet  the  greater  needs  of  the  body.  This  is  partly  because  the 
pulmonary  vessels  become  dilated  and  the  bloodflow  through  the  lungs 
is  favored,  and  partly  because  of  the  influence  of  the  reserve  and  sup- 
plemental airs  on  the  tension  of  the  arterial  blood  gases  during  the  res- 
piratory cycle.  For  example,  if  the  lungs  were  completely  depleted 
of  air  during  expiration,  the  blood  leaving  them  at  the  end  of  this  act 


THE    MECHANICS    OF    RESPIRATION 


329 


would  be  entirely  venous.  On  the  other  hand,  if  the  amount  of  air  left 
in  the  lungs  at  the  end  of  expiration  were  above  the  normal  amount, 
each  increment  of  C02  given  off  from  the  blood,  or  of  02  absorbed  by 
it  would  produce  less  change  in  the  pressure  of  the  C02  or  02. 

Patients  suffering  from  dyspnea,  particularly  those  suffering  from 
cardiac  dyspnea,  can  not  breathe  as  comfortably  when  lying  as  when 
sitting.  This  condition  is  known  as  orthopnea.  The  advantage  of  the  sit- 
ting over  the  lying  position  for  breathing  can  not  be  satisfactorily  ex- 
plained. The  greater  vital  capacity  in  the  upright  position;  the  favor- 
ing of  the  return  of  the  venous  blood  from  the  cerebral  vessels  by 
gravity;  the  increased  caliber  of  the  pulmonary  vessels  because  of  the 
enlarged  thoracic  cavity  (see  page  335)  ;  and  the  increase  in  the  reserve 
air  of  the  lungs — are  all  factors  to  be  considered. 

The  Vital  Capacity. — At  one  time  it  was  thought  that  the  vital  capacity 
of  the  lungs  was  related  to  their  ventilatory  capabilities,  but  for  years 
the  determination  of  this  value  in  patients  has  been  considered  unimpor- 
tant. Eecently  Peabody  and  Wentworth10  have  called  attention  to  the 
fact  that  patients  with  heart  disease  become  dyspneic  more  readily  than 
do  healthy  subjects,  and  that  this  tendency  seems  to  depend  largely 
on  their  inability  to  increase  the  depth  of  the  respiration  in  a  normal 
manner.  They  find  that  this  inability  to  breathe  deeply  corresponds  to 
a  diminished  vital  capacity  of  the  lungs,  that  is,  the  volume  of  the 
greatest  possible  expiration  after  the  deepest  inspiration.  They  believe 
that  any  condition  which  limits  the  possibility  of  increasing  the  minute 
volume  of  air  breathed  must  be  an  important  factor  in  the  production 
of  dyspnea. 

In  normal  adults  the  following  averages  (Table  I),  were  secured  from 
a  large  series  of  clinical  cases.  The  subjects  are  grouped  into  two 
classes,  each  group  being  subdivided  according  to  height. 


TABLE  I 
THE  VITAL  CAPACITY  OF  THE  LUNGS  of  NORMAL  MALES 


GROUP 

NUMBER 
STUDIED 

HEIGHT  IN 
FEET  AND 
INCHES 

NORMAL 
VITAL 
CAPACITY 
C.C. 

NUMBER 
WITHIN 
10%    OF 
NORMAL 

HIGHEST 
VITAL 
CAPACITY 

LOWEST 
VITAL 
CAPACITY 

HIGH- 
EST 

% 

LOWEST 
% 

NUMBER 
BELOW 
90%  OF 
NORMAL 

I 
II 

III 

14 

44 

38 

6'  + 

Over  5' 

8^2"  to  6' 
5'   3"  to 
5'  8y2" 

5,100 
4,800 

4,000 

9 

41 

31 

7,180 

5,800 
5,080 

5,030 
4,300 

3,450 

141 
121 

127 

99 
90 

86 

0 
0 

1 

THE  VITAL  CAPACITY  OF  THE  LUNGS  OF  NORMAL  FEMALES 


I 

10 

Over   5' 

3,275 

5 

4,075 

2,800 

124 

86 

2 

6" 

II 

13 

Over  5' 

3,050 

9 

3,425 

2,660 

112 

88 

2 

4"    to    5' 

6" 

III 

21 

5'  4"  or 

2,825 

16 

3,820 

2,500 

135 

89 

1 

less 

(Peabody  and   Wentworth.) 


330 


THE   RESPIRATION 


It  would  appear  that  in  normal  people  the  vital  capacity  is  at  least 
85  per  cent,  and  almost  always  90  per  cent  or  more,  of  the  standard 
adopted  for  each  group.  In  elderly  persons  a  slight  decrease  from  these 
standards  may  be  expected. 

TABLE  II 

THE  RELATION  OF  THE  VITAL  CAPACITY  OF  THE  LUNGS  TO  THE  CLINICAL  CONDITION  IN 
PATIENTS  WITH  HEART  DISEASE* 


GROUP 

VITAL 

NUM- 

MOR- 

SYMPTOMS 

WORK- 

REMARKS 

CAPACITY 

BER  OF 

TALITY 

OF  DECOM- 

ING 

% 

CASES 

% 

PENSATION 
% 

% 

I 

90  - 

25 

0 

0 

92 

Few  symptoms  ref- 

erable to  heart. 

II 

70  to  90 

41 

5 

2 

54 

History  of  dyspnea 

with  exertion,  yet 

able  to  do  moder- 

ate work. 

III 

40  to  70 

67 

17 

89 

7 

Dyspnea  with  mod- 

e  r  a  t  e     exercise. 

Few  able  to  work. 

IV 

Under  40 

23 

61 

100 

0 

Bedridden,      with 

marked    signs    of 

cardiac  insuf- 

ficiency. 

(Peabody  and  Wentworth.) 

"Certain  cases  were  tested  several  times  and,  owing  to  changes  in  the  vital  capacity  they  appear 
in  more  than  one  group.  In  the  "mortality"  column  they  are  included  only  in  the  lowest  group  into 
which  they  fell.  "Symptoms  of  decompensation"  indicate  dyspnea  while  at  rest  in  bed  or  on  very 
slight  exertion.  Under  "working"  are  included  only  those  actually  at  work,  and  able  to  continue. 
Many  other  patients  in  Group  II  were  able  to  work,  but  they  are  not  included  as  they  were  still  in 
the  hospital. 

Table  II  shows  that  there  is  a  remarkably  close  relationship  between 
the  clinical  condition  of  cardiac  patients,  particularly  as  regards  the 
tendency  to  dyspnea,  and  the  vital  capacity  of  the  lungs.  Peabody  and 
Wentworth  believe  that  the  determination  of  the  vital  capacity  affords 
a  clinical  test  as  to  the  functional  condition  of  the  heart,  since  compen- 
sated patients  who  do  not  complain  of  dyspnea  on  exertion  have  a  nor- 
mal vital  capacity.  Patients  with  more  serious  disease  in  whom  dyspnea 
is  a  prominent  symptom,  have  a  low  vital  capacity;  and  the  decrease  in 
vital  capacity  runs  parallel  with  the  clinical  condition.  As  a  patient 
improves,  his  vital  capacity  tends  to  rise ;  as  he  becomes  worse,  it  tends 
to  fall.  In  other  diseases  in  which  mechanical  conditions  interfere  with 
the  movements  of  the  lungs,  the  tendency  to  dyspnea  corresponds  closely 
to  the  decrease  in  the  vital  capacity.  The  cause  of  the  decrease  in  the 
vital  capacity  of  the  lung  in  cardiac  decompensation  is  difficult  to  ex- 
plain satisfactorily.  It  may  be  the  limitation  in  the  movements  of  the 
lungs  produced  by  engorgement  of  the  pulmonary  vessels,  by  the  weak- 
ness of  the  intercostal  muscles,  the  rigidity  of  the  bony  thorax, 
emphysema,  or  accumulation  of  fluid  in  the  pleural  cavities. 


THE    MECHANICS   OP    RESPIRATION  331 

In  cardiac  disease  the  air  in  the  lungs  at  the  end  of  a  normal  expiration 
is  usually  increased.  This  is  similar  to  the  condition  which  attends  exer- 
cise, and  is  probably  a  physiological  adaptation  to  give  optimum  aeration 
to  the  blood,  as  explained  above. 

It  has  become  more  and  more  evident,  since  Peabody  and  Wentworth's 
researches,  that  a  determination  of  the  vital  capacity  is  of  great  importance 
in  the  diagnosis  and  prognosis  of  several  diseases,  including  heart  disease 
and  tuberculosis.  It  is  also  important  in  guaging  the  effects  of  treatment. 
In  order  that  the  value  actually  found  in  a  given  patient  may  be  compared 
with  the  value  which  a  healthy  individual  of  the  same  body  build  would 
give,  it  is  necessary  for  clinical  purposes  that  some  reliable  and  yet  simple 
method  be  available  from  which  the  normal  value  may  be  computed. 
Lundsgaard  and  Van  Slyke51  and  Dreyer5?  have  worked  out  several  ratios 
for  this  purpose,  and  West50  has  shown,  by  observations  on  129  persons, 
the  most  useful  of  these  is  one  based  on  the  body  surface.  The  body  sur- 
face is  determined  from  measurement  of  height  and  weight  by  the  graphic 
chart  of  DuBois,  the  use  of  which  is  explained  on  page  576. 

The  vital  capacity  can  be  satisfactorily  measured  by  using  a  simple 
spirometer  of  about  8  liters  capacity  and  three  trials  should  be  allowed,  the 
largest  expiration  being  recorded.  The  average  value  for  vital  capacity 
(in  liters  divided  by  the  body  surface  (in  square  meters)  is  2.61  1.  per  sq. 
m.  and  for  women  2.07  (e.  g.,  vital  capacity  =  5,300  1. ;  body  surface  2.01, 
therefore,  ratio  =2.63).  The  deviation  from  the  values  should  not  be  be- 
yond 15  per  cent,  the  great  proportion  of  normal  individuals  being  within 
10  per  cent  of  the  above  averages.  Athletes  give  decidedly  higher  values 
and  old  people  give  lower  ones. 


CHAPTER  XXXVII 
THE  MECHANICS  OF  RESPIRATION    (Cont'd) 

THE  MECHANISM  BY  WHICH  THE  CHANGES  IN  CAPACITY  OF 
THE  THORAX  AND  LUNGS  ARE  BROUGHT  ABOUT 

By  R.  G.  PEARCE,  B.A.,  M.D. 

The  changes  that  take  place  in  the  form  and  the  dimensions  of  the 
thorax  during  respiration  are  brought  about  by  movements  of  the  ribs, 
diaphragm,  sternum,  and  vertebrae.  The  share  which  each  plays  must 
be  considered  separately. 

The  Movements  of  the  Ribs 

The  first  seven  pairs  of  ribs  progressively  increase  in  length,  and  are 
attached  directly  to  the  sternum  by  cartilaginous  bands.  The  eighth  to 
the  twelfth  pairs  progressively  decrease  in  length,  and  as  far  as  the 
tenth  they  are  indirectly  attached  to  the  sternum  by  cartilages  which  join 
the  seventh.  The  eleventh  and  twelfth  have  their  anterior  ends  free,  and 
may  be  considered  a  part  of  the  abdominal  wall  and  not  an  intrinsic  part 
of  the  thoracic  cage. 

Each  pair  of  ribs,  together  with  its  articulating  cartilage  and  vertebrae, 
forms  a  ring,  the  plane  of  which  is  directed  forward  and  downward. 
The  spinal  articulations  of  the  upper  ribs  differ  from  those  of  the  lower 
ones.  In  the  former  the  articulations  on  the  tubercle  exist  as  convex 
ovoid  facets,  which  fit  into  corresponding  hollow  facets  on  the  transverse 
processes  of  the  vertebrae,  while  the  corresponding  facets  of  the  lower 
ribs  are  flat.  Each  transverse  process  from  above  downward  is  tilted  a 
little  more  backward  than  the  one  above,  so  that  the  angle  at  which  the 
ribs  are  set  to  the  spine  increases  from  above  downward.  This  manner 
of  articulation  of  the  upper  ribs  with  the  vertebrae  prevents  any  rotation 
in  the  spinosternal  axis,  so  that  there  can  be  no  so-called  bucket-handle 
movement  in  this  region  (Keith).  The  articulation,  however,  allows  the 
neck  of  the  rib  to  rotate  in  an  axis  approximately  transverse  to  the  body. 
The  angle  which  the  shaft  of  the  rib  makes  near  its  neck,  together  with 
the  arch  of  the  shaft,  which  is  directed  downward  and  forward,  has  the 
effect  of  causing  the  transverse  rotation  of  the  neck  of  the  rib  to  be 

332 


THE    MECHANICS   OF    RESPIRATION 


333 


converted  into  an  upward  movement,  which  is  greatest  in  that  part  of  the 
shaft  lying  parallel  to  the  axis  of  rotation  of  the  neck  (Fig.  111). 

The  upper  ribs  from  the  first  to  the  fifth  form  a  cone-shaped  top  to  the 
thorax,  whereas  the  lower  ones  form  a  vertical  series,  each  being  situated 
almost  directly  above  its  neighbor.  The  upper  set  is  arranged  for  the 
expansion  of  the  conical  upper  lobe  of  the  lungs,  the  lower  for  the  ex 
pansion  of  the  more  or  less  cylindrical  lower  lobes.  During  inspiration 
the  anteroposterior  diameter  of  the  conical  portion  of  the  thorax,  in- 
creases, because  the  ribs,  together  with  the  sternal  connections,  move 
through  progressively  increasing  arches,  and  each  lower  rib  tends  to  over- 
ride the  rib  just  above.  The  maximal  rise  of  the  ribs  from  the  first  to  the 
tenth  during  inspiration  shifts  more  and  more  from  the  anterior  to  the 


Fig.    111. — A,   first  dorsal    vertebra;    B,   sixth   dorsal    vertebra   and    rib.      Axis    of    rotation    shown    in 

each    case. 

lateral  aspects  of  the  thorax,  because  the  angle  formed  by  the  shaft  near 
the  neck  of  the  rib  approaches  nearer  to  the  articulating  joints  on  the 
vertebras. 

An  examination  of  the  shape  of  the  first  rib,  its  relationship  to  adjacent 
structures  and  its  movements,  shows  that  it  differs  from  the  others  in 
its  respiratory  function.  The  first  pair  of  ribs  and  the  manubrium  sterni 
are  bound  closely  together  by  short,  wide  costal  cartilages,  and  form  a 
structural  unit  which  Keith1  calls  the  -thoracic  operculum.  This  lid  is 
articulated  behind  with  the  first  thoracic  vertebra  by  a  joint,  which  is 
more  nearly  transverse  than  that  of  the  rest  of  the  costal  series ;  and  in 
front  with  the  manubrium,  which  is  also  articulated  with  the  clavicles 


334  THE   RESPIRATION 

above  and  with  the  body  of  the  sternum  below.  The  freedom  of  move- 
ment at  the  angle  which  the  manubrium  makes  with  the  sternum  at  this 
joint  is  related  to  the  type  of  breathing.  When  the  lower  portion  of  the 
sternum  is  elevated  during  inspiration,  the  movement  of  the  joint  is  not 
free,  but  when  the  sternum  is  retracted,  the  movement  at  the  angle  may 
amount  to  16°.  Lack  of  movement  of  the  sterno-manubrial  joint  has 
been  considered  by  some  physicians  as  one  of  the  predisposing  causes  of 
pulmonary  tuberculosis.  During  inspiration,  the  first  rib  and  its  anterior 
attachments  are  raised  by  the  scaleni,  and  serve  as  a  point  towards  which 
the  second,  third,  fourth  and  fifth  ribs  are  elevated.  During  expiration, 
they  are  depressed  toward  the  lower  ribs,  which  form  a  more  or  less 
fixed  base. 

The  combined  effect  of  these  influences  is  to  produce  a  motion  of  the 
upper  ribs  which  is  described  by  the  clinician  as  being  undulatory.  This 
movement  is  more  apparent  in  the  upper  part  of  the  thorax,  because 
here  the  relative  difference  in  the  length  of  the  ribs  is  greatest.  Hoover 
attributes  a  certain  diagnostic  significance  to  loss  of  the  undulatory 
movement,  diminution  in  the  extensibility  of  the  underlying  lungs  causing 
it  to  become  less  or  to  disappear.  The  phenomenon  is  elicited  by  placing 
the  tip  of  the  ring  finger  on  the  second  rib  in  the  midclavicular  line,  the 
tip  of  the  middle  finger  on  the  third  rib  midway  between  the  midclavicu- 
lar and  anteroaxillary  line,  and  the  tip  of  the  index  finger  on  the  fourth 
rib  in  the  midaxillary  line.  The  patient  is  then  instructed  to  make  a 
moderately  rapid  and  deep  inspiration.  The  finger  on  the  third  rib  will 
be  observed  to  move  farther  than  that  on  the  second  rib,  and  the  finger 
on  the  fourth  rib  will  move  farther  than  that  on  the  third.  The  move- 
ment of  each  rib  from  above  downward  succeeds  and  exceeds  that  of 
the  rib  just  above. 

When  there  is  a  moderate  degree  of  impairment  in  the  ventilation  of 
the  upper  lobe,  the  three  ribs  move  in  unison  and  through  the  same  dis- 
tance, so  that  the  undulatory  movement  is  lost  although  the  ribs  involved 
may  exhibit  a  considerable  excursion.  The  undulatory  movement  is  also 
impaired  by  any  disease  which  encroaches  on  the  air  spaces,  invades  the 
interstitial  tissue  of  the  lung,  or  displaces  the  lung  as  in  the  case  of  an 
enlarged  heart  or  a  distended  pericardial  sac.  Another  possible  factor 
in  this  phenomenon  is  that  any  inflammatory  process  in  the  lung  or  ad- 
jacent tissue  will  produce  a  reflex  inhibition  of  the  muscles  of  the  ribs, 
and  thus  limit  the  expansion  of  the  thorax. 

The  axis  of  movement  of  the  lower  ribs,  as  of  the  upper  ribs,  accurately 
corresponds  with  that  indicated  by  their  articulation  with  the  vertebra, 
because  the  muscles  attached  to  them,  as  well  as  the  diaphragm,  influence 
their  movements  to  a  large  extent.  Anteriorly  the  lower  ribs  from  the 


THE    MECHANICS   OF    RESPIRATION 


335 


sixth  to  the  tenth  are  joined  to  the  sternum  by  the  cartilages  which  unite 
the  sixth,  seventh,  eighth,  ninth,  and  tenth,  so  that  any  movement  in 
which  the  ribs  are  raised  is  accompanied  by  an  anterior  movement  of  the 
sternum  (Fig.  112).  The  ribs  are  so  articulated  to  the  spinal  column  that 
the  inspiratory  act  causes  the  lateral  and  anterior  part  of  each  rib  arch 
to  move  forward  and  outward  more  than  the  one  above  it. 

In  natural  breathing  in  the  standing  or  sitting  posture  there  is  a 
slight  extension  of  the  spine  during  inspiration.  This  serves  to  increase 
all  diameters  of  the  thorax  and  its  absence  is  undoubtedly  an  important 


Fig.  112. — Lower  half  of  the  thorax  from  the  6th  dorsal  to  the  4th  vertebra,  seen  from  the 
front,  c,  ensiform  process;  d,  d' ,  aorta;  e,  esophagus;  /,  aperture  in  tendon  of  diaphragm  for 
passage  of  vena  cava  inferior;  /,  2,  3,  trilobate  expansions  of  tendinous  center  of  diaphragm;  4,  5, 
costal  portions,  right  and  left,  of  diaphragm  muscle;  6,  right  crus  of  diaphragm;  8,  o,  internal 
intercostal  muscles,  which  are  absent  near  the  vertebral  column,  where  it  joins  p  and  9,  the  ex- 
ternal intercostals;  10,  10,  subcostal  muscles  of  left  side.  (From  1/uschka.) 

contributory  factor  in  reducing  the  vital  capacity  of  an  individual  when 
lying  on  the  back.  Figures  given  by  Hutchinson  for  the  effect  which 
posture  has  on  the  vital  capacity  are  of  interest  because  of  their  bearing 
on  the  cause  of  orthopnea.  In  the  same  individual  he  found  the  following 
vital  capacities: 

Standing  4300  c.c. 

Sitting  4200  c.c. 

Supine  3800  c.c. 

Prone  3620  c.c. 


336 


THE   RESPIRATION 

The  Action  of  the  Musculature  of  the  Ribs 


In  a  general  way,  the  external  intercostal  muscles  may  be  considered 
as  a  broad  extension  of  the  scalene  muscles  over  the  thoracic  walls,  with 
the  ribs  as  intersections.  The  scaleni  serve  to  fix  the  position  of  the 


Fig.  113. — Intercostal  muscles  of  5th  and  6th  spaces.  A,  side  view;  B,  back  view;  IV,  4th 
dorsal  vertebra;  V,  5th  rib  and  cartilage;  /,  /,  M.  levatores  costarum,  2,  2,  external  intercostals; 
3,  3,  internal  intercostals,  exposed  by  removal  of  the  external  muscles.  In  A,  there  are  no  external 
intercostals  in  the  intercartilaginous  spaces;  in  B  there  are  no  intercostals  near  the  vertebral 
column.  (From  Allen  Thomson.) 

first  rib  so  that  it  forms  an  anchorage  for  the  action  of  the  external 
intercostal  muscles  in  raising  the  lower  ribs.  They  also  raise  the  upper 
three  pairs  of  ribs  along  with  the  manubrium  and  sternum. 

The  function  of  the  intercostal  muscles  has  been  the  subject  of  much 


Fig.  114. — Hamberger's  schema  to  demonstrate  the  functional  antagonism  of  internal  and  ex- 
ternal intercostals. 

When  the  ribs  ac  and  bd  pass  into  the  inspiratory  positions  ag  and  bf,  the  intercostal  space 
dilates  (bh  is  greater  than  ofc) ;  the  sternum  gf  moves  away  from  the  vertebral  column  ab  (bf  is 
greater  than  be) ;  the  fibers  of  the  external  intercostals  ak  shorten  (ak  is  greater  than  a/) ;  and 
those  of  the  internal  intercostals  ck  lengthen  (ck  is  greater  than  lg).  The  reverse  occurs  when 
the  inspiratory  position  is  taken.  (From  Luciani's  Human  Physiology.) 


THE    MECHANICS    OF    RESPIRATION 


337 


debate,  and  can  not  be  said  to  be  definitely  settled.  The  direction  of  the 
fibers  in  the  internal  intercostals  indicates  that  they  are  expiratory  in 
function,  since  they  can  not  shorten  in  the  inspiratory  position;  while, 
on  the  other  hand,  the  fibers  of  the  external  intercostals  can  not  shorten 
in  the  expiratory  position,  and  hence  must  be  considered  inspiratory  in 
character  (Fig.  113).  In  1751  Hamberger  showed  that  mechanically  this 
is  the  case,  and  gave  the  schema  shown  in  Fig.  114. 

The  function  of  the  intercartilaginous  muscles,  however,  must  be 
inspiratory,  as  is  shown  in  Fig.  115.  It  is  possible,  however,  that  the 
main  function  of  both  intercostal  muscles  is  to  regulate  the  tone  of  the 
intercostal  spaces  and  so  prevent  their  suction  inwards  when  the  nega- 
tive pressure  in  the  thorax  increases  (i.e.,  suction  becomes  greater). 


Fig.  115. — Schema  to  demonstrate  that  the  function  of  the  internal  intercartilaginous  intercos- 
tals is  identical  with  that  of  the  external  interosseous  intercostals. 

The  ribs  and  costal  cartilage  may  be  regarded  as  rods  bent  at  the  angles  acd  and  bef,  in 
which  the  articular  points  c  and  e  represent  the  symphysis  between  the  bony  and  the  cartilaginous 
parts  on  which  traction  is  made.  During  inspiration  the  fibers  of  the  intercartilaginous  muscles, 
which  have  the  direction  gh,  move  the  sternum  df  away  from  the  vertebral  column  ab,  like  the 
fibers  of  the  external  intercostals,  which  run  in  the  direction  kl.  During  this  double  action  the 
angles  c  and  e  must  be  decreased,  because  the  muscles  of  the  upper  intercostal  spaces  work  simul- 
taneously, and  the  entire  thorax  is  slightly  elevated  during  inspiration.  From  this  scheme  it  is 
apparent  that  the  external  intercostals  and  the  intercartilaginous  muscles  must  be  the  same.  (From 
L,uciani's  Human  Physiology.) 

The  Action  of  the  Diaphragm 

The  ascent  of  the  ribs,  while  producing  an  increase  in  the  antero- 
posterior  and  transverse  diameters  of  the  thorax,  would  decrease 
the  vertical  diameter  if  this  were  not  counteracted  by  the  fixation 
of  the  lower  ribs  and  the  descent  of  the  diaphragm.  The  periph- 
eral edges  of  the  diaphragm  are  attached  behind  to  the  lumbar  vertebrae, 
laterally  to  the  lower  edges  of  the  six  lower  ribs  and  their  cartilages, 
and  in  front  to  the  tip  of  the  ensiform  cartilage.  The  fibers  converge  to 


338  THE   RESPIRATION 

enter  the  central  tendon,  and  the  lateral  sheets  are  pressed  upward  by 
the  intraabdominal  positive  and  intrathoracic  negative  pressures,  so  that 
they  form  a  dome-shaped  vault,  with  the  liver  in  the  right  side  and  the 
stomach  and  the  spleen  in  the  left. 

During  expiration  the  lateral  edges  of  the  diaphragm  are  in  contact 
with  the  parietal  pleura  of  the  thoracic  cavity,  forming  what  are  known 
as  the  pleural  sinuses.  During  inspiration  the  fibers  of  the  diaphragm 
shorten;  this  straightens  out  the  arch  of  the  diaphragm  and  pulls  the 
lateral  edges  of  the  diaphragm  away  from  the  parietal  pleura,  thus  open- 
ing up  the  pleural  sinuses,  into  which  the  lungs  descend.  Usually  the 
opening  up  of  the  sinuses  is  accompanied  by  a  slight  retraction  of  the 
external  chest  wall,  which  is  known  as  Litten's  diaphragm  phenomenon. 
The  descent  of  the  diaphragm  may  produce  a  movement  of  from  10  to 
15  mm.  on  each  side,  which  accounts  for  a  rather  important  fraction  of 
the  volume  of  air  exchange  by  the  lungs.  The  central  portion  of  the 
diaphragm  does  not  move  much  in  normal  respiration,  but  in  forced 
respiration  its  movement  may  be  considerable. 

Because  of  its  attachments  to  the  lower  six  ribs,  the  contraction  of  the 
diaphragm  tends  to  pull  the  margins  of  the  ribs  towards  the  median  line, 
but  under  normal  conditions  this  movement  is  opposed  by  the  action  of 
the  external  intercostals  in  raising  the  ribs  and  expanding  the  horizontal 
diameters  of  the  thorax,  and  by  the  lower  vertebral  muscles,  which  fix 
the  position  of  the  lower  ribs. 

The  relative  part  which  the  diaphragm  and  the  external  intercostal 
muscles  play  in  the  widening  of  the  lower  part  of  the  thorax  is  of  som& 
importance  from  the  standpoint  of  diagnosis.  It  has  generally  been  held 
that  the  contraction  of  the  diaphragm  produces  a  widening  of  the  lower 
part  of  the  thorax,  because  in  its  descent  it  presses  upon  the  abdominal 
viscera  and  so  distends  the  abdomen  and  pushes  out  the  lower  ribs. 
That  this  might  occur  seems  not  improbable,  but  Hoover2  has  recently 
shown  by  experimental  and  clinical  observations  that  the  flaring  in  the 
costal  margins  seen  in  normal  inspiration  depends  on  other  factors.  He 
calls  attention  to  the  fact  that  the  contraction  of  the  intercostals  raises 
the  ribs  and  increases  the  angular  divergence  of  the  subcostal  borders. 
This  widening  of  the  angle  made  by  the  costal  margins  at  the  tip  of  the 
sternum  is  very  pronounced  in  paralysis  of  the  diaphragm  while  in 
paralysis  of  the  intercostal  muscles,  the  costal  borders  are  drawn  towards 
the  median  line  and  the  subcostal  angle  is  decreased.  This  shows  that 
the  diaphragm  must  tend  to  diminish  the  angle. 

The  line  of  traction  of  the  diaphragm  is  a  straight  one  joining  the  cen- 
tral tendon  with  the  edge  of  the  ribs.  When  the  diaphragm  forms  a 
well-defined  arch,  it  exerts  its  traction  at  a  disadvantage,  and  the  ex- 


THE    MECHANICS    OF    RESPIRATION 


339 


Fig.   116. — Diagram    to    show    the    effect    of    high    and    low    positions    of    the    diaphragm    on    the 
costal  angle. 


Line  1.  Normal    position    of    diaphragm       Costal    margins    move    out    during    inspiration. 

Line  2.  High  position  of  diaphragm.     Normal  outward  movement  of  costal  margins  accentuated. 

Line  3.  Low  position  of  diaphragm.      Costal  margins  move  in  during  inspiration. 

Line  4.  Very    low   position    of    diaphragm.      Costal    margins    move    out    during   inspiration. 

Line  5.  Actual  line  of  traction   of  diaphragm.      (From   T.   Wingate   Todd.) 


340 


THE    RESPIRATION 


Fig.    117. — Diagram  to  show   the  effect   of  clinical  displacements   of  the  diaphragm   on   the   costal 
angle. 

Line  1.  Normal  position   of  diaphragm.     Costal  margins   move  out   during  inspiration. 

Line  2.  Position  of  diaphragm  in  general  cardiac  enlargement.      Costal  margin  from  ensiform  to 

ninth  rib  moves  toward  median  line. 
Line  3.  Position  of  diaphragm  in  left-sided  cardiac  enlargement.     Left  costal  margin   is  fixed  or 

moves  in  during  inspiration. 
Line  4.  Position   of  diaphragm  in  right-sided   cardiac  enlargement.     Right   costal  margin   is  fixed 

or  moves  in  during  inspiration. 
Line  5.  Costal  margin.      (From  T.  Wingate  Todd.) 


THE    MECHANICS    OF    RESPIRATION  341 

ternal  intercostals  have  the  mastery  and  cause  the  costal  borders  to 
spread.  When  the  arch  of  the  diaphragm  is  depressed,  as  in  pleurisy 
with  effusion,  emphysema,  and  empyema,  the  line  of  traction  and  the 
line  of  the  muscular  fibers  of  the  diaphragm  correspond  more  closely, 
so  that  the  diaphragm  is  able  to  use  its  full  force  against  the  intercostal 
muscles,  with  the  result  that  the  costal  border  moves  towards  the  median 
line.  The  curves  of  the  different  fibers  of  the  diaphragm  vary  greatly; 
the  arch  is  much  less  marked  in  the  portion  attached  to  the  costal  margin 
near  the  median  line  than  in  that  attached  in  the  axillary  line.  For  this 
reason  the  anterolateral  part  of  the  diaphragm  requires  less  depression 
to  give  it  a  horizontal  position  than  is  required  for  parts  occupying  a 
more  lateral  position.  A  small  pericardial  effusion  or  an  increase  in  the 
size  of  the  heart  may  therefore  depress  the  diaphragm  sufficiently  to  give 
it  mastery  over  the  intercostals  in  the  front  portion,  so  that  the  costal 
border  may  here  move  towards  the  midline,  while  the  lower  borders 
move  in  a  perfectly  normal  manner  (see  Figs.  116  and  117). 

During  forced  breathing  several  muscles  are  brought  into  play,  among 
the  most  important  of  which  are  the  scaleni,  sternomastoid,  trapezius, 
pectorals,  rhomboids,  and  serratus  magnus. 

There  has  been  considerable  debate  as  to  whether  expiration  is  normally 
an  active  or  a  passive  process.  Undoubtedly  the  expiratory  phase  under 
normal  conditions  does  not  require  the  same  muscular  effort  as  does  that 
of  inspiration,  but  there  are  many  observations  which  indicate  that  ex- 
piration is  partly  under  muscular  control.  The  abdominal  musculature, 
for  example,  increases  in  tone  during  expiration,  so  as  to  bring  about  a 
rise  in  the  abdominal  pressure,  with  the  result  that  the  relaxed  diaphragm 
is  pushed  up  into  the  thoracic  cavity.  To  this  extent  at  least,  expiration 
is  accompanied  by  increased  muscular  activity. 

Before  leaving  the  subject  of  the  diaphragmatic  movements,  reference 
must  be  made  to  the  recent  observations  of  Lee,  Guenther  and  Meleney3 
bearing  on  the  general  physiological  properties  of  the  diaphragmatic 
muscle.  They  point  out  that  most  skeletal  muscles  in  the  living  body 
contract  with  varying  degrees  of  intensity  and  at  irregular  intervals, 
between  which  relatively  long  periods  of  rest  occur,  but  the  diaphragm 
from  birth  to  death  performs  a  continuous  succession  of  brief  contrac- 
tions of  fairly  regular  rhythm  and  uniform  extent,  alternating  with  brief 
periods  of  rest.  Its  muscle  fibers,  together  with  those  of  the  other 
respiratory  muscles,  therefore  hold  a  unique  position  among  skeletal 
muscles,  which  suggests  a  crude  analogy  with  that  of  the  heart.  They 
have  compared  the  physiological  properties  of  the  diaphragm  with  those 
of  the  extensor  longus  digitorum,  the  sartorius,  and  the  soleus,  and  found 


342  THE    RESPIRATION 

that  the  diaphragm  is  composed  of  a  much  more  efficient  muscular  tissue 
than  that  of  the  other  muscles. 

The  Effects  of  the  Respiratory  Movements  on  the  Lungs. — The  changes 
produced  in  the  dimensions  of  the  lungs  by  the  inspiratory  expansion  of 
the  thoracic  cavity  are  not  uniform,  since  different  parts  of  these  struc- 
tures are  not  equally  extensible.  From  an  anatomical  standpoint,  the 
lungs  may  be  divided  into  three  zones:  (1)  The  inner  or  root  zone  contain- 
ing the  bronchus,  artery  and  vein,  and  their  main  subdivisions.  The 
large  amount  of  fibrous  tissue  in  this  region  offers  great  resistance  to 
any  expanding  force.  (2)  The  intermediate  zone,  containing  the  vascular 
and  bronchial  ramifications  radiating  towards  the  surface  of  the  lungs, 
with  pulmonary  tissue  implanted  between  the  rays.  This  part  of  the 
lungs  has  varying  degrees  of  extensibility,  the  pulmonary  tissue  having 
the  most  and  the  vascular  and  bronchial  the  least.  (3)  The  outer  zone, 
perhaps  25  to  30  mm.  in  depth,  composed  of  pulmonary  tissue  and 
equally  extensible  throughout  (Keith1).  The  expansion  of  the  lung  is 
accomplished  by  a  moving  apart  of  the  less  extensible  rays  of  tissue  so 
as  to  permit  the  expansion  of  the  more  extensible  pulmonary  tissue  be- 
tween them.  Keith  compares  the  mechanism  to  that  seen  in  the  opening 
of  a  Japanese  fan. 

Because  the  lung  expands  in  the  direction  of  least  resistance,  study 
of  the  inflated  dead  lung  does  not  reveal  the  normal  expansion  brought 
about  by  the  thoracic  movements.  In  the  living  body  expansion  is  more 
limited  in  some  regions  than  in  others.  Of  the  five  areas  which  may  be 
distinguished  on  the  surface  of  the  lungs,  three  are  in  contact  with  rela- 
tively immovable  parts  of  the  chest  wall,  and  therefore  can  not  be  ex- 
panded directly.  These  are:  the  mediastinal,  in  contact  with  the  pericar- 
dium and  the  structures  of  the  mediastinum ;  the  dorsal  surface,  in  contact 
with  the  spinal  column  and  the  posterior  aspect  of  the  thoracic  cage,  and 
the  apical  surface.  The  motions  of  the  first  pair  of  ribs  and  the  manu- 
brium  expand  chiefly  the  anterior  and  ventrolateral  part  of  the  apex 
of  the  lung,  and  have  only  an  indirect  influence  on  the  dorsal  part  of  the 
apex — i.  e.,  the  part  lying  directly  in  front  of  the  necks  of  the  first  and 
second  ribs,  the  most  common  site  of  pulmonary  tuberculosis.  The  two 
surfaces  of  the  lungs  which  are  directly  expanded  are  the  diaphragmatic 
and  the  ventrolateral  or  sternocostal.  Meltzer4  found  that  the  negative 
pressure  in  the  thorax  during  inspiration  was  least  along  the  relatively 
stationary  walls  of  the  thorax,  and  greatest  in  the  regions  nearest  the 
diaphragm.  From  this  he  concludes  that  some  of  the  expanding  force 
is  lost  as  it  passes  through  the  lungs  to  the  surfaces  of  indirect  expansion. 
Many  observers  have  claimed  that  the  expansion  of  the  lung  does  not 
take  place  throughout  instantaneously  and  equally.  This  is  illustrated 


THE    MECHANICS   OF    RESPIRATION  343 

by  the  fact  that,  in  the  region  immediately  surrounding  a  localized  con- 
solidation, a  fluid  has  increased  resonance,  which  would  not  be  the  case 
if  the  relaxation  produced  was  equally  distributed  throughout  the  lung. 
The  root  of  the  lung,  which  has  generally  been  regarded  as  more  or 
less  fixed,  undergoes  in  normal  breathing  a  definite  forward,  downward 
and  outward  movement,  and  the  heart  shares  in  this  movement  (Keith). 
The  movements  of  the  lower  ribs  and  diaphragm  are  responsible  for  the 
expansion  of  the  lower  lobes  and  dorsal  portion  of  the  upper  lobes  of  the 
lungs,  whereas  the  movement  of  the  upper  five  ribs  expands  the  anterior 
portion  of  the  upper  lobes.  The  relative  infrequency  of  pleuritic  fric- 
tion-sounds and  pain  over  the  upper  lobes  as  compared  with  their  fre- 
quency over  the  lower  lobes  is  explained  by  the  fact  that  the  expansion 
of  the  upper  lobes  is  accomplished  with  little  displacement  of  the  pleural 
surfaces,  whereas  in  the  lower  lobes  expansion  is  accompanied  by  a  glid- 
ing of  the  lungs  across  the  ribs. 


CHAPTER  XXXVIII 
THE  CONTROL  OF  THE  RESPIRATION 

The  participation  of  such  widespread  groups  of  muscles  in  the  respira- 
tory act  demands  that  some  mechanism  be  provided  to  insure  its  adequate 
control.  With  every  inspiration,  for  example,  the  muscles  of  the  alse 
nasi  act  so  as  to  cause  dilatation  of  the  nares,  the  vocal  cords  are  ab- 
ducted, and  the  intercostal  muscles,  along  with  the  scalenes  and  the 
diaphragm  are  contracting  while  the  muscles  of  the  abdominal  wall  are 
relaxing;  and  all  these  events  occur  at  exactly  the  proper  time  so  as  to 
bring  about  the  most  efficient  opening  up  of  the  thoracic  cavity.  Evi- 
dently there  must  be  some  mechanism  to  insure  this  perfect  control.  This 
is  effected  through  the  nervous  system. 

THE  RESPIRATORY  NERVE  CENTERS 

The  efferent  fibers  to  the  various  groups  of  muscle  originate  in  their 
respective  motor  neurons,  which  in  most  cases  are  situated  in  the  gray 
matter  of  the  spinal  cord.  The  harmonious  action  of  these  motor  neu- 
rons, or  subsidiary  centers,  is  brought  about  by  the  transmission  to  them 
of  impulses  from  a  higher  or  master  center  placed  in  the  medulla  ob- 
longata,  the  pathway  of  transmission  between  this  master  center  and  the 
subsidiary  centers  being  in  the  lateral  columns  of  the  spinal  cord. 

The  evidence  that  the  chief  respiratory  center  is  in  the  medulla  is  fur- 
nished by  observing  the  effects  produced  on  the  respiratory  movements 
by  serial  destruction  of  the  cerebrospinal  axis  from  above  downward. 
By  this  method  the  approximate  position  of  the  center  is  found,  its  exact 
location  being  then  determined  by  punctiform  destruction  or  stimulation 
of  the  supposed  locus  of  the  center.  If  we  destroy  the  cerebrum  from 
before  backward,  piece  by  piece,  we  shall  find  that  no  marked  effect  is 
produced  on  the  respirations  until  we  arrive  at  about  the  middle  of  the 
medulla,  when  immediate  paralysis  of  the  respiratory  movements  occurs. 
If  we  now  proceed  to  puncture  various  areas  on  the  floor  of  the  fourth 
ventricle  in  another  animal,  we  shall  find  an  area  called  the  noeud  vital, 
located  about  the  tip  of  the  calamus  scriptorius,  destruction  of  which 
causes  immediate  cessation  of  respiration.  It  is  believed  that  the  center 
resides  in  the  group  of  nerve  cells  known  to  neurologists  as  the  fasciculus 
solitarius.  It  is  bilateral. 

344 


THE    CONTROL    OF    THE    RESPIRATION 


345 


The  subsidiary  centers  are  entirely  dependent  upon  the  master  center 
for  their  harmonious  action,  as  is  shown  by  the  fact  that  if  the  phrenic 
motor  neuron — which  is  situated  in  the  cervical  spinal  cord  between  the 
fourth  and  sixth  -spinal  segments — is  isolated  from  the  medulla  by  a 
lateral  hemisection  of  the  cord  just  above  the  fourth  segment  and  by 
mesial  section  of  the  cord  opposite  the  center,  the  corresponding  half  of 
the  diaphragm  no  longer  participates  in  the  respiratory  act  (see  Fig.  118), 

The  chief  center  on  either  side  of  the  midline  of  the  medulla  is  con- 
nected with  the  motor  neurons  of  both  sides  of  the  spinal  cord,  as  is 
proved  by  the  following  experiment.  When  the  central  end  of  the  vagus 
nerve  is  stimulated,  the  respiratory  center  becomes  excited  and  the  respi- 
rations more  pronounced,  the  participation  of  the  muscles  on  both  sides 
of  the  body  being  equal  in  extent.  If  now  we  bisect  the  medulla  down  the 


Fig.    118. — Diagram  to  show  cuts  required  for  isolation  of   the  phrenic  center. 

midline  and  repeat  the  stimulation  of  one  vagus,  the  muscles  on  both  sides 
will  still  participate  in  the  increased  respiration,  which  they  will  likewise  do 
if  the  cervical  cord  is  bisected  or  hemisected  but  the  medulla  left  intact 
(Fig.  119).  The  simplest  interpretation  of  these  results  is  that  commis- 
sural  fibers  connect  both  halves  of  the  respiratory  center  in  the  medulla 
and  that  each  half  is  also  connected  with  the  motor  neurons  of  both  sides 
of  the  spinal  cord.  Often,  especially  in  young  animals,  a  hemisection  of 
the  cord  causes  cessation  of  the  movements  of  the  diaphragm  on  the  same 
side;  but  this  paralyzed  side  at  once  begins  to  contract  again  when  the 
phrenic  of  the  opposite  side  is  cut,  probably  because  the  respiratory 
impulse  descending  from  the  chief  center,  on  finding  its  way  along  the 
motor  center  of  the  same  side  of  the  cord  blocked,  is  forced  to  follow  the 
crossed  path.  The  crossing  in  the  cord  is  believed  to  take  place  at  the 
same  level  as  that  at  which  the  subsidiary  center  is  located  (W.  T. 
Porter12). 


346 


THE   RESPIRATION 


The  question  now  arises  as  to  how  the  chief  center  functionates.  Is  it 
purely  reflex  in  the  sense  that  it  depends  for  its  activity  entirely  on  the 
transmission  to  it  of  nervous  impulses  from  elsewhere,  or  is  it  automatic 
in  the  sense  that  it  can  work  independently  of  such  impulses?  The  au- 
tomaticity  of  the  heart  makes  it  seem  not  improbable  that  the  center 
which  controls  the  co-ordinate  action  of  the  respiratory  muscles  would 
also  have  an  inherent  or  automatic  power.  The  activity  of  such  an  auto- 
matic respiratory  center  would,  of  course,  be  subject  to  great  variation 
as  a  result  of  changes  in  the  composition  of  the  blood  supplying  it,  and 
the  fact  that  it  was  automatic  would  not  remove  it  from  the  influence  of 
nervous  impulses.  Indeed  it  is  possible  to  conceive  of  the  automaticity 
of  the  center  as  being  of  a  low  order,  with  its  normal  functioning 
dependent  upon  afferent  nerve  impulses.  Its  automaticity  might,  then, 


Medulla 


Spinal  cord 
e,  roofs 


C.3 


Fig.  119. — Diagram  to  show  certain  positions  in  the  medulla  and  upper  cervical  cord,  where 
sections  may  be  made  without  seriously  disturbing  the  respirations.  Sections  made  separately  will 
not  disturb  the  respiration,  nor  interfere  with  the  effect  of  vagus  stimulation.  If  both  sections 
are  made  at  once,  however,  breathing  will  be  seriously  interfered  with  on  the  side  of  the 
hemisection,  and  this  side  will  not  respond  to  vagus  stimulation. 

be  merely  a  factor  of  safety  called  into  play  only  when  the  influences 
ordinarily  controlling  the  center  were  for  some  reason  removed. 

The  question  which  at  present  confronts  us,  however,  is  whether  the 
center  may  or  may  not  act  automatically.  Many  experiments  have  been 
undertaken  to  test  this  point,  the  nature  of  all  of  them  depending  upon 
the  isolation  of  the  center  as  completely  as  possible  from  afferent  nerve 
paths.  The  most  successful  experiment  has  been  performed  as  follows: 
The  influence  of  the  higher  nerve  centers  was  removed  by  cutting  across 
the  peduncles  of  the  cerebrum  or  the  pons.  The  influence  of  afferent  im- 
pulses traveling  up  the  spinal  cord  was  removed  by  completely  severing 
the  spinal  cord  below  the  level  of  the  phrenic  nerves  and  sectioning  all 
the  posterior  or  sensory  spinal  roots  of  the  cervical  cord  above  the  level 
of  this  section.  The  vagi  were  also  cut  to  remove  the  impulses  traveling 


THE    CONTROL   OF    THE   RESPIRATION 


347 


by  them  to  the  respiratory  center.  By  such  an  operation  the  only  lower 
respiratory  neurons  left  intact  are  those  of  the  phrenic  nerve,  so  that  the 
only  respiratory  movements  that  are  possible  are  those  in  which  the 
diaphragm  participates  and  the  muscles  of  the  alse  nasi  and  larynx.  It 
was  found  that  the  animal  after  the  operation  went  on  breathing,  though 
imperfectly.  The  respirations  however  soon  became  more  marked  and 
asphyxial  in  character,  indicating  that  the  blood  was  not  becoming 


u 


Diaphragm. 

Fig.    120. — Diagram    tc    show    where    cuts    are    made    to    isolate    the    chief    respiratory    center    from 
afferent   impulses.     The   nerve   roots   have   been   erroneously   reversed   in   this   diagram. 

properly  aerated  and  that  the  chemical  changes  occurring  in  it  were 
acting  directly  on  the  center,  stimulating  it  to  greater  activity.  The 
conclusion  seems  warranted  that  the  respiratory  center  can  act  auto- 
matically, for  the  only  possible  afferent  nerves  left  in  the  above  prepara- 
tion were  those  carried  to  the  center  by  the  fifth  nerve  (Fig.  120). 

That  the  respiratory  center  is  extraordinarily  sensitive  to  changes  in 
the  composition  of  the  blood  flowing  through  it  is  a  fact  that  has  been 
known  for  a  long  time,  but  it  is  only  within  recent  years  that  the  exact 


348  THE   RESPIRATION 

nature  of  this  control  and  the  remarkable  sensitivity  of  the  center  towards 
it  have  been  thoroughly  established.  We  shall  return  to  this  important 
subject  later.  Meanwhile  we  shall  proceed  to  examine  the  manner  in 
which  the  center  is  affected  by  sensory  impulses  transmitted  to  it. 

THE  REFLEX  CONTROL  OF  THE  RESPIRATORY  CENTER 

The  afferent  nerve  fibers  going  to  the  respiratory  center  may  conven- 
iently be  divided  into  two  groups:  those  coming  from  the  respiratory  or- 
gans and  those  coming  from  other  parts  of  the  body. 

Afferent  Impulses  from  the  Respiratory  Organs 

If  the  vagus  nerves  are  cut  or  their  continuity  severed  by  freezing 
a  portion  of  them,  the  respiratory  movements  become  markedly  slower. 
Evidently,  the  vagus  nerves  in  some  way  hurry  up  the  respiratory 
movements.  Again,  if  the  central  end  of  either  vagus  is  stimulated 
with  the  ordinary  interrupted  faradic  current,  a  profound  effect  on 
the  respiratory  movements  is  usually  observed.  This  effect  is  how- 
ever not  strictly  predictable.  Usually  there  is  a  quickening  of  respira- 
tion, and  if  the  stimulus  is  a  strong  one,  there  may  be  a  standstill  of  the 
thorax  in  the  inspiratory  position.  On  the  other  hand,  if  the  central 
end  of  the  nerve  is  stimulated  with  other  types  of  stimuli,  as  by  slow, 
weak  faradic  shocks  or  by  the  stimulus  produced  by  the  closure  of  an 
ascending  voltaic  current,  the  effect  may  be  to  prolong  expiration  rather 
\than  excite  inspiration.  Such  results  would  seem  to  indicate  that  the 
Vagus  contains  two  kinds  of  afferent  fibers  to  fke  respiratory  center,  one 
kind  stimulating  inspiration,  the  other,  stimulating  expiration. 

Supposing  that  both  these  kinds  of  fibers  exist,  the  next  question  is,  how 
do  they  become  excited  at  their  terminations  in  the  lungs  ?  The  most  nat- 
ural assumption  is  that  the  mechanical  distention  and  collapse  of  the 
alveoli  which  occurs  with  each  respiratory  act,  serves  as  the  stimulus — 
an  hypothesis  to  which  support  is  offered  by  the  observation  that,  when 
air  is  blown  into  the  lungs  so  as  to  distend  the  alveoli,  the  animal  im- 
mediately makes  a  forced  expiratory  movement,  whereas  when  the  air 
is  sucked  out,  the  thorax  assumes  the  inspiratory  position. 

Of  the  many  methods  that  have  been  employed  to  produce  disten- 
tion of  the  alveoli,  the  best  is  undoubtedly  that  recently  employed  by 
Haldane13  and  Boothby.14  The  person  or  animal  is  made  to  respire  through 
a  tube  in  which  is  inserted  a  three-way  stopcock,  which  communicates 
either  with  the  outside  air  or  with  a  side-tube  leading  to  a  spirometer 
or  bag  containing  air  under  slight  pressure,  so  that  when  the  stopcock 
is  turned  breathing  takes  place  against  a  definite  positive  pressure. 


THE    CONTROL    OF    THE    RESPIRATION  349 

Such  a  method  is  obviously  much  more  physiological  than  one  in  which 
the  air-tube  is  suddenly  clamped  at  the  end  of  inspiration  and  the  lungs 
left  in  a  distended  condition.  When  the  air  under  pressure  is 
breathed  there  is  usually  a  cessation  of  breathing,  called  apnea. 
The  extent  to  which  it  occurs  varies  very  considerably  in  different  an- 
imals and,  in  the  case  of  man,  in  different  individuals.  Thus,  when  a 
man  is  made  suddenly  to  breathe  into  compressed  air,  the  apnea  often 
lasts  for  about  half  a  minute,  the  pause  being  then  broken  by  a  deep  ex- 
piration followed  by  a  further  pause,  then  again  an  expiration,  and  so 
on  with  progressively  shorter  pauses.  Disregarding  for  the  present 
any  influences  which  changes  in  the  composition  of  the  air  in  the  lungs 
or  of  the  gases  in  the  blood  might  have  in  producing  the  apnea,  we  may 
consider  the  possibility  that  it  is  the  result  of  stimulation  of 
the  termination  of  afferent  vagus  fibers  in  the  walls  of  the  alveoli. 
This  is  an  old  view,  but  the  most  recent  experimental  evidence 
does  not  lend  support  to  it.  It  was  shown  by  Boothby  and  Berry,14  for 
example,  that  a  similar  apnea,  though  indeed  of  shorter  duration,  could 
be  produced  in  dogs  in  which  the  pulmonary  branches  of  both  vagus 
nerves  had  been  severed  two  months  previously.  The  apnea  is,  there- 
fore, not  a  reflex  through  the  vagus,  and  must  be  interpreted  as  due  to  nerv- 
ous impulses  passing  to  the  respiratory  center  from  some  other  part  of 
the  nervous  system,  perhaps  from  centers  higher  up,  or  to  stimuli  trans- 
mitted to  the  respiratory  center  possibly  through  afferent  fibers  in  the 
respiratory  muscles. 

It  has  usually  been  taught  that  section  of  the  vagus  nerves  of  both 
sides  results  in  death  from  pneumonia  within  a  few  days.  E.  A.  Schafer 
has  shown  that  this  is  not  the  case  but  that  animals  (cats)  can  be  kept 
alive  practically  indefinitely  if  precautions  are  taken  to  prevent  the 
obstruction  of  the  larynx  which  supervenes,  through  paralysis  of  the 
laryngeal  muscles,  when  the  inferior  laryngeal  nerves  are  cut.  The 
obstruction  causes  asphyxia  followed  by  congestion  and  edema  of  the 
lungs.  If  the  larynx  be  cauterized  so  as  to  prevent  obstruction  double 
vagotomy  even  in  the  neck  has  no  greater  influence  on  breathing  than 
perhaps  a  slight  and  often  transitory  slowing.53 

The  formerly  very  popular  theory  that  respiration  is  controlled  au- 
tomatically by  alternate  distention  and  collapse  of  the  alveoli,  acting 
through  the  afferent  fibers  of  the  vagus  nerve  on  the  respiratory  center 
in  such  a  way  as  to  excite  the  opposite  act  following  each  inspiration  and 
expiration,  must,  therefore,  be  abandoned.  But  we  cannot  deny  that 
the  vagus  plays  a  most  important  role  in  the  control  of  the  function  of 
the  respiratory  center,  for  apart  from  the  effect  which  we  have  seen  to 
follow  the  severance  of  continuity  of  the  nerve,  there  is  the  important 


f 


350  THE   RESPIRATION 

observation  of  Alcock  and  others15  that  when  nonpolarizable  electrodes 
are  placed  on  the  vagus  nerve  and  connected  with  a  galvanometer,  a 
current  of  action  occurs  toward  the  end  of  each  inspiration  in  quiet 
breathing;  and  when  the  respirations  are  forced,  a  current  of  action 
appears  during  both  inspiration  and  expiration.  Another  reason  for 
believing  that  the  vagi  have  some  important  function  to  perform  in  con- 
nection with  the  control  of  respiration  is  the  fact,  observed  by  F.  H.  Scott,16 
that  in  an  intact  animal,  when  atmospheres  containing  increasing  percent- 
ages of  carbon  dioxide  are  respired,  the  respirations  become  both  deeper 
and  quicker,  whereas  in  one  whose  vagi  have  been  cut  the  carbon  diox- 
ide causes  only  a  deepening  of  the  respirations.  From  this  result  it 
would  appear  that  the  vagi  exert  an  influence  on  the  rate  of  the  respira- 
tions but  not  on  their  depth,  this  effect,  as  we  shall  see  later,  being  de- 
pendent primarily  on  changes  in  the  composition  of  the  blood  supplying 
the  respiratory  center.  It  is  probable  that  both  controlling  agencies  act 
together — the  hormone,  serving  to  maintain  the  center  in  a  proper  state 
of  excitability,  and  the  nervous,  controlling  the  rate  of  discharge  so  that 
the  movements  may  not  be  excessive.  The  influence  of  nervous  impulses 
on  the  rhythm  has  been  shown  by  Stewart,  Pike  and  Guthrie17  who 
observed  that  after  resuscitation  from  acute  brain  anemia,  the  respira- 
tions when  they  returned  were  of  the  same  rhythm  as  that  of  the  artifi- 
cial respirations  employed  during  the  resuscitation. 

Afferent  Impulses  from  Other  Parts  of  the  Body 

To  this  group  belong  afferent  nerves  from  practically  every  part  of 
the  body.  That  impressions  from  the  skin  affect  the  respiratory  center 
is  well  known  by  the  increased  breathing  caused  by  applications  of  cold 
water.  The  influence  of  these  afferent  impulses  is  often  very  marked, 
and  is  frequently  taken  advantage  of  in  stimulating  a  newborn  infant  to 
take  the  first  breath.  \Stimulation  of  the  terminations  of  the  fifth  nerve 
in  the  mucous  membrane  of  the  nose,  as  by  inhaling  a  pungent  odor, 
immediately  inhibits  respiration.  To  these  occasionally  acting  afferent 
impulses  may  be  added  the  impulses  that  are  conveyed  to  the  respiratory 
center  from  the  higher  nerve  centers  of  the  cerebrum.  These  impulses 
are  largely  voluntary  in  nature,  and  enable  us  to  hold  our  breath  at  will. 
Some  of  the  cerebral  impulses  are  however  also  involuntary,  their  exist- 
ence being  seen  by  observing  the  respirations  of  an  animal  before  and 
after  sectioning  the  pons  or  peduncles.  The  respirations  for  a  time  at  least 
become  distinctly  affected,  but  they  later  return  with  perfect  regularity. 
They  may  become  very  irregular,  however,  if  the  vagi  as  well  as  the  pons 
are  cut  but  if  the  brain  stem  is  cut  further  forward,  as  at  the  level  of 
the  anterior  corpora  quadrigemina,  section  of  the  vagi  only  produces 


THE    CONTROL    OF    THE   RESPIRATION  351 

slowing  of  the  breathing.  Other  experimental  evidence  of  the  existence 
of  cerebral  respiratory  fibers  is  furnished  by  cerebral  localization  experi- 
ments. During  stimulation  of  the  cerebral  cortex,  for  example,  a  marked 
effect  on  the  respiratory  movements  is  often  noted. 

Respiratory  rhythm,  unlike  that  of  the  heart,  has  often  to  be  modified 
in  order  that  the  respiratory  mechanism  may  be  used  for  other  purposes 
than  the  ventilation  of  the  lungs.  This  alteration  in  rhythm  may  take 
the  form  of  a  mere  inhibition,  such  as  the  act  of  swallowing;  or  the 
respiration  may  be  altered,  as  in  phonation  and  singing.  More  consid- 
erable alteration  in  the  expiratory  discharge  occurs  in  coughing  and 
sneezing,  and  still  more  in  the  acts  of  micturition,  defecation,  and  parturi- 
tion. We  must  conclude  therefore  that  the  rhythmic  stimuli  sent  out 
from  the  respiratory  center  are  so  weak  that  stimuli  from  other  sources 
may  instantly  inhibit  or  change  their  form  at  any  stage  of  the  cycle. 

Stimulation  of  the  endings  of  the  glossopharyngeal  nerve  inhibits  res- 
piration, which  explains  the  holding  of  the  breath  that  occurs  in  swal- 
lowing. 

The  superior  laryngeal  branch  of  the  vagus  has  an  occasional  influence 
on  the  respiratory  center,  its  particular  function  being  in  connection  with 
the  act  of  coughing.  When  a  foreign  body  irritates  the  mucous  membrane  of 
the  larynx,  the  nerve  fibers  transmit  impulses  to  the  respiratory  center 
which  excite  a  violent  expiration  and  at  the  same  time  cause  the  glottis  to 
close.  The  closure  of  the  glottis  lasts,  however,  only  during  the  first  part 
of  the  expiration;  it  then  opens,  with  the  result  that  the  sudden  release 
of  intrapulmonic  pressure  causes  the  expulsion  of  the  foreign  substance 
from  the  air  passages.  Sneezing  is  a  similar  mechanism,  being  due  to 
stimulation  of  the  endings  of  the  fifth  nerve  in  the  nasal  mucosa,  the 
only  difference  being  that  the  initial  obstruction  to  the  forced  expira- 
tion is  higher  up. 


CHAPTER  XXXIX 
THE  CONTROL  OF  RESPIRATION  (Cont'd) 

THE  HORMONE  CONTROL  OF  THE  RESPIRATORY  CENTER 

Just  as  the  rhythmical  activity  of  the  heart  is  readily  influenced  by 
changes  in  the  composition  of  the  blood  supplying  it,  so  also  is  that  of 
the  respiratory  center.  In  the  case  of  the  heart  it  is  the  cations — cal- 
cium, potassium  and  sodium — that  have  the  most  pronounced  effect, 
whereas  in  the  case  of  the  respiratory  center  it  is  largely  the  relative  con- 
centration of  hydrogen  and  hydroxyl  ions — the  H-ion  concentration 
(CH)  of  the  blood.  This  influence  can  be  shown  in  a  general  way  by 
injecting  acid  or  alkaline  solutions  into  the  peripheral  end  of  the  carotid 
artery  of  an  anesthetized  animal,  or  better  still  of  one  that  has  been 
decerebrated.  Acid  injections  stimulate  the  respiratory  activity;  alka- 
line injections  tend  to  depress  it.  When  the  acid  or  alkaline  solutions 
are  injected  intravenously  in  other  parts  of  the  body,  so  that  they  be- 
come thoroughly  mixed  with  the  blood  before  the  respiratory  center  is 
reached,  the  effects  are  not  nearly  so  pronounced,  because  the  buffer  in- 
fluence of  the  blood  has  time  to  develop  (see  page  36) . 

From  the  results  of  such  injection  experiments,  however,  one  could 
not  draw  the  conclusion  that  under  normal  conditions  the  activity  of 
the  respiratory  center  is  affected  by  measurable  changes  in  CH  of  the 
blood,  for,  as  we  have  seen,  constancy  of  CH  is  one  of  the  most  remark- 
able properties  of  the  animal  fluids.  To  justify  the  conclusion  that  the 
respiratory  center  is  affected  by  changes  in  CH,  it  is  necessary  to  observe 
the  behavior  of  some  easily  measurable  acid  or  alkaline  constituent  of 
the  blood  that  undergoes  changes  in  amount  that  are  proportional  to  an 
alteration  in  CH.  In  order  to  understand  what  this  acid  or  basic 
substance  may  be,  it  will  be  advisable  to  recapitulate  the  main  factors 
concerned  in  maintaining  CH  at  a  constant  level.  This  value  is  obviously 
dependent  upon  the  balance  between  basic  and  acid  substances,  so  that 
any  variations  which  it  undergoes  must  be  caused  by  changes  in  the 
relative  amount  of  one  of  these.  Changes  in  base  may  occur,  exoge- 
nously,  by  altering  the  alkali  content  of  the  food,  or,  endogenously,  in 
various  ways  but  particularly  by  variations  in  the  amount  of  ammonia 
produced  during  the  course  of  metabolism  of  protein.  Thus,  when  sud- 
den demands  are  made  by  the  organism  for  an  increased  amount  of  base, 
the  ammo  groups — split  off  from  the  ammo  bodies — become  converted 

352 


THE    CONTROL    OF    THE   RESPIRATION  353 

into  ammonia  instead  of  into  the  neutral  substance,  urea.  But  the  chief 
variations  seem  to  concern  acids  rather  than  the  basic  substances.  These 
acids  may  be  divided  into  three  groups:  fixed  inorganic  acids,  represented 
by  phosphoric;  fixed  organic  acids,  represented  by  lactic;  and  volatile 
acids,  represented  by  carbon  dioxide.  Of  these  three  groups,  the  first 
shows  the  least  tendency  to  change,  and  the  third,  the  greatest.  Changes 
in  the  second  group  (fixed  organic  acids)  are  effected  partly  by  altera- 
tions in  their  rate  of  excretion  through  the  urine  and  partly  by  their 
rate  of  oxidation  into  volatile  acid.  The  sudden  and  rapid  changes  in 
the  third  group  are  brought  about  by  the  diffusion  of  the  C02  of  the 
blood  into  the  alveolar  air.  Gross  changes  in  the  acid  content  of  the 
blood  are  therefore  mainly  effected  through  alteration  in  the  amount  of 
the  fixed  acids,  whereas  sudden  changes  are  effected  by  alteration  in  the 
amount  of  the  volatile  acid.  It  is  important  to  note  here  that  the  fixed 
organic  acids  do  not  participate  to  any  great  extent  in  the  makeup  of 
the  acid  content  of  normal  blood:  they  appear  only  under  unusual  or 
pathological  conditions,  as  in  dyspnea  or  ketosis  (page  715).  The  varia- 
tions in  CH  that  ordinarily  affect  the  activity  of  the  respiratory  center 
are  therefore  dependent  upon  changes  in  the  volatile  acid,  a  direct 
measure  of  which  is  found  in  the  tension  of  C02  in  the  arterial  blood  and, 
as  we  shall  see,  of  the  alveolar  air  (page  356).  The  correlation  between 
CH  of  the  blood  and  respiratory  activity  must  be  a  very  close  one  if  CH 
is  to  be  maintained. 

The  Laws  of  Gases. — In  order  to  understand  the  principles  upon  which 
alterations  in  C02  tension  are  dependent,  it  will  be  necessary  for  us  to 
review  briefly  some  of  the  gas  laws.  Among  these  laws  the  first  in  im- 
portance is  the  law  of  pressure,  which  states  that,  other  things  being 
equal,  the  pressure  of  a  gas  is  inversely  proportional  to  its  volume;  if 
a  gas  occupying  a  certain  volume  is  compressed  by  a  pump  so  that  it  oc- 
cupies one-half  of  its  previous  volume,  its  pressure  will  become  doubled. 
The  second  is  the  law  of  partial  pressure,  which  states  that  the  partial 
pressure  of  a  gas  in  a  mixture  of  gases,  having  no  action  on  one  another, 
is  equal  to  that  which  this  particular  gas  would  exert  were  it  alone  present 
in  the  space  occupied  by  the  mixture.  Thus,  atmospheric  air  consists 
roughly  of  79  volumes  per  cent  of  nitrogen  and  21  of  oxygen;  the  par- 

21 

tial  pressure  of  the  oxygen  is  therefore  equal  to  ^^-  X  760  mm.    Hg, 

1UU 

this  last  figure  being  the  barometric  pressure  of  air  at  sea  level.  The 
third  is  the  law  of  solution  of  gases,  which  is  to  the  effect  that  the  amount 
of  gas  which  goes  into  solution  in  a  liquid  having  no  chemical  attraction 
for  the  gas,  is  proportional  to  the  partial  pressure  of  gas.  If  water  is 
exposed  to  air,  the  amount  of  oxygen  which  it  dissolves  will  be  the  same 
as  if  the  water  had  been  exposed  to  oxygen  at  a  pressure  equal  to  that 


354  THE   RESPIRATION 

of  the  partial  pressure  which  it  produces  in  air.  The  same  will  be 
the  case  with  the  nitrogen  of  the  air.  The  actual  amount  of  gas  which 
becomes  dissolved  in  the  fluid,  pressure  and  temperature  being  constant, 
depends  partly  on  the  nature  of  the  gas  and  partly  on  the  nature  of  the 
fluid.  For  example,  the  solubility  of  oxygen  in  water  is  considerably 
different  from  that  in  a  neutral  oil;  or,  taking  the  same  solvent,  nitro- 
gen and  C02  do  not  dissolve  to  the  same  extent  in  water.  It  becomes 
necessary,  therefore,  in  calculating  what  amount  of  a  particular  gas 
will  dissolve  in  a  particular  fluid  to  use  a  figure  known  as  the  coefficient 
of  solubility  of  the  gas  —  that  is,  the  amount  of  gas  taken  up  by  a  unit 
volume  of  fluid  at  standard  temperature  and  pressure;  for  example,  to 
say  that  the  coefficient  of  absorption  of  nitrogen  in  water  at  0°  C.  is 
0.0239  means  that,  at  this  temperature  and  at  normal  barometric  pres- 
sure, 1  c.c.  of  water  will  dissolve  0.0239  c.c.  of  nitrogen  when  exposed  to 
a  pure  atmosphere  of  this  gas.  Obviously,  then,  if  water  were  exposed 
to  79  per  cent  of  an  atmosphere  of  nitrogen  (as  in  air)  the  amount  which 

79 
would  become  dissolved  in  each  c.c.  would  be        TX  0.0239  =  0.0189  c.c. 


In  solutions  containing  no  chemical  substances  with  which  the  gas  can 
enter  into  combination,  it  is  evident  that  the  tension  of  the  gas  will  be 
proportional  to  the  amount  of  gas  that  can  be  displaced  or  pumped  out 
from  the  fluid.  On  the  other  hand,  when  a  chemical  compound  is  formed, 
the  combined  gas  will  exercise  no  direct  influence  on  the  tension,  so  that 
this  will  be  independent  of  the  amount;  in  such  cases  separate  methods 
will  have  to  be  used  for  the  determination  of  amount  and  tension.  Let 
us  take  the  case  of  pure  water  exposed  to  an  atmosphere  of  C02:  the 
amount  of  C02  which  goes  into  solution  will  depend  entirely  on  the 
pressure.  If  a  trace  of  alkali  is  dissolved  in  the  water,  however,  some 
of  the  C02  will  become  combined  to  form  carbonate,  so  that  a  much 
larger  quantity  of  C02  will  be  displaceable  from  the  solution  (as  by 
adding  a  mineral  acid  to  it)  than  corresponds  to  the  tension  of  C02  in 
the  atmosphere  surrounding  it.  Since  blood  contains  alkali  the  condi- 
tions are  analogous  with  those  of  a  weak  alkaline  solution. 

The  Tension  of  C02  and  02  in  the  Arterial  Blood.  —  If  we  were  to 
pass  blood  at  body  temperature  in  a  very  thin  film  over  the  walls  of  a 
confined  space  containing  a  mixture  of  gases  one  of  which  was  C02,  it 
is  evident  that  the  percentage  of  C02  in  the  atmosphere  contained  in 
this  space  would  remain  unchanged  only  when  the  tension  of  this  gas  in 
the  blood  was  the  same  as  that  in  the  confined  atmosphere.  If,  on  the 
other  hand,  the  tension  of  C02  in  the  blood  should  correspond  to  a  per- 
centage that  is  higher  than  that  in  the  atmosphere,  then  C02  would  dif- 
fuse from  the  blood,  and  at  the  end  of  the  experiment  an  analysis  of  the 


THE    CONTROL    OF    THE   RESPIRATION 


355 


atmosphere  in  the  space  would  show  that  the  C02  percentage  had  been 
raised.  If  the  blood  contained  a  lower  tension  than  that  corresponding 
to  the  percentage  of  C02  in  the  space,  some  of  the  C02  would  diffuse 
into  the  blood,  and  its  percentage  in  the  atmosphere  would  be  lowered. 
By  successively  exposing  blood  to  gas  mixtures  that  contain  slightly 
different  percentages  of  C02,  we  should  ultimately  find  one  with  which 
the  free  C02  in  the  blood  was  in  perfect  equilibrium,  and  we  should  be 
able  to  state  that  the  tension  of  this  gas  in  the  blood  was  equal  to  a 
certain  percentage  in  the  atmosphere  surrounding  the  blood  (see  Fig. 
121). 

Many  forms  of  apparatus  based  on  the  above  principle  have  been  in- 
vented for  the  examination  of  the  tension  of  the  gases  in  the  blood. 
The  most  accurate  is  that  devised  by  Krogh,18  the  principle  of  which 


CO, 

IT 


Fig.    121. — Diagram    to    show    principle    for    measurement    of    the    tension    of 
CO2    tension    of    blood    is    supposed    to    be    5.75. 


blood.      The 


differs  slightly  from  that  just  described  in  that  a  bubble  of  air  is 
exposed  to  a  relatively  large  quantity  of  blood,  so  that  after  a  time 
actual  equilibrium  of  gas  tension  becomes  established  between  the  bub- 
ble and  the  gases  of  the  blood.  This  apparatus  is  shown  in  Figs.  122 
and  123.  It  consists  of  a  graduated  tube  of  narrow  bore  sur- 
rounded by  a  water  jacket.  To  the  upper  end  of  the  graduated  tube 
a  small  syringe  is  attached.  The  lower  end  of  the  graduated  tube  ex- 
pands into  a  thistle-shaped  bulb,  closed  below  by  a  cork,  through  which 
is  inserted  a  tube  (inflow  tube)  ending  near  the  top  of  the  bulb  in  a 
fine  opening  and  connected  outside  with  an  artery.  An  outflow  tube  is 
also  connected  with  the  thistle-shaped  bulb. 

At  the  beginning  of  the  experiment  the  thistle-shaped  bulb  and  the 
graduated  tube  are  filled  with  physiological  saline.  By  means  of  the 
syringe  a  small  bubble  of  air  is  then  introduced,  so  that  it  lies  at  the 


356 


THE   RESPIRATION 


junction  of  the  thistle-shaped  bulb  and  the  graduated  tube.  As  the  blood 
is  allowed  to  enter  through  the  inflow  tube,  it  is  ejected  in  a  fine  stream 
around  the  bubble  of  air,  which  moves  about  in  the  stream.  The  blood 
displaces  the  saline  out  of  the  bulb  into  the  side  tube.  After  the  bub- 
ble has  been  subjected  to  the  influence  of  the  blood  for  some  minutes, 
the  gases  in  it  come  into  perfect  equilibrium  with  those  in  the  blood. 
The  percentage  of  02  and  C02  in  the  bubble  will  therefore  correspond 
to  the  tension  of  these  gases  in  the  blood.  The  analysis  is  effected  by 
drawing  the  bubble  into  the  graduated  tube  by  means  of  the  syringe, 


Fig.   122. 


Fig.   123. 


Fig.  122. — The  gas  analysis  pipette  for  the  microtonometer  shown  in  Fig.  123.  For  description 
see  context.  (From  A.  Krogh.) 

Fig.  123. — Microtonometer,  to  be  inserted  into  a  blood  vessel.  The  small  circle  represents  the 
bubble  of  air.  For  further  description  see  context.  (From  A.  Krogh.) 

measuring  its  capacity,  transferring  it  into  a  bulb  containing  KOH, 
which  absorbs  the  C02,  then  taking  it  back  into  the  capillary  tube  and 
again  measuring.  The  shrinkage  obviously  corresponds  to  the  amount 
of  C02.  The  bubble  is  then  transferred  into  potassium  pyrogallate  solu- 
tion, where  the  02  is  absorbed.* 

The  Tension  of  C02  and  02  in  Alveolar  Air. — Having  seen  how  we 
may  determine  the  tension  of  the  gases  in  blood,  we  must  now  consider 


*Since  the  above  was  written,  a  more  efficient  tonometer  devised   by  the  late  T.    G.    Brodie  has 
been  described  by  O'Sullivan  (Am.  Jour.  Physiol.,  Sept.,  1918). 


THE    CONTROL    OF    THE   RESPIRATION  357 

the  method  by  which  the  tensions  of  these  gases  in  alveolar  air  can  be 
determined.  The  simplest  and  until  recently  the  most  accurate  method 
is  that  of  Haldane  and  Priestley.19  This  consists  in  having  an  individual, 
with  his  nostrils  clamped,  breathe  quietly  through  a  piece  of  hose  pipe 
about  a  meter  long,  which  has  at  the  mouth  end  a  short  side-tube  lead- 
ing to  an  evacuated  gas-sampling  bulb  of  about  50  c.c.  capacity.*  (Fig. 
124).  After  the  subject  has  become  accustomed  to  breathing  through  the 
tube,  he  is  asked  to  make  a  forced  expiration  and  at  the  end  of  it  to  close 
the  mouthpiece  with  his  tongue.  .  At  this  moment  the  operator  opens  the 
tap  of  the  sampling  tube,  allowing  the  air  from  the  tubing  through 
which  the  individual  has  made  the  forced  expiration  to  rush  in  and  fill 
it.  This  sample  represents  the  air  from  the  alveoli  (see  page  319),  and 
is  analyzed  for  percentages  of  C02  and  02.  Since  each  normal  inspira- 
tion dilutes  the  alveolar  air  somewhat,  it  is  necessary,  for  constant  re- 


Fig.    124. — Apparatus    for    collection    of    a    sample    of    alveolar    air    by    Haldane's    method.      It    is 
better  to  use  a  mouthpiece  than  a  mask. 

suits,  to  make  two  analyses  of  alveolar  air  from  each  subject,  one  taken 
at  the  end  of  a  normal  inspiration  and  the  other  at  the  end  of  normal 
expiration.  The  average  of  the  two  results  is  taken  as  the  composition 
of  the  alveolar  air. 

On  account  of  the  difficulty  in  securing  intelligent  cooperation  in  the 
application  of  this  method,  particularly  with  children,  other  methods  have 
been  devised.  One  of  the  simplest  is  that  of  Fridericia,  which  is  a  modifica- 
tion of  the  Haldane-Priestley  method,  the  apparatus  for  which  is  shown 
in  the  figure  (Fig.  125),  and  the  manipulation  of  which  is  outlined  in 
the  legend.  Another  is  to  take  a  mixed  sample  of  the  very  last  portion 
of  several  normal  expirations.  On  account  of  the  extended  use  which  is 
being  made  of  measurements  of  alveolar  air  composition,  both  in  lab- 

*In  place  of  the  gas-sampling  tube  it  is  much  more  convenient  and  equally  accurate  to  employ  one 
of  the  modern  ground  glass  piston  syringes  (Luer).  The  piston  should,  of  course,  be  well  smeared 
with  a  good  mineral  grease. 


358 


THE    RESPIRATION 


Fig.  125. — Fridericia's  apparatus  for  measuring  the  CC>2  in  alveolar  air.  The  person  expires 
forcibly  through  the  tube  with  the  stopcocks  as  in  I.  A  is  closed  and  the  tube  placed  in  water  to 
cool  the  air,  after  which  B  is  turned  as  in  II.  The  entrapped  column  of  air  equals  100  c.c.  A 
solution  of  caustic  alkali  is  now  sucked  into  C  with  stopcocks  as  in  II.  B  is  then  turned  as  in 
I  but  with  A  still  closed,  and  the  alkali  solution  allowed  to  enter  b,  after  which  B  is  turned  off, 
the  excess  of  alkali  solution  in  C  allowed  to  run.  out  and  the  burette  shaken.  The  burette  is 
then  submersed  up  to  a  in  a  cylinder  of  water,  with  B  as  in  III.  After  allowing  for  cooling, 
the  level  at  which  the  water  stands  gives  the  per  cent  of  CO^. 


20  $9 


in,  inspired 
air 


Co* 


130     to       50 


30 


Fig.  126.  —  Curves  to  show  the  relationship  between  the  O2  and  CO2  tensions  in  alveolar  air 
(dotted  lines)  and  arterial  blood  (continuous  lines).  It  will  be  observed  that  the  tension  of  CO2 
in  blood  is  slightly  above  that  in  alveolar  air,  but  that  the  reverse  relationship  obtains  for  O2.  In 
the  upper  part  of  the  curve  the  Q->  tension  in  the  alveolar  air  was  experimentally  altered,  causing 
a  corresponding  alteration  in  the  62  tension  of  the  blood.  '  This  result  is  of  practical  significance 
in  connection  with  O2  alterations  in  gas  poisoning,  pneumonia,  etc.  (From  A.  and  M.  Krogh.) 


THE    CONTROL    OF    THE    RESPIRATION 


359 


oratory  and  in  clinical  work,  a  special  chapter  has  been  devoted  to  the 
subject,  giving  in  detail  the  more  recent  methods  devised  by  K.  G.  Pearce. 

Lastly,  it  should  be  noted  that  several  observers  believe  that  a  more 
reliable  estimate  of  the  alveolar  tension  of  C02  (and  of  02)  can  be  made 
by  analyzing  a  sample  of  ordinary  expired  air  and  calculating  the  per- 
centages of  C02  and  02  in  the  alveolar  air  by  allowing  a  constant  dead- 
space  capacity  of  140  c.c.  (Krogh,  etc.). 

If  we  compare  the  C02  tension  of  arterial  blood,  as  measured  by  the 
Krogh  method,  with  that  of  alveolar  air,  we  shall  find  that  there  is  a 
remarkable  correspondence,  indicating,  therefore,  that,  when  the  arterial 


44  %  Cox  ia  it  sptred 


220 


Fig.    127. — Same   as   Fig.    126,   except   that  in   this   case   the   tension   of   CO2   in   the   alveolar  air  was 
experimentally  altered.      (From  A.   and   M.   Krogh.) 

blood  leaves  the  alveoli,  its  partial  pressure  or  tension  of  C02  is  exactly 
equal  to  that  in  the  alveolar  air.  This  is  shown  in  the  accompanying 
curves  of  experiments  performed  by  Krogh.  The  dotted  line  in  these 
curves  represents  the  tension  of  C02  or  02  in  alveolar  air,  and  the  con- 
tinuous line,  these  tensions  in  arterial  blood.  Close  correspondence 
will  be  observed  between  the  C02  curves  even  when  sudden  changes  in 
alveolar  C02  were  induced  by  artificial  means.  In  the  case  of  the  02 
tensions,  however,  that  of  the  blood  is  always  lower  than  that  of  the 
alveolar  air,  the  differences  being  especially  marked  when  the  02  ten- 
sion in  the  alveoli  is  raised  (Figs.  126  and  127). 

Tension  of  C02  and  02  in  Venous  Blood. — If  we  examine  the  C02  tension 
of  the  venous  blood  coming  to  the  lungs,  we  shall  find  that  it  is  distinctly 


360  THE    RESPIRATION 

higher  than  that  in  the  alveolar  air.  The  earliest  method  for  measuring 
it  consisted  in  passing  a  lung  catheter  into  the  right  bronchus  and  then 
blocking  the  passage  above  the  open  end  of  the  catheter  by  inflating  a 
rubber  collar  or  ampulla.  The  renewal  of  air  in  the  right  lung  is  thereby 
prevented,  and  a  sample  of  the  stagnant  air  can  be  removed  and  analyzed. 
In  such  a  case,  however,  the  blood  will  have  circulated  several  times 
round  the  body,  and  with  only  one  lung  operating  the  risk  is  incurred 
that  more  C02  is  being  discharged  into  the  blocked  lung  than  cor- 
responds to  the  tension  of  C02  of  venous  blood  under  normal  conditions. 

Much  more  practical  methods  are  those  of  Haldane,  Yandell  Hender- 
son and  R.  G.  Pearce,  which  are  much  the  same  in  principle.  In  Pearce's 
method,  the  person  first  of  all  inspires  from  a  gas  meter  containing  a 
gaseous  mixture  with  about  10  per  cent  of  C02.  Immediately  after  fill- 
ing the  lungs,  he  makes  a  rapid  forced  expiration  into  a  tube  provided 
with  a  valve  having  four  openings.  This  valve  is  turned  through  a 
complete  circuit  during  the  expiration,  so  that  four  fractions  of  the  ex- 
pired air  can  be  collected  in  rubber  bags  connected  with  side  tubes 
opening  opposite  the  four  openings  in  the  valve.  The  first  fraction  will 
contain  a  little  less  than  10  per  cent  C02,  the  second  distinctly  less, 
while  the  fourth  will  contain  the  same  as  the  third,  indicating  that  equi- 
librium between  the  C02  of  the  alveolar  air  and  the  blood  must  have  been 
attained.  This  figure  therefore  gives  us  the  tension  of  C02  in  the  venous 
blood  of  the  lungs.  In  Henderson's  method  the  rebreathing  is  per- 
formed into  gas  receivers  containing  6  per  cent  C02. 

These  results  then  indicate  that  the  whole  process  by  which  C02  is 
exchanged  in  the  lungs  is  dependent  on  the  law  of  gas  diffusion ;  the  gas 
diffuses  from  a  place  of  higher  to  a  place  of  lower  pressure,  and  does 
so  until  equilibrium  is  attained. 

The  tension  of  02  in  venous  blood  may  be  determined  by  the  applica- 
tion of  similar  principles.  After  a  deep  expiration  nitrogen  is  inspired 
from  a  rubber  bag  for  3-5  breaths  (10-20  sees.)  and  a  sample  of  alveolar 
air  is  immediately  taken.  The  percentage  of  02  in  this  alveolar  air  will 
be  found  to  be  the  same  whether  it  be  taken  after  3  or  5  breaths,  show- 
ing that  an  equilibrium  with  the  tension  of  this  gas  in  the  blood  must 
have  been  reached.  If  taken  earlier,  the  02  will  be  too  high,  and  if  taken 
later  it  will  be  too  low  (because  the  blood  will  have  circulated  twice 
round  the  body).  This  02  percentage  corresponds  with  the  partial  pres- 
sure (tension)  of  02  in  the  mixed  venous  blood  but  it  is  somewhat  lower 
than  the  latter  because  under  the  conditions  of  the  experiment  the 
C02  in  the  alveolar  air  is  only  that  of  arterial  blood  (40  mm.)  (Bar- 
croft,  etc.84). 


THE    CONTROL    OF    THE    RESPIRATION  361 

FALLACIES  IN  THE  ESTIMATION  OF  THE  ALVEOLAR  GASES 

Methods  such  as  that  of  Haldane  and  Priestley,  which  calculate  the 
mean  percentage  composition  of  the  alveolar  air  by  analysis  of  a  sample 
taken  from  the  end  of  a  prolonged  forced  expiration,  give  values  which 
are  too  high  for  C02  and  too  low  for  02.  There  are  several  reasons 
for  this:  (1)  In  the  time  taken  for  the  prolonged  deep  expiration  an 
appreciable  amount  of  C02  will  be  given  off  by  the  blood  to  the  alveolar 
air,  and  oxygen  will  be  absorbed — that  is,  the  sample  will  not  contain 
the  same  percentages  of  C02  and  02  at  different  stages  of  expiration. 
(2)  The  portion  of  the  tidal  air  which  reaches  the  alveoli  dilutes  the 
alveolar  air  and  thus  causes  the  amount  of  C02  given  off  by  the  blood  to 
vary  during  the  different  phases  of  respiration.  If  we  bear  in  mind  that 
the  tensions  of  C02  in  the  alveolar  air  and  in  the  blood  leaving  the  lungs 
are  always  the  same  (page  360),  and  that  the  entire  fall  in  C02  tension 
in  the  alveolar  air  occurs  during  inspiration,  then  it  is  clear  that  the 
blood  in  the  pulmonary  capillaries  must  have  a  maximum  tension  and 
load  of  C02  at  the  end  of  expiration,  and  a  minimum  tension  and  load 
of  C02  at  the  end  of  inspiration.  Accordingly,  the  average  of  the  per- 
centage of  C02  and  02  at  the  end  of  inspiration  and  expiration,  as  de- 
termined by  the  Haldane-Priestley  method  or  by  any  of  its  modifications, 
must  fail  to  give  the  correct  mean  tension  of  these  gases  in  the  alveolar 
air  during  expiration.  The  error  which  makes  the  C02  higher  than  it 
should  be,  makes  the  percentage  of  02  less  than  it  should  be.  These  in- 
fluences taken  along  with  the  fact,  which  will  be  shown  later,  that  the 
evolution  of  C02  from  the  blood  is  relatively  more  rapid  at  low  than  at 
high  tension  of  C02,  indicates  that  the  blood  in  the  pulmonary  capil- 
laries during  inspiration  must  contribute  a  greater  part  of  the  C02 
excreted  during  a  respiratory  cycle  than  that  in  the  pulmonary  capil- 
laries during  expiration,  and  moreover  that  a  greater  part  of  the  C02 
excreted  must  be  evolved  at  a  tension  which  is  below  the  mean  tension 
of  the  C02  present  in  the  entire  time  of  the  expiration.  We  conclude, 
therefore,  that  the  average  tension  of  C02  in  the  alveolar  air,  determined 
by  the  actual  tension  under  which  the  gas  is  evolved  from  the  blood,  is 
less  than  the  average  tension  of  C02  in  the  alveolar  air  during  the  time 
of  a  respiratory  cycle. 

In  the  case  of  02  the  conditions  are  different.  While  the  diluting 
effect  of  the  alveolar  tidal  air  is  marked  in  altering  the  amount  of  C02 
given  off  during  the  different  phases  of  a  respiration,  it  can  have  little 
influence  on  the  amount  of  02  taken  up  by  the  blood  under  normal  con- 
ditions. This  is  evident  from  a  study  of  the  dissociation  curve  of  hemo- 
globin (page  396),  which  shows  that  at  tensions  above  65  mm.  Hg  the 


362  THE    RESPIRATION 

hemoglobin  is  practically  saturated  with  02.  Since  the  tension  of  02 
in  the  alveolar  air  under  normal  conditions  is  greater  than  65  mm. 
(95-100  mm.),  the  rate  of  absorption  of  02  must  be  practically  maximal 
during  the  respiratory  cycle — that  is,  it  will  not  change  at  different 
phases  of  it. 

While  the  relationship  of  the  alveolar  gases  is  continually  changing 
at  different  stages  of  the  respiratory  cycle,  their  mean  relationship  for 
periods  including  several  respirations  or  for  complete  respirations  is 
more  or  less  constant,  being  controlled  by  the  type  of  the  metabolism, 
and  mathematically  expressed  by  the  respiratory  quotient  (page  582). 
The  average  relative  percentages  of  the  two  gases  in  the  alveolar  air 
must  therefore  be  the  same  as  in  the  tidal  air.  In  the  alveolar  air  col- 
lected by  the  Haldane  method,  however,  the  above  factors  cause  the 
respiratory  quotient  to  be  less  than  that  in  the  tidal  air. 

These  points  have  been  insisted  upon  because  much  of  the  knowledge 
of  the  gaseous  exchange  between  the  blood  and  the  air  in  the  lungs,  as 
well  as  the  control  of  respiration,  has  been  built  upon  data  obtained  by 
the  Haldane-Priestly  method,  and  in  considering  this  work,  which  we 
shall  do  in  subsequent  pages,  it  is  advisable  that  we  be  aware  of  the 
limitations  of  the  method  employed.  The  method  has  been  an  invaluable 
one  for  opening  up  a  hitherto  entirely  unexplored  field  of  research,  but 
now,  the  pioneer  work  having  been  done,  we  must  employ  methods 
which  will  enable  us  to  explore  more  exactly.  (R.  G.  Pearce.) 


CHAPTER  XL 
THE  CONTROL  OF  RESPIRATION  (Cont'd) 

VARIATIONS  IN  THE  ALVEOLAR  C02  AND  THE  ACID  BASE 
BALANCE  IN  HEALTH  AND  DISEASE 

At  this  stage  and  before  we  proceed  to  examine  the  respiratory  dis- 
turbances due  to  blood  changes,  it  will  be  advantageous  to  review  the 
general  nature  of  the  adjustments  which  may  occur  in  the  body  to  com- 
pensate for  disturbances  in  the  acid-base  equilibrium,  and  to  indicate  the 
type  of  symptoms  which  develop  if  these  compensations  are  not  promptly 
effected. 

To  understand  the  relationships  it  is  most  satisfactory  to  study  a  C02 
absorption  curve  such  as  is  shown  in  Fig.  128.  As  has  already  been 
explained  on  page  50  this  curve  is  obtained  by  finding  the  percentages  of 
C02  (ordinates)  absorbed  by  blood  exposed  at  38°  C.  in  a  tonometer  to 
varying  tensions  of  C02  (abscissae).  Two  such  curves  are  shown  in  the 
chart  to  represent  the  extreme  limits  which  are  found  in  normal  blood. 
The  percentage  of  C02  going  into  simple  solution  in  the  blood  is  readily 
calculated  for  each  tension,  by  multiplying  this  by  0.0672,  the  coefficient 
of  solubility  of  C02  in  blood  (slanting  straight  line  near  the  abscissa). 
It  is  then  an  easy  matter  to  calculate  PH  for  the  different  parts  of  the 
C02  curve  (see  equation  on  page  50).  If  this  be  done  for  curves  of  vary- 
ing heights  (e.g.,  blood  of  different  individuals  or  blood  of  the  same 
individual  under  varying  conditions)  it  has  been  found  by  Y.  Henderson 
and  Haggard  that  lines  joining  the  same  PH's  all  meet  at  the  zero  point. 
By  drawing  such  lines  on  the  chart  we  can  at  a  glance  tell  PH  if  we  know 
the  total  C02  absorbed  and  the  partial  pressure  of  C02.  Taking  the 
normal  range  of  PH  as  7.3-7.5  and  of  total  C02  at  40  mm.  C02  pressure, 
43  and  55  vols.  per  cent,  we  can  see  from  the  chart  the  relationship  of 
these  values  to  PH  in  various  abnormal  conditions.  These  may  be  classi- 
fied as  follows: 

Decrease  in  PH  (increased  H-ion  concentration). 

1.  Addition  of  C02  (I  in  diagram).  The  simplest  form  of  this  is  where 
atmospheres  containing  excess  of  C02  are  respired.  A  true  acidosis  is 
established  and  it  is  compensated  for  by  greatly  increased  breathing  (to 
get  rid  of  the  C02),  by  excretion  of  excess  of  acid  by  the  kidneys  and  by 
an  increase  in  the  bases  of  the  blood.  The  condition  may  occur  in 

363 


364 


THE    RESPIRATION 


asphyxia  and  in  emphysema  where  it  is  due  to  the  curtailment  of  the 
respiratory  epithelium.  In  the  latter  case  cyanosis  is  also  common  be- 
cause 02  diffusion  is  even  more  interfered  with  (see  page  407).  When 
it  is  compensated  the  blood  condition  shifts  to  area  II  on  the  chart,  i.e., 
PH  is  normal  but  the  blood  takes  up  an  excess  of  C02.  This  variety  of 
acidosis  is  more  fully  discussed  in  Chapter  XLI. 

2.  Addition  or  accumulation  of  nonvolatile  acids,  either  acids  absorbed 
from  the  intestine  or  injected  intravenously  or  when  metabolic  acids 
fail  to  be  adequately  excreted  such  as  in  severe  diabetic  ketosis  and 
nephritis.  This  causes  an  alkali  deficit.  Under  these  conditions  (area  III 
in  chart)  PH  is  low  and  the  C02  absorbing  power  is  much  reduced  because 


20  30 


40  50  60  70  80 

MILLIMETERS      CO,  TENSION 


90 


Fig.    128. — Curves   showing  relationship   between   total   COs   in   solution   and   PH    at  varying 
CO2   pressure.      (Redrawn   from   D.   D.   Van    Slyke.) 

the  foreign  acid  has  appropriated  some  of  the  base  (BHC03  +  HA  = 
BA  +  H2C03).  Compensation  is  effected  by  deepened  breathing  (air 
hunger)  to  get  rid  of  C02,  excretion  of  acid  urine  and  increased  excretion 
of  ammonia.  If  compensation  fails,  coma  is  the  result.  If  it  is  adequate 
the  blood  condition  shifts  to  the  left  on  the  diagram  to  occupy  area  IV, 
i.e.,  PH  falls  within  normal  limits  although  the  blood  cannot  take  up  its 
proper  amount  of  C02. 

During  muscular  exercise  both  of  the  above  types  of  acid  may  come 
into  play,  the  nonvolatile  acid  in  this  case  being  lactic  (page  438). 


THE    CONTROL   OF    THE   RESPIRATION  365 

Increase  in  Pn  (diminished  H-ion  concentration). 

3.  Addition  of  excess  of  alkali  to  the  Hood,  either  by  intravenous  in- 
jection of  carbonate  solutions,  or  by  overdosing  with  bicarbonates  or 
phosphates.    There  is  a  great  excess  of  total  C02  as  shown  in  area  V  of 
chart, -  When  the  alkalosis  is  extreme,  symptoms  of  tetany  supervene 
(page  805).    The  compensation  in  this  case  involves  the  following:     (a) 
Diminished  excretion  of  C02  brought  about  by  lessened  breathing  (-the" 
percentage  of-GG2  in  the  alveolar  air  is  however  increased  because  of 
the  curtailment  in  the  amount  of  air  breathed),     (b)  Liberation  of  lactic 
acid  into  the  blood, (Macleod  and  Knapp).     (c)   Increased  excretion  of 
alkali   (as  bicarbonate)    and  diminished   excretion   of  ammonia  in  the 
urine.    When  compensation  is  adequate  the  blood  picture  shifts  to  area  II 
(the  same  position  as  for  compensated  C02  excess). 

4.  Removal  of  excess  of  H2CO&  (free  C02)  from  the  body.    This  results 
from  increased  breathing,   being  readily  induced  either  voluntarily  or 
as  a  result  of  stimulation  of  the  respiratory  center  by  anoxemia  (page 
378)   or  by  excitation  of  afferent  respiratory  nerves.     H2C03  being  re- 
duced, there  is  a  relative  excess  of  BHC03  making  the  condition  one  akin 
to  that  following  alkali  administration  (i.e.,  a  true  alkalosis,  although 
the  absolute  amount  of  alkali  is  much  less)  and  being  accompanied  by 
the  same  symptoms  (tetany)  and  compensated  byv  the  same  mechanisms 
(increased  excretion  of  alkali  by  the  urine,  disappearance  of  ammonia 
and  probably  production  of  lactic  acid)  as  when  excess  of  alkali  is  admin- 
istered.   The  blood  condition  immediately  after  the  removal  of  the  C02 
corresponds  to  that  of  area  VI  on  the  chart,  it  then  shifts  to  that  of 
area  IV  (the  same  as  in  compensated  alkali  deficit).     This  form  of  al- 
kalosis is  particularly  important  from  the  clinical  standpoint  since  it 
must  tend  to  be  produced  in  all  forms  of  hyperpnea  not  due  to  actual 
addition  or  accumulation  of  acids  in  the  organism.     It  is  the  condition 
established  in  mountain  sickness' (page  415). 

In  all  the  above  cases  if  compensation  proceeds  satisfactorily  the  blood 
condition  ultimately  returns  to  area  VII  on  the  chart,  i.e.,  PH  lies  between 
7.30  and  7.50  with  the  vol.  of  combined  C02  between  43  and  55  when 
the  blood  is  exposed  to  40  mm.  C02  pressure. 

Finally  it  should  be  pointed  out  that  analysis  of  the  percentage  of 
C02  in  the  alveolar  air  and  of  the  percentage  of  C02  in  arterial  blood 
(simultaneously  collected),  or  of  PH  and  the  total  C02  of  blood,  will 
give  us  the  necessary  data  to  find  the  actual  blood  condition  from  the 
chart,  provided  only  that  the  breathing  is  normal.  If  the  conditions  be 
uncompensated,  the  alveolar  C02  will  be  either  too  high  or  too  low  ac- 
cording to  whether  there  is  hypnea  or  hyperpnea. 


CHAPTER  XLI 
THE  CONTROL  OF  RESPIRATION  (Cont'd) 

THE  NATURE  OF  THE  RESPIRATORY  HORMONE 

The  practical  importance  of  the  observations  described  in  the  foregoing 
chapters  in  the  investigation  of  the  relationship  between  CH  of  the 
blood  and  respiratory  activity  will  now  be  plain,  and  it  remains  for  us 
to  consider  the  physiological  evidence  that  such  a  relationship  exists.  In 
the  first  place,  let  us  consider  the  behavior  of  the  acid-base  equilibrium 
during  conditions  of  abnormal  breathing — hyperpnea  and  dyspnea.* 

As  C02  accumulates  and  O2  becomes  used  up  in  a  confined  space,  the 
breathing  becomes  intensified.  In  searching  for  the  exact  cause  of  this 
effect,  we  must  first  of  all  ascertain  whether  the  hyperpuea  is  due  to  the 
deficiency  of  02  or  to  the  accumulation  of  C02  or  to  both  acting  to- 
gether. Many  of  the  experiments  bearing  on  these  problems  can  be 
more  satisfactorily  performed  on  man  than  on  laboratory  animals,  be- 
cause anesthesia  is  not  necessary  and  the  subjective  symptoms  experi- 
enced are  of  great  value  in  the  interpretation  of  the  results.  If  an  in- 
dividual is  placed  in  a  large  air-tight  chamber  (2000  liters'  capacity), 
and  the  depth  and  rate  of  breathing  observed  as  the  C02  accumulates  and 
the  02  becomes  used  up  in  the  air  of  the  chamber,  no  distinct  change  in 
respiration  will  be  observed  by  the  person  himself  until  the  C02  per- 
centage of  the  air  has  risen  to  almost  3.  Above  this  point,  however,  the 
hyperpnea  becomes  more  and  more  pronounced,  until  finally,  when  the 
C02  percentage  has  risen  to  about  6  and  the  02  percentage  has  fallen  to 
13.5,  it  becomes  unbearable  (dyspnea).  From  the  results  of  the  fore- 
going observation  alone  we  could  not,  however,  decide  whether  the 
excitation  of  the  respiratory  center  is  due  to  the  deficiency  of  02  or  to 
the  increase  of  C02.  If  the  experiment  is  repeated  with  the  difference 
that  the  C02  as  it  accumulates  is  absorbed  by  soda  lime,  no  perceptible 
hyperpnea  will  develop  even  when  the  02  is  as  low  as  in  the  previous 
experiment.  We  may  conclude,  therefore,  that  in  the  first  experiment 
C02  accumulation  must  have  acted  as  the  main  respiratory  stimulus,  and 
that  oxygen  deficiency,  if  it  stimulates  at  all,  must  do  so  to  a  less  degree 
than  increase  in  C02. 

*Hyperpnea  means  slightly  increased  breathing;  dyspnea,  labored  breathing,  but  yet  with  suffi- 
cient ventilation  to  maintain  life;  asphyxia,  the  results  of  insufficient  breathing. 

366 


THE    CONTROL    OF    THE   RESPIRATION  367 

There  is  an  obvious  reason  why  the  adjustment  of  pulmonic  ventilation 
should  not  depend  primarily  upon  changes  in  02  supply  to  the  respira- 
tory center.  If  it  were  so,  many  other  tissue  activities  and  other  nerve  cen- 
ters would  suffer  from  the  02  deficiency  before  there  was  time  for  the 
breathing  to  become  stimulated  sufficiently  to  make  good  the  loss  of  02.  As  a 
matter  of  fact,  headache,  dizziness,  nausea  and  even  fainting  are  almost 
certain  to  be  caused  whenever  any  muscular  exercise  is  attempted  in  an 
atmosphere  containing  a  deficiency  of  02  but  no  excess  of  C02  (cf.  moun- 
tain sickness) .  An  adequate  02  supply  of  the  body  is,  therefore,  insured 
by  changes  in  C02  tension  of  the  blood. 

Quantitative  Relationship  between  C02  of  Inspired  Air  and  Pulmonary 
Ventilation. — These  results  suggest,  as  the  next  step  in  the  investigation 
of  our  problem,  the  determination  of  the  quantitative  relationship  be- 
tween the  C02  percentage  of  the  respired  air  and  the  amount  of  air 
breathed  (pulmonic  ventilation).*  That  there  is  such  a  relationship  has 
been  most  successfully  demonstrated  by  R.  W.  Scott,20  who  used  for  his 
purpose  decerebrate  cats.f  The  trachea  was  connected,  through  a  T-tube 
provided  with  valves,  with  tubing  leading  to  a  large  bottle  and  a  Gad-Krogh 
spirometer,  so  that  the  animal  breathed  out  of  the  bottle  into  the 
spirometer,  these  two  being  also  connected  together.  The  spirom- 
eter was  made  to  record  its  movements  on  a  drum,  so  that  an  accurate 
record  of  the  depth  and  frequency  of  the  respirations  was  secured.  Sam- 
ples of  air  were  removed  from  the  bottle  by  ground-glass  plunger  syringes 
at  frequent  intervals  during  the  time  that  the  animal  was  respiring  into 
the  tubing. 

The  results  are  given  in  the  accompanying  curve  (Fig.  129),  which  shows 
that  there  is  a  perfect  correspondence  between  the  C02  percentage  in  the 
air  of  the  bottle  and  the  pulmonary  ventilation.  Moreover,  when  the 
bottle  was  filled  with  02  instead  of  air  to  start  with,  the  same  results 
were  obtained,  showing  that  the  C02  accumulation  alone  was  responsible 
for  the  hyperpnea.  In  these  cases  the  percentage  of  02  remaining  in  the 
system  after  hyperpnea  had  become  extreme,  was  far  above  that  at  which 
excitation  of  the  center  as  a  result  of  02  deficiency  is  possible. 

Experiments  of  a  similar  type  had  previously  been  performed  by  Por- 
ter and  his  pupils,21  but  their  object  was  not  so  much  to  show  the  close 
parallelism  between  the  C02  content  of  the  respired  air  and  the  pulmonic 

*A  distinction  is  somewhere  drawn  between  pulmonic  ventilation  and  alveolar  ventilation,  the 
former  being  the  total  amount  of  air  that  enters  and  leaves  the  lungs,  and  the  latter,  that  which  en- 
ters and  leaves  the  alveoli.  This  distinction  is  based  on  the  assumption  that  the  capacity  of  the  dead 
space  may  vary  considerably  from  time  to  time,  which,  as  pointed  out  elsewhere,  is  erroneous.  For 
practical  purposes  pulmonic  ventilation  is  the  safer  value  to  give. 

fDecerebrate  animals  must  be  used  in  these  experiments,  since  anesthetics  markedly  depress  the 
activity  of  the  respiratory  center. 


368 


THE   RESPIRATION 


ventilation  as  to  demonstrate  the  changes  produced  in  the  sensitivity  of 
the  respiratory  center  in  pneumonia. 

Possibility  that  C02  Specifically  Stimulates  Center. — After  showing 
that  C02  acts  as  an  excitant  of  the  respiratory  center,  the  question  arises 
as  to  whether  the  action  depends  on  the  raising  of  the  CH  of  the  blood,  or 
whether  it  may  be  a  specific  action  of  the  C02.  Many  attempts  have 


SOQ 


400 


300 


ZOO 


/OO 


L 


Fig.  129. — Composite  curve  obtained  from  the  data  on  sixteen  experiments,  showing  the  re- 
spiratory response  to  CO2  in  the  decerebrate  cat.  Abscissae  =  percentage  of  CO2  in  the  inspired 
air.  Ordinates  =  the  percentile  increase  the  tidal  air  per  minute.  (From  R.  W.  Scott.) 

been  made  to  decide  this  question  experimentally,  the  general  principle 
of  the  experiments  being  to  determine  whether  CH  of  the  blood  runs 
parallel  with  the  C02  content  of  the  respired  air  and  with  the  hyperpnea. 
Using  the  gas-chain  method  (page  31),  Hasselbalch  and  Lundsgaard22 
found  that  the  hyperpnea  produced  in  rabbits  by  breathing  in  C02-rich 


THE    CONTROL   OF    THE   RESPIRATION 


369 


air  runs  approximately  parallel  with  the  increase  in  the  CH  of  the  blood, 
but  on  account  of  the  experimental  difficulties  encountered  they  could  not 
decide  whether  changes  in  CH  are  alone  responsible  for  the  effect.  These 
authors  had  previously  demonstrated  that  changes  in  CH  can  be  induced 
in  blood  removed  from  the  body  by  experimental  alteration  of  the  C02 
tension  within  the  physiological  limits.  An  increase  of  one  millimeter 
in  C02  tension  was  found  to  cause  an  increase  in  CH  of  0.0065  x  10-7 
(see  page  27). 

R.  W.  Scott's  experiments,  above  referred  to,  have,  however,  yielded 
more  definite  results.  By  using  the  colorimetric  method  for  determining 
CH  of  the  blood  (see  page  32),  it  could  be  readily  shown,  as  is  evident 

THE  EFFECT  OF  REBREATHING  CARBON  DIOXIDE  ON  THE  MINUTE  VOLUME  AND  ON  THE 

H-ION  CONCENTRATION  AND  TOTAL  CARBONATE  CONTENT  OF  THE  ARTERIAL 

BLOOD  IN  THE  DECEREBRATE  CAT 


FIFTEEN 

MINUTES 

PRELIMINARY  PERIOD* 

REBREATHING  PERIOD 

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*PH  is  the  actual  value  given  in  the  table.     This  is  inversely  proportional  to  CH. 

from  the  table  (cols.  8  and  14),  that  a  marked  rise  in  CH  became  evident 
when  the  inspired  air  contained  5  per  cent  or  more  of  C02.  That  this 
rise  was  due  to  increase  in  the  C02  tension  was  shown  not  only  by  finding 
a  greater  percentage  of  C02  (cols.  9  and  15)  in  the  blood,  but  also  by 
being  able  to  demonstrate  that  when  C02-free  air  was  bubbled  through 
the  blood  removed  during  the  dyspnea,  CH  immediately  returned  to  the 
normal  which  it  also  did  in  the  -blood  removed  after  the  animal  had 
breathed  for  a  few  minutes  in  outside  air  (col.  16)  when  the  C02  content 
likewise  returned  (col.  17).  Had  the  increase  in  acidity  been  caused  by 
nonvolatile  acids — lactic,  for  example — these  results,  particularly  the 
latter,  could  not  have  been  obtained. 


370  THE   RESPIRATION 

Although  there  is  therefore  no  doubt  that  the  CH  of  the  blood  may 
be  raised  because  of  an  increase  in  C02  in  solution  in  the  blood  plasma — 
a  C02  acidosis,  as  we  may  call  it  (see  page  371) — this  does  not  prove  that 
the  stimulation  of  the  respiratory  center  is  brought  about  solely  by  CH- 
The  increase  in  C02  might  in  itself  also  serve  as  a  stimulus.  That  such 
is  actually  the  case  was  demonstrated  by  finding  that,  if  CH  of  the  blood 
was  first  of  all  lowered  by  injecting  alkali  intravenously,  hyperpnea  still 
developed  in  proportion  as  the  C02  accumulated  in  the  inspired  air;  and 
that  CH  of  the  blood,  when  the  hyperpnea  was  at  its  highest,  was  below 
that  of  normal  blood.  Some  other  factor  than  CH  must  obviously  be 
responsible  for  this  result.  This  is  undoubtedly  dependent  on  the  C02. 

Further  corroboration  of  the  claim  that  C02  has  a  specific  stimu- 
lating effect  on  the  respiratory  center  that  is  independent  of  CH,  has 
been  furnished  by  Hooker,  Wilson  and  Connett.23  These  authors  suc- 
ceeded in  keeping  the  centers  of  the  medulla  alive  by  perfusion  with 
defibrinated  blood  through  the  blood  vessels  of  the  brain,  and  found 
that,  although  the  respiratory  movements  of  the  diaphragm  became  de- 
pressed with  a  decrease  and  excited  with  an  increase  in  CH  of  the  per- 
fusion fluid,  a  greater  activity  of  the  center  was  produced  when  the  fluid 
contained  a  high  tension  of  C02  than  with  another  fluid  of  the  same  CH 
but  with  a  low  tension  of  C02.  We  conclude  that,  although  the  CH  is  the 
important  respiratory  hormone,  carbon  dioxide  per  se  also  has  a  stimu- 
lating influence. 

A  similar  conclusion  had  previously  been  arrived  at  by  Lacquer  and 
Verzar54  who  studied  the  activity  of  the  respiratory  center  in  young  rab- 
bits perfused  through  the  aorta  with  isotonic  solutions  in  which  the  CH  was 
caused  to  vary  by  the  addition  of  different  acids.  It  was  found  that  when 
CH  was  about  the  neutral  point  (even  slightly  on  the  alkaline  side),  but 
the  solution  contained  C02,  much  more  marked  stimulation  occurred  than 
when  CH  was  raised  by  adding  some  other  acid.  Collip77  has  also  ob- 
served that  the  respirations  may  be  stimulated  by  intravenous  injections 
of  sodium  bicarbonate. 

These  conclusions  are  confirmed  by  observations  on  the  influence  of 
C02  on  other  living  cells  than  those  of  the  respiratory  center.  Rona  and 
Neukirch55  found  that  the  isolated  intestine  when  made  to  beat  in  oxy- 
genated saline  solution  (page  497)  is  very  sensitive  to  C02,  and  Jacobs56 
has  more  recently  made  some  very  interesting  observations  on  the  toxic 
effects  of  C02  as  compared  with  that  of  other  acids,  on  the  tadpoles  of 
the  toad,  and  on  several  species  of  protozoa.  It  was  found  that  a  saturated 
solution  of  C02  is  incomparably  more  toxic  than  are  solutions  of  various 
inorganic  and  organic  acids  of  the  same  CH  as  the  C02  solution.  On  the 
other  hand  neutral  solutions  of  NaHC03  are  nontoxic,  which  indicates 


THE    CONTROL    OF    THE    RESPIRATION  371 

that  it  cannot  be  the  HC03-anion  as  some  have  supposed,  that  is  the  toxic 
agent.  The  order  of  resistance  of  various  protozoa  to  CO2  was  found  to 
bear  no  relation  to  that  which  they  bear  to  other  acids.  It  may  be,  however, 
that  the  more  toxic  effect  of  the  C02  is  dependent  upon  the  greater  rate 
at  which  it  penetrates  cell  membranes  than  other  acids.  It  would  there- 
fore enter  the  cells  of  the  respiratory  center  and  by  dissociation  cause 
alteration  of  CH  in  the  protoplasm.  In  the  light  of  this  possibility  it  is  of 
interest  that  whereas  other  acids  cause  cessation  of  the  movements  of  flag- 
ella  in  protozoa  with  no  visible  changes  in  the  interior  of  the  cells,  C02 
has  little  effect  on  the  flagella  but  causes  marked  alterations  in  the  intra- 
cellular  activities.  Jacobs  has  also  shown  that  an  acid  reaction  may 
develop  within  the  petals  of  certain  flowers  when  these  are  suspended 
in  a  bicarbonate  solution  that  is  itself  faintly  alkaline.  He  has  also 
succeeded  in  arranging  a  laboratory  experiment  in  which  a  similar 
migration  of  undissociated  carbonic  acid  through  a  layer  of  xylol  caused 
a  neutral  solution  in  contact  with  it  to  become  acid.78 

Relationship  Between  Alveolar  CO,  and  Respiratory  Activity. — Vari- 
ations in  the  respiratory  hormone,  whatever  this  may  be,  are  associated 
with  changes  in  the  C02  content  of  the  alveolar  air.  Increase  in  the 
alveolar  C02  immediately  stimulates  respiration  unless  under  certain 
conditions  which  will  be  discussed  later.  Indeed  the  respiratory  center 
is  so  very  sensitive  towards  this  stimulus  that  whenever  the  percentage 
of  C02  in  the  inspired  air  tends  to  rise,  pulmonary  ventilation  is  excited  to 
a  degree  which  is  just  sufficient  to  maintain  the  tension  of*  C02  in  the 
alveolar  air  at  the  normal  level.  There  is  therefore,  no  better  method  for 
testing  the  excitability  of  the  center  than  to  measure  the  increase  of 
pulmonary  ventilation  produced  by  adding  known  percentages  of  CO., 
to  the  inspired  air.  If  the  amount  of  C02  in  the  inspired  air  is  sufficient 
to  raise  the  C02  in  the  alveoli,  in  spite  of  the  greater  breathing,  hyperp- 
nea becomes  very  marked ;  thus,  it  has  been  found  that  if  enough  C02 
is  inspired  to  cause  an  increase  of  from  0.2-0.3  per  cent  in  alveolar  C02 
in  man  the  alveolar  ventilation  is  doubled,  or,  more  precisely  stated,  an 
increase  of  ten  liters  in  the  air  entering  and  leaving  the  alveoli  per 
minute  results  from  raising  the  alveolar  C02  tension  by  2.2  to  3.1  mm. 
Hg  (Douglas24). 

The  relationship  between  breathing  and  alveolar  C02  is  by  no  means  al- 
ways so  simple  as  in  the  instances  just  described.  In  these  hyperpnea  is  sec- 
ondary to  an  increase  in  alveolar  C02  but  there  are  many  cases  where  the 
reverse  relationship  obtains — namely,  where  decreased  alveolar  C02  is  sec- 
ondary to  hyperpnea  caused  by  stimulation  of  the  respiratory  center  by 
some  other  agency  than  increase  in  C02  tension  of  the  blood.  These  agen- 

*The  tension   is    found  by   the   equation   given     on   page   374. 


372  THE   RESPIRATION 

cies  include  afferent  nerve  stimulation,  lowering  of  the  02-tension,  or  in- 
crease in  CH  of  the  blood  brought  about  by  other  acids  than  C02  such 
as  occurs  in  clinical  cases  of  acidosis  (see  page  654). 

The  whole  question  is  very  closely  linked  with  that  of  the  control  of  the 
reaction  of  the  body  fluids  and  with  the  etiological  factors  in  acidosis. 
When  it  is  fully  answered,  many  obscure  clinical  conditions  in  which  respi- 
ratory disturbances  occur  will  be  much  better  understood  than  they  are  at 
present.  On  account  of  the  great  importance  of  the  subject,  considerable 
attention  will  be  devoted  in  the  next  few  pages  to  some  of  the  researches 
which  have  been  made  bearing  on  the  relationship  between  the  C02  of 
the  alveolar  air  and  the  various  modified  types  of  breathing  that  can  be 
produced  experimentally  or  which  become  developed  under  altered  physi- 
ological conditions. 

Even  at  the  risk  of  repetition  let  us  consider  what  will  happen  when 
excess  of  C02  is  added  to  the  blood  in  the  body,  either  as  a  result  of 
respiring  C02-rich  air  or  because  of  increased  production  of  this  gas  in 
the  tissues,  as  in  muscular  exercise.  The  tension  of  C02  in  the  blood 
will  first  of  all  increase  and  tend  to  raise  CH  since,  as  we  have  seen,  this 

TT    QQ 

depends   on  the  molecular   ratio  -  —  —  —    (where   B  HC03   stands  for 

B  HC03 

NaHC03  and  other  similar  compounds).  The  excess  of  C02  will  be  re- 
moved, partly  by  increased  breathing  and  partly  by  basic  substances, 
including  Na,  being  set  free  to  combine  with  it.  In  these  ways  the 

TT    p(") 

ratio  ~  will  tend  to  come  back  to  its  normal  value  but  now  with 


both  free  C02  and  total  bicarbonates  absolutely  greater  than  before,  so 
that  the  C02  combining  power  of  the  blood  will  be  raised  (page  42). 

On  the  other  hand,  when  fixed  acids  are  added  to  the  blood  they  will 
appropriate  some  of  the  base  (B)  and  liberate  H2C03  so  that  both  the 
tension  of  C02  and  CH  will  rise  (PH  become  less),  equilibrium  being  then 
reestablished  by  increased  breathing  and  blowing  off  of  C02.  If  the 

increased  breathing  does  not  suffice  in  both  these  cases  to  restore  the 

TT  c*r\ 

normal  —  J*     J*    ratio,   other  compensating  mechanisms  come  into  play, 
B 


namely,  increased  excretion  of  acid  by  the  urine  and  combination  with 
ammonia  (page  381). 

When  the  H2C03  is  lowered  as  by  increased  breathing,  changes  of  an 
opposite  character  occur  and  these  will  be  discussed  in  the  following 
pages. 


CHAPTER  XLII 

THE  CONTROL  OF  RESPIRATION  (Cont'd) 
THE  ALVEOLAR  C02-TENSION.     ANOXEMIA. 

The  Constancy  of  the  Alveolar  C02-Tension  Under  Normal  Conditions 

Since  a  close  relationship  exists  between  the  alveolar  C02-tension  and 
the  respiratory  activity,  it  is  to  be  expected  that  the  two  would  bear  a 
strict  proportionality  to  each  other,  and  since  the  breathing  under  normal 
conditions  does  not  vary  much,  the  C02-tension  should  also  be  constant. 
Many  observations  show  this  to  be  the  case.  The  tension  is  remarkably 
constant  from  day  to  day  and  even  from  month  to  month  in  the  same 
individual,  provided  the  physiological  conditions  are  the  same.  A  slight 
seasonal  variation  is  said  to  exist,  a  rise  in  the  temperature  of  the  en- 
vironment of  the  individual  causing  a  slight  depression  in  the  C02-ten- 
sion,  while  a  fall  in  temperature  causes  a  slight  rise  (Haldane).  These 
changes  are  independent  of  any  demonstrable  change  in  rectal  temper- 
ature and,  therefore,  are  probably  due  to  the  influence  of  the  temperature 
on  the  skin. 

Since  it  is  the  number  of  molecules  of  C02  in  a  given  volume  of  alve- 
olar air  (i.  e.,  the  partial  pressure  or  tension)  that  is  of  importance,  it 
is  only  when  the  barometric  pressure  is  the  same  that  the  percentage  of 
C02  in  the  sample  of  alveolar  air  can  be  constant.  To  allow  for  this, 
all  results  are  reduced  to  standard  barometric  pressure  (760  mm.  Hg). 
If  the  barometric  pressure  is  lowered,  there  will  have  to  be  a  higher 
percentage  of  C02  in  the  sample  in  order  that  there  may  be  the  same 
tension  of  this  gas  in  the  air  of  the  alveoli ;  and  vice  versa  when  the  bar- 
ometric pressure  is  raised.  The  equation  by  which  this  tension,  ex- 
pressed in  millimeters  of  mercury,  is  determined  is :  100 :760  ( — aq)  :  :a:p, 
where  a  is  the  percentage  actually  found  in  the  air  of  the  sampling  tube 
and  p  the  tension.  A  correction  ( — aq)  is  introduced  in  this  equation  to 
allow  for  the  vapor  tension  of  the  air  in  the  alveoli,  for  of  course  H20 
molecules  will  behave  like  C02  molecules  in  causing  a  partial  pressure. 

When  reduced  to  this  standard,  it  has  been  found  that  the  tension  of 
C02  in  the  alveolar  air  tends  to  remain  constant  under  the  varying  baro- 
metric conditions  that  obtain  at  sea  level  or  at  moderate  departures  from 
this.  This  is  shown  in  the  following  table : 

373 


374  THE    RESPIRATION 


(1) 
BAROMETRIC 
PRESSURE 
(MM.  HG) 

(2) 

CO,  ACTUALLY  FOUND 
IN  DRY  ALVEOLAR 
AIR 

(PER  CENT) 

(3) 

PARTIAL  PRESSURE 
OF  C02  IN  MOIST 
ALVEOLAR  AIR  AFTER 
CALCULATING  FOR 
BAROMETRIC  PRESSURE 

Top  of  Ben  Nevis 
Oxford 
Foot  of  Dolcoath  Mine 
Compressed  air  cabinet 

646.5 
755 
832 
1260 

6.62 
5.95 
5.29 
3.52 

5.23* 

5.53 

5.48 
5.64 

• 

(B'-A)  P' 

-     "P     \irViprp    P    —    ficmrfx; 

in  last  column;  B'  =  figures  in  first  column;  A  =  aqueous  tension  of  alveolar  air;_  P'  =  figures  of 
second  column;  B  —  barometric  pressure  at  sea  level.  A  is  obtained  from  tables  giving  the  aqueous 
tension  at  different  temperatures. 

The  Alveolar  C02-Tension  in  Conditions  of  Anoxemia 

The  foregoing  observations  have  shown  that  the  respiratory  hormone 
is  related  to  the  tension  of  C02  in  the  blood  supplying  the  respiratory 
center,  and  that  this  tension  acts  partly  by  causing  alteration  in  CH 
of  the  blood,  and  partly  because  C02  has  direct  effect  on  the  center.  These 
conclusions  do  not  imply  that  other  changes  in  the  composition  of  the 
blood  may  not  act  on  the  respiratory  center,  indeed  there  is  plenty  of 
evidence  to  show  that  deficiency  of  oxygrw  fffl  fhe  ^^-^1  blood  or  anoxe- 
mia  also  acts.  This  influenceTs,  howeverTless  evidentjliaji  .that  of  changes 
in^^HjDr^XlJD^-and  it  varies  with  the  degree  of  deficiency,  being  stimulatory 
when  the  deficiency  is  moderate,  and  inhibitory  when  it  is  extreme.  It  is 
not  surprising,  therefore,  that  some  considerable  confusion  should  have 
existed  as  to  the  precise  role  of  02  deficiency  in  its  effect  on  the  respira- 
tions and  it  is  only  within  the  last  year  or  two  that  the  problem  has  been 
satisfactorily  elucidated. 

The  most  important  indication  that  alterations  in  the  C02-tension  of  the 
blood  cannot  alone  be  responsible  for  changes  in  respiratory  activity  is 
afforded  by  the  observation  that  the  alveolar  C02  does  not  always,  as  in 
the  cases  described  in  the  previous  chapter,  run  parallel  with  alveolar  ven- 
tilation. The  opposite  relationship  often  obtains,  namely,  decreased  al- 
veolar C02  and  hyperpnea  (see  page  379),  and  it  is  our  purpose  in  the 
present  chapter  to  show  how  this  is  often  associated  with  a  condition  of 
oxygen  deficiency.  It  is  most  important  that  we  consider  this  phase  of  the 
subject  in  some  detail  because  of  the  application  which  it  has  in  the  eluci- 
dation of  many  problems  of  respiratory  disturbance,  as  met  with  in  the 
clinic.  The  disturbances  in  respiratory  function  which  can  be  brought 
about  experimentally  in  normal  animals  are  in  many  cases  exactly  like  those 
which  are  met  with  in  various  diseases,  particularly  those  which  depend 
on  inadequate  absorption  of  oxygen  by  the  blood. 

The  General  Effects  of  Deficiency  of  Oxygen,  or  Anoxemia. — Various 


THE    CONTROL   OF   THE   RESPIRATION  375 

methods  have  been  employed  in  the  investigation  of  this  subject.  The 
most  important  of  these  are  as  follows:  (1)  Breathing  from  a  tank  con- 
taining varying  mixtures  of  oxygen  and  nitrogen  (Dreyer  apparatus). 
This  apparatus  was  used  extensively  in  the  British  Army  in  testing  the 
ability  of  candidates  for  the  aviation  service  to  withstand  low  oxygen. 
Its  greatest  value  is  that  the  alteration  in  oxygen  content  of  the  inspired 
air  can  be  made  either  gradually  or  quickly.  (2)  Breathing  from  a 
tank  through  tubes  provided  with  valves  which  direct  the  expired  air 
so  as  to  make  it  pass  through  an  apparatus  for  absorption  of  the  C02, 
before  it  re-enters  the  tank.  The  subject,  therefore,  re-breathes  the  air 
of  the  tank  from  which  he  gradually  absorbs  the  oxygen.  In  this  method 
the  02-content  of  the  inspired  air  falls  gradually,  and  effects  are  pro- 
duced which  must  be  similar  to  those  which  would  be  caused  by  slow 
ascent  to  higher  altitudes.  The  rate  at  which  the  02  falls  can  be  varied 
by  altering  the  size  of  the  tank.  When  a  very  rapid  fall  is  desired  rubber 
bags  can  be  used  in  place  of  tanks.  An  apparatus  on  this  principle  was 
employed  for  testing  aviators  particularly  in  the  United  States  Army. 
(3)  Breathing  in  an  air-tight  cabi.net  containing  properly  arranged  soda 
lime  absorbers  to  take  up  the  C02 ;  the  oxygen  decreases  at  a  rate  which  is 
inversely  proportional  to  the  size  of  the  cabinet.  (4)  Breathing  in  a 
strongly  built  steel  chamber  connected  with  a  powerful  pump  by  means 
of  which  the  chamber  can  be  partially  evacuated  and  the  pressure  main- 
tained at  any  desired  level.  Such  a  chamber  has  been  used  by  Haldane, 
Kellas  and  Kennaway  in  important  experiments,  the  results  of  which  we 
shall  consider  immediately.  (5)  Adding  a  sufficient  percentage  of  carbon 
monoxide  gas  to  the  inspired  air  to  combine  with  a  considerable  propor- 
tion of  the  hemoglobin  of  the  blood  and  so  render  it  incapable  of  carrying 
the  oxygen. 

The  observations  made  by  the  use  of  these  methods  have  been  com- 
pared with  those  made  during  life  at  high  altitudes,  particularly  in  con- 
nection with  mountaineering.  The  latter  observations  are  of  particular 
importance  in'  the  study  of  the  adaptive  processes  which  come  into  play 
to  render  persons  who  have  become  accustomed  to  high  altitudes  immune 
to  the  distressing  symptoms  from  which  others  suffer. 

There  is  considerable  variability  in  the  reactions  of  different  persons  to 
decreased  oxygen  and  these  cause  symptoms  which  are  partly  subjective  and 
partly  objective  in  nature.  Slight  differences  are  observed  according 
to  whether  the  anoxemia  is  produced  by  a  lowering  of  barometric  pressure 
(decompression),  or  by  simply  reducing  the  percentage  of  oxygen  in 
the  inspired  air.  In  the  former  case  there  is  also  a  slight  difference 
between  the  symptoms  following  decompression  in  an  experimental  cham- 
ber, and  those  observed  on  a  high  mountain.  In  a  general  way  the  symp- 


376 


THE   RESPIRATION 


toms  are  less  marked  when  the  barometric  pressure  is  reduced  than  when 
the  oxygen  percentage  is  simply  diminished. 

The  Symptoms  During  Gradual  Reduction  of  the  Percentage  of  Oxy- 
gen.— Measurements  have  been  made  of  a  number  of  physiological  func- 
tions in  a  large  number  of  healthy  young  men  who  were  condidates  for 
the  flying  corps  of  the  various  armies  participating  in  the  recent  war. 


£*•  -*'- 


7?£5H    /N  UEC/L.  P£7?     M/N. 


180 


160 


140 


TOO 


80 


60 


40 


_. 


4      6      8      10     11    M-     76     18     W 


14    26    3L8    30 


"  JB.H 


Fig.    130. — The   behavior    of   the    respiratory   volume,    the    blood   pressure,    and    the    pulse    during 
progressive   anoxemia. 

The  results  are  of  value  in  showing  to  what  extent  the  candidates  can  be 
expected  to  withstand  the  rarefied  air  met  with  at  great  altitudes.  The 
accompanying  chart  (Fig.  130)  taken  from  the  "Air  Service  Manual" 
of  the  United  States  Army  depicts  the  results  obtained  on  a  perfectly 
normal  individual.  The  percentage  of  02  in  the  air  breathed  at  vari- 
ous stages  of  the  test  is  read  on  the  right  edge  of  the  chart  by  find- 


THE    CONTROL    OF    THE   RESPIRATION  377 

ing  the  ordinate  which  is  crossed  by  the  thick  continuous  line.  In 
this  observation  the  subject  withstood  oxygen  deficiency  without  alarm- 
ing symptoms  until  a  percentage  of  nearly  six  was  reached.  These 
symptoms  are  giddiness  and  then  fainting  along  with  various  psy- 
chological effects.  The  respiratory  volume,  the  pulse  rate  and  the 
systolic  and  diastolic  blood  pressures  are  also  shown  (see  legend  of 
figure  for  details)  and  it  will  be  observed  that  the  respiratory  vol- 
ume did  not  change  greatly  until  the  oxygen  percentage  had  fallen 
to  below  twelve.  Usually,  however,  the  volume  is  slightly  increased 
even  with  a  slight  reduction  in  the  oxygen,  the  depth  rather  than  the 
rate  of  the  breathing  being  responsible  for  the  change.  Ellis57  has  more 
particularly  investigated  the  precise  percentage  of  oxygen  at  which  the 
respiratory  volume  becomes  just  perceptibly  increased  and  found  it  to  be 
somewhat  above  eighteen.  By  the  time  8  per  cent  02  is  reached  the 
majority  of  men  show  about  a  doubling  in  the  amount  of  air  breathed. 
If  they  do  not  respond  in  this  way,  they  are  almost  certain  to  break  down 
by  fainting,  because  the  increased  respiration  is  the  mechanism  by  which 
the  deficiency  of  oxygen  is  compensated  for.  There  is  usually  little  change 
in  the  pulse  rate  until  the  oxygen  has  fallen  below  fifteen  per  cent.  A 
total  acceleration  of  15-40  beats  per  minute  is  normal  when  the  02  is 
lowered  to  seven  per  cent.  The  systolic  blood  pressure  usually  remains 
unchanged  down  to  a  partial  pressure  corresponding  to  14  or  even  9  per 
cent  of  oxygen.  Below  these  levels  the  systolic  pressure  rises  15-20  mm. 
Hg.  above  normal.  If  it  rises  more  than  this  it  is  considered  unfavora- 
ble, since  it  indicates  that  vasodilatation  has  not  occurred  as  it  ought 
to — as  a  result  of  the  low  oxygen.  A  sudden  fall  in  systolic  pressure 
precedes  fainting.  The  diastolic  pressure  remains  practically  unchanged 
throughout  the  test,  but  it  ought  to  show  a  slight  decline  as  the  systolic 
pressure  rises.  The  decline  shows  that  vasodilatation  is  occurring. 

When  the  anoxemia  is  continued  for  a  time,  the  pulse  usually  returns 
towards  the  normal  rate  and  the  systolic  and  diastolic  pressures,  if 
they  were  affected,  also  tend  to  return  to  the  normal  levels  (Lutz  and 
Schneider58).  These  authors  found  the  same  results  whether  the  02 
was  reduced  by  lowering  of  the  barometric  pressure  or  by  reduction  of 
the  percentage  of  the  gas. 

Cyanosis  is  a  normal  reaction  but  it  should  be  delayed  in  its  onset. 
In  some  cases  a  pale  and  death-like  color  develops  in  place  of  cyanosis. 
This  is  an  unfavorable  sign. 

The  actual  time  taken  to  reach  the  limit  of  endurance  in  the  test  de- 
pends of  course  on  the  capacity  of  the  spirometer.  This  is  usually  chosen 
so  that  a  test  occupies  from  20  to  30  minutes. 

The  Symptoms  During  Lowering  of  the  Barometric  Pressure  in  a  Pneu- 


378  THE    RESPIRATION 

matic  Chamber. — These  have  been  carefully  described  by  Haldane,  Kellas 
and  Kennaway,59  who  exposed  themselves  and  others  to  380  mm.  baro- 
metric pressure  (corresponding  to  about  19,000  feet  above  sea  level)  for 
at  least  an  hour  on  several  successive  days,  the  pressure  being  lowered  to 
this  level  very  quickly  (5  minutes).  The  symptoms  varied  somewhat  in 
the  different  subjects.  The  respirations  increased  in  depth  and  frequency 
at  first  but  then  returned  more  or  less  to  normal  in  four  out  of  six  of  the 
observed  persons.  In  one  they  remained  very  rapid,  and  in  another 
they  showed  a  great  tendency  to  become  periodic.  The  pulse  al- 
ways increased  at  first  and  then  returned  almost  to  normal.  Cyanosis 
was  always  present  but  did  not  diminish  with  continued  exposure.  Al- 
though mental  and  sensory  symptoms  were  not  perceived,  the  sudden  raising 
of  the  oxygen  percentage  caused  the  light  to  become  brighter  and  sounds 
to  become  louder.  Vigorous  muscular  work  caused  marked  hyperpnea, 
quick  pulse,  increased  cyanosis  and  mental  confusion.  There  were  none 
of  the  symptoms  of  mountain  sickness  (page  415)  and  no  ill-effects  were 
experienced  on  leaving  the  chamber. 

At  still  lower  pressures  the  above  mentioned  changes  in  pulse  and  respira- 
tions became  much  more  pronounced  and  decided  mental  symptoms  ap- 
peared, for  example  it  became  very  difficult  to  count  the  pulse,  or  to 
record  the  other  observations.  Loss  of  memory  was  common,  but  there  was 
no  loss  of  consciousness.  A  most  interesting  mental  symptom  sometimes 
observed  was  fixedness  of  ideas.  This  has  also  been  noted  in  coal  gas  poison- 
ing, and  in  high  balloon  ascensions.  Thus,  in  one  experiment  the  sub- 
ject persisted  in  having  the  pressure  held  at  a  certain  (very  low)  level 
for  no  evident  reason,  just  as  those  exposed  to  carbon  monoxide  can  not 
be  diverted  from  remaining  exposed  to  the  gas. 

These  symptoms  have  been  described  in  some  detail  since  it  is  im- 
portant that  they  be  compared  with  those  in  clinical  cases  in  which 
oxygen  deficiency  exists.  They  constitute  the  reactions  of  healthy  in- 
dividuals to  conditions  which  may  become  established  as  a  result  of 
disease,  and  it  is  obviously  most  important  in  such  cases  that  they  be 
distinguished  from  the  more  definitely  pathological  symptoms. 

On  comparing  the  above  symptoms  to  those  of  mountain  sickness  it 
will  be  noted  that  there  is  a  marked  difference  (see  page  415).  One  pe- 
culiarity of  the  latter  condition  is  that  prolonged  stay  in  the  rarefied  air 
brings  about  an  acclimatization,  so  that  after  some  days  the  person  is 
practically  normal.  The  attempt  was  made  in  the  above  experiments 
to  bring  about  a  similar  acclimatization  with  partial  success. 

The  Nature  of  the  Changes  Produced  in  the  Body  in  Anoxemia. — A 
careful  study  of  this  aspect  of  the  problem  is  most  important,  not  only 
because  it  throws  much  light  on  the  manner  of  control  of  the  respiratory 


THE    CONTROL    OF    THE   RESPIRATION  379 

center,  but  also  because  it  helps  us  to  explain  the  nature  of  the  altera- 
tions which  occur  in  the  acid-base  equilibrium  of  the  body  in  all  condi- 
tions which  tend  to  bring  about  anoxemia.  The  immediate  increase  in 
breathing  is  the  first  of  the  symptoms  which  demands  attention.  Ob- 
viously it  cannot  be  due  to  the  excitation  of  the  respiratory  center  by  an 
increase  in  the  free  C02  of  the  arterial  blood  (see  page  366).  Two  possi- 
bilities remain — either  the  reduction  of  free  oxygen  in  the  blood  per  se 
excites  the  center,  or  this  reduction  in  oxygen  causes  incompletely  oxi- 
dized acid  substances — such  as  lactic  acid — to  appear  in  the  blood  so 
as  to  raise  CH.  A  clue  as  to  which  of  these  causes  is  responsible  is  fur- 
nished by  observation  of  the  C02  tension  of  the  alveolar  air.  It  will  be 
recalled  that  this  does  not  change  when  the  barometric  pressure  is 
slightly  altered  (page  373),  but  it  is  otherwise  when  the  reduction  is 
extreme;  a  progressive  decrease  occurs.  Thus,  in  one  of  the  experiments, 
the  alveolar  C02  tension  to  start  with  was  40.7  mm.  Hg.  After  lowering 
the  barometric  pressure  to  about  500  mm.,  the  alveolar  tensions  were :  after 
25  minutes,  36  mm. ;  after  90  minutes,  36.8  mm. ;  after  175  minutes,  25.7 ; 
after  465  minutes,  34.9  mm.  This  shows  clearly  that  increase  of  free  C(X 
in  the  blood  cannot  be  the  cause  for  the  hyperpnea.  Further  evidence  for 
this  conclusion  is  afforded  by  the  fact  that  the  breathing  after  some  time 
returned  towards  the  normal  although  the  alveolar  C02  tension  remained 
low. 

Increase  in  CH  of  the  arterial  blood  on  account  of  the  appearance  of 
unoxidized  acids,  has  been  considered  as  the  possible  cause  for  the  symp- 
toms of  anoxemia.  This  hypothesis  demands  close  attention  because  it 
has  been  very  widely  accepted  and  has  seemed  to  be  supported  by  nu- 
merous observations,  both  physiological  and  clinical.  Physiologists, 
for  example,  have  known  for  long  that  lactic  acid  accumulates  in  the 
blood  and  appears  in  the  urine  in  all  conditions  in  which  there  is  de- 
ficient oxidation  in  the  tissues.  Thus,  Araki  found  it  in  the  urine  after 
asphyxia  produced  either  by  obstruction  to  breathing  or  by  inspiring 
coal  gas.  Hopkins  and  Fletcher  showed  that  it  appears  in  muscle  when- 
ever this  is  made  to  contract  in  deficiency  of  oxygen,  and  Ryffle  found 
it  increased  in  the  blood  and  was  present  in  the  urine  excreted  after  vigor- 
ous muscular  exercise.  From  the  clinical  side  the  evidence  has  been  fur- 
nished by  observing  the  behavior  of  patients  suffering  from  acidosis 
due  to  the  appearance  of  oxybutyric  acid  (page  737),  as  in  diabetes,  or 
of  other  acids,  as  in  certain  cases  of  nephritis.  In  these  cases  hyperp- 
nea is  accompanied  by  a  lowered  tension  of  alveolar  C02  and  by  a  lowered 
capacity  of  the  blood  to  combine  with  C02,  that  is  a  lowered  alkaline 
reserve  (page  38).  If  the  alkaline  reserve  of  the  blood  be  determined 
after  exposure  of  an  animal  (man)  to  low  oxygen,  it  has  also  been  found 
to  be  decreased. 


380  THE    RESPIRATION 

Taking  all  these  facts  together,  a  strong  case  appeared  to  be  made 
for  the  acidosis  hypothesis  and  this  seemed  to  be  almost  established  since 
Haldane  and  his  collaborators  were  apparently  able  to  apply  it  in  ex- 
plaining the  results  of  their  numerous  investigations  of  the  respiratory 
function.  It  will  be  observed,  however,  that  all  of  the  evidence  is  cir- 
cumstantial in  nature,  and  that  the  changes  observed  in  anoxemia  may 
be  due  to  entirely  different  causes.  Lowering  of  the  alkaline  reserve  of 
the  blood,  lowering  of  the  tension  of  C02  in  the  alveolar  air,  and  hyperp- 
nea  can  undoubtedly  all  result  from  deficiency  of  oxygen-supply  to  the 
tissues,  but  the  sequence  in  which  the  changes  occur  may  be  exactly  the 
reverse  of  that  which  is  assumed  in  the  acidosis  hypothesis;  it  is  pos- 
sible, namely,  that  the  deficiency  in  oxygen  first  excites  the  respiratory 
center,  the  increased  breathing  then  causes  a  blowing  oif  of  the  free  C02 
from  the  blood,  and  the  alkali  that  is  thus  set  free  is  then  excreted  from 
the  blood  in  the  endeavor  to  hold  CH  at  a  constant  level.  If  some  method 
were  available  for  precise  measurements  of  CH  of  the  arterial  blood  at 
frequent  intervals  it  would  be  possible  to  settle  this  question  once  and  for 
all,  but  such  is  not  the  case,  and  we  must  seek  for  proof  for  the  new 
hypothesis  by  indirect  means.*  Assuming  then  that  the  respiratory 
center  is  excited  by  a  slight  degree  of  anoxemia,  let  us  see  how  the  known 
facts  fit  in.  The  diminution  in  oxygen  in  the  blood  excites  the  respiratory 
center  and  causes  increased  breathing.  This  results  in  a  blowing  off  of 
C02  from  the  blood  into  the  alveolar  air,  so  that  there  comes  to  be 
relatively  more  C02  excreted  than  02  absorbed,  and  the  respiratory 
quotient  becomes  raised.  We  have  shown  this  very  clearly  in  experi- 
ments on  decerebrated  cats  breathing  in  oxygen-poor  atmospheres ;  even 
when  the  oxygen  percentage  was  only  slightly  reduced,  R.Q.  had  already 
risen  to  over  unity.  As  a  result  of  this  blowing-off  of  C02,  CH  of  the  blood 
must  tend  to  fall  and  a  condition  of  alkalosis,  rather  than  of  acidosis 
results.  This  may  explain  the  tendency  for  the  breathing  to  return  to- 
wards the  normal.  It  is  important  for  practical  reasons  to  realize  that 
when  this  condition  becomes  established  increased  breathing  will  not 
compensate  for  the  anoxemia,  for  the  advantage  gained  by  higher  satura- 
tion of  the  blood  with  oxygen  is  counteracted  by  the  alkalosis  in  which 
the  hemoglobin  holds  on  to  the  oxygen  with  greater  avidity.  When 
such  is  the  case,  as  already  pointed  out  elsewhere  (p.  401),  the  oxy- 
gen is  not  so  readily  given  up  to  the  tissues.  Under  these  con- 
ditions neither  increased  breathing  nor  increased  bloodflow  can  force 
more  oxygen  into  the  tissues,  so  that  both  the  respirations  and  the  pulse 
become  less  rapid  after  the  initial  acceleration.  It  is  this  prolonged 

*It  may  be  stated,  however,  that  CH  of  the  blood  of  man  after  he  has  been  for  some  time  in 
rarefied  air  is  still  normal  as  judged  by  determination  of  the  dissociation  curve  of  his  blood  (page 
402)  in  a  partial  pressure  of  CO2  equal  to  that  of  his  alveolar  air  (Barcroft).  This  result  shows 
at  least  that  the  acid-base  equilibrium  is  ultimately  restored  under  the  altered  conditions. 


THE    CONTROL    OF    THE    RESPIRATION  381 

anoxemia  that  causes  the  symptoms  of  mountain  sickness  and  many  of 
these  of  pathological  conditions  such  as  pneumonia  or  CO-poisoning. 
The  only  possible  treatment  is  to  raise  the-  tension  of  oxygen  in  the 
alveolar  air  sufficiently  to  force  some  into  solution  in  the  plasma  (see 
page  445). 

After  a  time  acclimatization  to  anoxemia  occurs  because  of  adjustments 
which  bring  CH  back  to  its  normal  value.  These  depend  on  excretion  of 
the  excess  of  alkali  by  the  kidneys  and  the  conversion  of  a  greater  pro- 
portion of  ammonia  into  urea  (page  650).  Hasselbach  and  Lindhard,60 
Collip  and  Backus,79  and  Grant  and  Goldman80  were  the  first  to  show 
that  CH  of  the  urine  becomes  reduced  early  in  anoxemia,  but  returns  to 
the  normal  after  acclimatization  is  established,  and  that  the  excretion 
of  ammonia  is  also  relatively  decreased  but  remains  low  even  after  ac- 
climatization. Haldane,  Kellas  and  Kennaway59  have  confirmed  these 
observations  by  showing  that  the  titrable  acid  of  the  urine  is  reduced 
by  one-half,  or  more.  Diminution  in  the  NH3  excretion  is  always  ob- 
served when  the  excretion  of  fixed  alkali  is  increased  in  proportion  to  the 
acid,*  and  it  indicates  that  the  function  of  the  organs  which  are  respon- 
sible for  conversion  of  NH3  to  neutral  urea,  must  become  stimulated  as 
a  protection  against  the  alkalosis.  The  question  therefore  arises  whether 
the  relative  decrease  in  the  acid  excretion  by  the  kidneys  (rendering  the 
urine  more  alkaline)  runs  parallel  with  the  diminished  production  of  am- 
monia. It  was  found  that  the  ratio  of  ammonia  to  acid  rose  markedly, 
showing  that  the  conversion  of  NH3  into  urea  did  not  occur  as  promptly 
as  the  increased  excretion  of  alkali  by  the  kidney.  Part  of  this  delay  is 
no  doubt  dependent  upon  the  time  required  for  the  ammonia  already 
present  in  the  blood  and  tissue  fluids  to  be  excreted  before  the  increased 
urea  formation  could  become  evident  in  the  urine.  The  results  as  a 
whole  show  that  the  kidneys  (and  liver)  on  the  one  hand,  and  the 
respiratory  center  on  the  other,  respond  to  changes  in  CH  of  the 
blood  which  are  far  below  those  that  can  be  detected  by  exist- 
ing physical  or  chemical  methods  of  measurement  (Haldane).  The 
respiratory  center  constitutes  the  first  line  of  defence  against  any  change  in 
CH  by  increasing  or  decreasing  the  rate  at  which  C02  is  blown  off  from  the 
blood.  The  kidneys  constitute  a  second  defence  by  altering  the  ratio  of 
acid  base  whicfcthey  allow  to  pass  into  the  urine,  andjhe  liver  and  other 
organs  form  a  third  line  of  defence  by  altering  the  amount  of  free  "NH3 
which  they  permit  to  enter  the  blood.  The  readjustment  of  the  alveolar 
C02  and  of  the  acid  and  ammonia  excretions  do  not  return  to  the  normal 
until  some  time  after  the  subject  has  been  breathing  at  normal  barometric 
pressure.  This  will  be  made  evident  by  consulting  Fig.  142-A. 

*Benedict  and  Nash  have  recently  shown  that  it  is  solely  in  the  kidneys  that  the  ammonia 
for  these  purposes  is  formed  (page  563). 


CHAPTER  XLIII 

THE  CONTROL  OF  RESPIRATION   (Cont'd) 
APNEA— PERIODIC  BREATHING 

Apnea 

If  a  man  breathes  forcibly  and  quickly  for  about  two  minutes,  tie 
will  experience  no  desire  to  breathe  for  a  further  period  of  about  the 
same  duration — he  becomes  apneic.  When  the  desire  to  breathe  returns, 
the  breathing  is  at  first  very  shallow,  and  frequently  periodic  in  type, 
but  gradually  it  becomes  more  marked,  until  at  last  normal  respiration 
is  reestablished.  How  may  the  results  be  explained?  The  cause  for  the 
absence  of  breathing  is  lowering  of  the  C02-tension  in  blood.  This  re- 
moves the  natural  stimulus  to  the  respiratory  center  because  a  temporary 
condition  of  alkalosis  with  low  C02-tension  is  induced.  Evidence  of  the 
establishment  of  alkalosis  by  forced  breathing  has  been  obtained  by  ex- 
amination of  the  acid  excretion  in  the  urine,  (see  page  381).  The  C02- 
tension  is  lowered  because  this  gas  has  been  " washed  out"  or  "blown 
off"  from  the  blood  into  the  overventilated  alveoli.  Although  this  over- 
ventilation  also  raises  the  pressure  (tension)  of  oxygen  in  the  alveoli, 
little,  if  any,  more  of  this  gas  can  be  absorbed  into  the  blood  because 
even  at  the  normal  alveolar  tension,  the  blood  takes  up  at  least  95  per 
cent  of  its  possible  load,  in  consequence  of  the  dissociation  curve.  These 
differences  in  the  rate  of  C02-loss  and  02-gain  cause  the  respiratory  quo- 
tient to  become  very  high  during  the  forced  breathing ;  it  may  indeed  rise 
nearly  to  2.  During  the  apneic  period  the  person  by  an  effort  can  expire 
some  alveolar  air,  and  if  this  be  analyzed  it  will  be  found  that  very  little 
C02  is  being  expelled  from  the  blood  though  the  02  is  being  absorbed  as 
usual.  Consequently  R.Q.  becomes  very  low  (0.2  has  been  observed). 
Gradually,  however,  the  C02  rises  again  in  the  blood  and  the  alkalosis 
disappears  so  that  the  respiratory  center  becomes  excited,  although  at 
first  only  feebly  and  irregularly.  If  alveolar  air  be  analyzed  when  the 
first  indication  of  breathing  returns  it  is  said  by  Haldane  that  the  C02 
tension  is  not  yet  back  to  the  normal  level  (see  Fig.  131).  This  indi- 
cates that  some  other  influence  is  helping  to  excite  the  respiratory  center 
and  this  no  doubt  is  anoxemia  for  the  percentage  of  02  in  the  alveolar 
air  has  now  fallen  to  a  very  low  level. 

382 


THE    CONTROL    OF    THE   RESPIRATION 


383 


Fig.  131. — Curves  showing  variations  in  alveolar  gas  tensions  after  forced  breathing  for  two 
minutes.  Thin  line  =  Oo  tension;  thick  line  —  CC*2  tension.  Double  line  —  normal  alveolar 
CO2  tension.  Dotted  line  shows  the  alveolar  CO2  tension  at  which  breathing  would  recommence 
at  the  end  of  apnea  with  the  alveolar  O2  pressures  shown  by  the  thin  line.  The  actual  breathing 
is  indicated  at  the  lower  part  of  the  figure.  It  is  periodic  to  start  with.  (From  Douglas  and 
Haldane.) 


384  THE   RESPIRATION 

In  agreement  with  this  explanation  it  has  been  found  that,  if  the 
last  two  or  three  forced  respirations  preceding  the  apnea  are  made  in 
an  atmosphere  of  02  instead  of  air,  so  as  to  fill  the  alveoli  with  02,  the 
apnea  can  be  maintained  for  a  very  much  longer  period;  and  when  the 
natural  desire  to  breathe  returns,  the  C02  tension  of  the  alveolar  air, 
instead  of  being  below  the  normal,  is  above  it.  The  effect  of  02  in  pro- 
longing apnea,  must,  therefore,  be  dependent  on  the  fact  that  it  prevents 
anoxemia.  By  this  means  the  period  during  which  the  breath  can  be 
held  after  breathing  02  is  sometimes  phenomenal;  in  one  individual,  for 
example,  after  breathing  forcibly  for  a  few  minutes  and  then  filling  the 
lungs  with  02,  apnea  lasted  for  eight  minutes  and  seventeen  seconds. 
The  excess  of  02  also  serves  to  drive  out  considerably  more  C02  from 
the  blood  in  the  alveolar  capillaries  (cf.  page  399).  Collip,79  and  Grant 
and  Goldman80  have  called  attention  to  the  peculiar  "tetany"-like  symp- 
toms that  develop  in  many  individuals  after  the  forced  breathing.  The 
condition  of  alkalosis  induced  by  the  forced  breathing  is  believed  to  be 
responsible  for  the  tetany  (cf.  page  381). 

THE  SUPPOSED  NERVOUS  ELEMENT  IN  APNEA 

The  apnea  following  forced  breathing  has  been  attributed  to  a  sort 
of  inhibition  of  the  respiratory  center  brought  about  by  its  repeated 
stimulation  by  afferent  impulses  transmitted  to  it  along  the  vagus  nerves, 
as  a  result  of  the  frequent  collapse  and  distention  of  the  alveoli.  In 
justification  of  this  nervous  interpretation,  it  was  claimed  that  apnea 
could  not  readily  be  produced  in  animals  after  severing  both  vagus 
nerves.  More  recent  work  has  shown  that  this  is  not  an  accurate  obser- 
vation, for  if  the  severing  of  the  vagi  is  accomplished  not  by  cutting 
but  by  freezing,  then  apnea  is  as  readily  produced  as  in  an  intact  animal 
(Milroy28). 

That  chemical  and  not  nervous  factors  cause  the  apnea  is  further 
demonstrated  by  the  well-known  experiment  of  Fredericq,  who,  after 
ligating  the  vertebral  and  one  of  the  carotid  arteries  in  two  dogs,  anas- 
tomosed the  central  end  of  the  remaining  carotid  of  the  one  to  the 
peripheral  end  of  the  carotid  of  the  other  animal,  thus  establishing  a 
crossed  circulation.  He  then  found  by  applying  forced  artificial  respira- 
tion to  the  one  animal,  that  the  apnea  which  supervened  affected  the 
other  animal  and  not  that  to  which  the  artificial  respiration  had 
actually  been  applied.  Another  proof  of  the  chemical  theory  of 
apnea  is  furnished  by  the  observation  that  if  forced  breathing  is  per- 
formed in  an  atmosphere  containing  C02  in  about  the  same  partial  pres- 
sure as  in  the  alveolar  air,  no  apnea  supervenes,  and  if  the  experiment 
is  repeated  several  times  with  progressively  declining  percentages  of 


THE    CONTROL    OF    THE   RESPIRATION 


385 


C02  in  the  air  each  time,  the  length  of  the  apneic  pause  proportionally 
increases  as  the  C02  pressure  in  the  inspired  air  diminishes. 

Periodic  Breathing 

TYPES  OF  PERIODIC  BREATHING 

In  the  best  known  of  these,  called  Cheyne-Stokes  respiration,  a  period 
of  hyperpnea  supervenes  upon  one  of  apnea,  each  period  following  in 
regular  sequence.  After  an  apneic  period,  the  breathing  begins  at  first 


•AAA-/ 


I 


132.— Various  types  of  periodic  breathing.     (From  Mosso's  "Life  of  Man  in  the  High  Alps.") 


faintly,  gradually  becomes  more  pronounced  until  it  is  markedly  exag- 
gerated, and  then  fades  off  again  to  the  apneic  pause.  Sometimes  the 
apneic  period  is  immediately  followed  by  one  of  intense  hyperpnea,  there 
being  no  gradual  increase  in  the  respiratory  movements.  Between  these 
two  types  all  varieties  of  the  condition  are  met  (Fig.  132). 

The  conditions  in  which  periodic  breathing  occurs  may  be  divided  into 


386  THE   RESPIRATION 

physiological  and  pathological  groups.  Of  the  physiological  conditions  the 
following  may  be  taken  as  examples:  (1)  Breathing  in  an  atmosphere 
containing  a  deficiency  of  02 ;  thus,  periodic  breathing  is  very  readily  pro- 
duced in  persons  living  in  rarefied  air.  It  is  often  more  particularly  after 
returning  to  air  at  normal  barometric  pressure,  that  the  periodic  breathing 
sets  in.  (2)  Breathing  through  a  long  tube  having  a  small  vessel  contain- 
ing soda  lime  inserted  between  the  tube  and  the  mouth,  the  whole  capacity 
of  this  vessel  and  tubing  being  about  a  liter.  This  will  cause  periodic 
breathing  in  persons  that  are  susceptible  to  oxygen  deficiency.  Even 
breathing  through  the  tube  without  soda  lime  will  sometimes  cause  a  periodic 
type  of  breathing  in  such  individuals.  (3)  The  initial  breathing  follow- 
ing an  apnea  induced  by  forced  ventilation  of  the  lungs.  In  this  post- 
apneic  periodicity,  the  apneic  periods  may  at  first  be  quite  marked,  but  as 
breathing  returns  they  become  gradually  shorter  and  the  breathing  in- 
tervals gradually  longer,  until  normal  respiration  is  restored  (Fig.  131). 
(4)  Restricted  breathing,  brought  about  either  by  limiting  the  quantity 
of  inspired  air  or  by  restricting  the  respiratory  movements  by  corsets. 

The  pathological  conditions  in  which  periodic  breathing  becomes  devel- 
oped are  particularly  those  associated  with  renaj^^disej^^njLiie^ebral 
hemorrhage.  In  many  of  these  cases,  the  periodic  breathing  does  not 
appear  to  depend  on  the  same  factors  as  are  concerned  in  the  experi- 
mental types.  The  symptoms  would  rather  appear  to  depend  on  some 
influence  of  the  higher  cerebral  (supranuclear)  centers  on  the  respiratory 
center.  At  least  some  other  evidence  of  disturbance  of  the  cerebral  func- 
tions is  always  forthcoming,  such  as  a  slight  paralytic  stroke,  and  the 
periodic  breathing  is  nearly  always  aggravated  during  sleep.  Many  of 
these  cases  are  greatly  benefited  by  administration  of  caffeine. 

In  both  the  physiological  and  the  pathological  groups,  the  breathing  may 
develop  a  periodic  character  only  when  the  person  is  asleep.  Infants  or 
very  old  people  may  indeed  exhibit  a  certain  degree  of  periodic  breathing 
apart  from  any  of  the  above  mentioned  causative  factors. 

CAUSES  OF  PERIODIC  BREATHING 

Great  interest  attaches  to  an  investigation  of  the  causes  of  periodic 
breathing,  but  it  can  not  be  claimed  that  any  perfectly  satisfactory  ex- 
planation has  as  yet  been  offered.  Pembrey31  attributes  it  to  a  diminished 
excitability  (a  raised  threshold)  of  the  respiratory  center  due  to  faulty 
blood  supply,  the  supposition  being  that,  when  thus  depressed,  the 
normal  CH  of  the  blood  is  unable  to  excite  the  center,  so  that  breathing 
stops.  During  the  resulting  apnea,  C02  again  accumulates  until  it  has 
raised  the  CH  sufficiently  to  excite  the  depressed  center.  Hyperpnea 
follows,  causing  a  washing  out  of  the  C02  and  a  resulting  diminution  of 


THE    CONTROL    OF    THE    RESPIRATION  387 

the  effective  stimulus,  so  that  again  the  center  fails  to  be  stimulated  and 
apnea  supervenes,  and  so  on.  Support  for  this  explanation  would  appear 
to  be  furnished  by  the  fact  that,  when  patients  exhibiting  periodic  breath- 
ing are  made  to  breathe  an  atmosphere  containing  a  high  percentage  of 
C02,  the  periodicity  of  the  breathing  may  give  place  to  regular  breath- 
ing; a  result  which  may  also  be  obtained  by  making  such  patients 
breathe  in  atmospheres  rich  in  oxygen.  In  the  former  case,  the  stimulus  is 
raised  to  meet  the  depressed  excitability  of  the  center;  in  the  latter,  the 
excitability  of  the  center  is  increased  because  of  better  oxygen  supply 
so  that  it  is  enabled  to  react  to  the  diminished  stimulus.  But  even 
granted  that  the  excitability  of  the  center  is  depressed,  it  is  difficult  to 
see  why  this  should  occasion  a  periodic  type  of  breathing  unless  we  as- 
sume that  it  is  only  when  stimulus  (i.  e.,  CH  of  blood)  and  threshold  of 
excitability  of  the  center  are  adjusted  at  a  certain  physiological  level  that 
smooth  and  continuous  action  can  go  on. 

The  fact  that  alterations  in  the  excitability  of  the  respiratory  center 
in  clinical  conditions  are  very  commonly  associated  with  periodic  breath- 
ing, suggests  that  similar  alterations  must  be  responsible  for  the  experi- 
mental forms.  Support  for  this  view  is  found  in  the  fact  that  most  of 
these  latter  are  produced  under  conditions  where  there  must  be  a  cer- 
tain degree  of  anoxemia.  Apparently  when  the  oxygen  tension  of  the 
blood  falls  to  a  certain  degree  the  excitability  of  the  center  becomes 
altered  and  when  it  is  so,  the  respiratory  hormone,  afforded  by  the  ten- 
sion of  C02,  causes  an  irregular  stimulation,  but  why  it  should  do  so 
is  impossible  to  explain.  A  further  factor  that  may  come  into  play 
is  dependent  on  the  time  taken  for  blood  to  travel  between  the  pulmo- 
nary alveoli  and  the  medulla.  This  may  explain  the  gradual  rather 
than  sudden  development  of  the  apneic  and  hyperpnejc  phases.  At 
present  all  we  can  do  in  attempting  to  explain  this  mysterious  phenom- 
enon is  to  examine  the  exact  conditions  under  which  it  occurs. 

The  most  simple  to  consider  first  is  the  periodic  breathing  that  is 
produced  in  a  person  susceptible  to  02  'want,  by  breathing  through 
a  tube  and  bottle  (of  a  total  capacity  of  1  liter),  containing  soda  lime. 
In  such  a  case  no  outside  air  can  enter  the  lungs,  so  long  as  the 
breathing  is  normal  on  account  of  the  dead  space  having  been 
too  greatly  prolonged.  The  oxygen  tension  of  the  rebreathed  air, 
therefore  quickly  falls  (while  at  the  same  time  the  C02  is  being  ab- 
sorbed), until  at  last  a  point  is  reached  at  which  the  respiratory  center 
is  directly  stimulated  by  anoxemia  (see  page  374).  The  deep  breaths 
(hyperpnea)  which  follow,  being  of  greater  volume,  cause  some  out- 
side air  to  be  inspired  so  that  the  02  want  is  made  good  and  the  hy- 
perpnea again  disappears,  possibly  to  the  extent  of  apnea,  since  now,  in 


388  THE   RESPIRATION 

consequence  of  a  coincident  ''washing  out"  of  C02,  there  has  been  a 
lowering  of  the  C02-tension  of  the  blood  below  the  threshold  value. 
During  the  apnea  the  02  is  rapidly  used  up,  till  a  point  is  reached  at 
which  the  center  again  becomes  excited.  In  such  an  experiment  the 
effects  of  anoxemia  such  as  cyanosis  may  show  themselves.  That  breath- 
ing under  these  conditions  should  be  periodic  and  not  merely  show  a 
steadily  increasing  hyperpnea  is  probably  due,  as  we  have  seen,  to  the  un- 
equal rates  at  which  the  02  and  C02  tensions  change  in  the  blood.  Be- 
cause of  a  " buffer  action"  the  latter  fluctuates  much  less  than  the  for- 
mer. Another  cause  for  the  periodicity  is  no  doubt  the  delay  between 
the  gas  exchange  in  the  lungs  and  the  arrival  of  the  arterialized  blood  in 
the  brain.  "When  the  02  tension  of  the  blood  supplying  the  respiratory  cen- 
ter falls  to  so  low  a  level  that  excitation  of  the  center  occurs,  the  resulting 
increased  breathing  aspirates  outside  02  into  the  alveoli.  After  a  moment 
or  so,  the  02  is  carried  by  the  blood  to  the  center,  so  that  its  stimula- 


Fig.  133. — Quantitative  record  of  breathing  air  through  a  tube  260  cm.  long  and  2  cm.  in  diameter. 

(From  Douglas  and  Haldane.) 

tion  by  02  deficiency  is  removed,  and  it  is  left  in  a  condition  in  which 
it  fails  to  discharge  any  impulses,  since  there  is  a  subnormal  C02  tension 
of  the  blood  as  a  consequence  of  the  hyperpnea.  A  little  time  must  now 
elapse  before  the  C02  again  rises  or  the  02  falls  sufficiently  to  excite  the 
center.  Periodic  breathing  can  be  brought  about  by  this  method  in  de- 
cerebrate  cats,  the  animals  being  caused  to  respire  through  a  tube  and 
small  flask  containing  soda  lime,  the  total  capacity  being  about  80-100  c.c. 
That  02  deficiency  is  responsible  for  the  result  is  indicated  by  the  fact 
that  administration  of  02  through  a  catheter  inserted  in  the  trachea 
brings  about  normal  breathing. 

A  similar  although  less  marked  degree  of  periodic  breathing  can 
sometimes  be  induced  by  merely  respiring  through  a  long  tube  without 
any  provision  for  the  absorption  of  C02.  In  this  case  it  is  more  difficult 
to  explain  the  cause  of  the  periodic  breathing,  but  that  the  main  factor 
concerned  is  one  of  02  deprivation  is  evidenced  by  the  fact  that  in  this, 


THE    CONTROL   OF   THE   RESPIRATION  389 

as  in  the  previous  experiment,  the  periodic  nature  of  the  respiration  is 
immediately  changed  to  the  regular  breathing  if  02  is  introduced  into 
the  tube.  The  interest  of  the  experiment  lies  in  the  fact  that  a  similar 
relative  elongation  of  the  dead  space  is  probably  accountable  for  the 
periodic  breathing  seen  in  the  winter  sleep  of  hibernating  animals.  Dur- 
ing this  condition,  on  account  of  the  depression  of  metabolism  less  02 
is  required  and  less  C02  is  produced,  so  that  the  exchange  of  gases 
through  the  pulmonary  endothelium  is  greatly  diminished.  The  dead 
space,  however,  remains  of  the  same  capacity,  which  amounts  to  the 
same  thing  as  if  the  latter  had  been  prolonged  under  unchanged  con- 
ditions of  pulmonary  gas  exchange. 

Important  evidence  that  changes  occurring  in  the  tensions  of  02 
and  C02  in  the  alveolar  air,  and  therefore  in  the  arterial  blood  of 
the  respiratory  center,  are  largely  responsible  for  periodic  breathing 
has  been  secured  by  studying  the  condition  that  develops  after  a  period 
of  apnea  produced  by  voluntary  forced  breathing.  The  results  of  such 
observations  are  given  in  the  curve  shown  in  Fig.  131,  in  which 
the  thin  line  represents  the  02  tension  of  the  alveolar  air,  the  thick 
line  the  C02  tension.  The  double  line  running  across  the  chart  repre- 
sents the  average  tension  of  C02  during  quiet  normal  breathing.  The 
respiratory  movements  are  represented  by  the  tracing  at  the  foot  of 
the  curve,  along  the  abscissa.  It  will  be  observed  that  the  oxygen  ten- 
sion falls  very  rapidly  during  the  apneic  period,  until  just  before  breath- 
ing recommences  it  may  be  as  low  as  30-35  mm.  Hg  instead  of  the  nor- 
mal of  about  95.  Meanwhile  the  C02  tension  rises  from  the  very  low 
level  of  12  mm.,  at  first  very  rapidly,  then  more  gradually,  although, 
when  breathing  recommences,  it  has  not  yet  gained  the  normal  level. 
As  a  result  of  the  first  periods  of  breathing,  the  02  tension  suddenly 
increases,  but  the  C02  falls  only  slightly.  During  the  next  apneic  stage 
the  02  quickly  comes  down  again,  and  the  C02  rises  so  as  almost  to  at- 
tain normal  tension  before  breathing  again  supervenes.  As  the  apneic 
periods  subsequently  become  less  pronounced,  the  C02  tension  comes  to 
stand  almost  at  its  normal  level,  whereas  considerable  variations  in  the 
02  tension  continue  to  occur.  If  the  lungs  are  filled  with  oxygen  by  in- 
haling the  gas  with  the  last  few  deep  breaths  the  return  of  breathing 
is  delayed  and  it  is  not  periodic  in  character. 

Besides  affording  substantial  support  to  the  hypothesis  which  was 
stated  above,  there  are  several  other  interesting  features  of  these  results 
which  demand  attention.  In  the  first  place,  it  is  plain  that  the  body 
is  possessed  of  some  mechanism  by  which  it  can  prevent  great  fluctua- 
tions in  the  C02  tension  of  the  blood,  whereas  towards  02  no  such 
"buffer  action"  is  displayed.  It  will  further  be  observed  that  the  CO, 


390  THE   RESPIRATION 

tension  of  the  alveolar  air  rises  very  rapidly  during  the  first  part  of 
the  apneic  period,  and  then  more  gradually,  the  explanation  being  that 
during  the  forced  breathing  the  C02  has  been  washed  out  from  the  blood 
but  not  from  the  body  as  a  whole. 

As  the  C02  tension  becomes  lowered  in  the  blood,  C02  will  diffuse 
out  of  the  tissues  to  maintain  equilibrium  between  blood  and  tissues. 
There  must  be  some  considerable  lag  in  this  process  however,  so  that 
when  the  forced  breathing  ceases  a  much  lower  tension  exists  in  the 
blood  than  in  the  tissues.  The  rapid  rise  in  alveolar  C02  early  in  the 
apnea  is  therefore  due  to  diffusion  from  the  tissues  up  to  the  equi- 
librium point. 

Periodic  breathing  is  produced  by  forced  respiration  more  readily  in 
rarefied  air  than  at  sea  level.  It  was  found  by  Douglas,26  after  breath- 
ing forcibly  for  one  minute  at  sea  level,  that  the  breathing  when  it 
returned  showed  8  to  10  different  periods  of  apnea  and  hyperpnea.  On 
repetition  of  the  experiment  at  an  altitude  giving  a  barometric  pres- 
sure of  600  mm.,  25  such  periods  followed  the  apnea;  at  a  height  cor- 
responding to  520  mm.,  40  periods.  Indeed,  at  high  altitudes  periodic 
breathing  may  be  brought  about  by  the  slightest  alteration  in  normal 
respiration ;  even  taking  a  deep  breath  may  be  sufficient  to  cause  distinct 
periodicity  in  the  succeeding  respirations,  and  in  many  persons  living 
at  high  altitudes  periodic  breathing  is  very  apt  to  occur  during  sleep. 
As  in  pathological  cases  exhibiting  Cheyne-Stokes  respiration,  the  peri- 
odic breathing  at  high  altitudes  can  be  immediately  removed  by  inspir- 
ing oxygen. 

Having  now  considered  in  detail  the  conditions  which  cause  altera- 
tions in  the  acid  base  equilibrium  of  the  body,  it  will  repay  the  reader 
to  refer  back  to  pages  50  and  3'62  where  they  are  discussed  from  a  more 
general  point  of  view. 


CHAPTER  XLIV 
RESPIRATION  BEYOND  THE  LUNGS 

Up  to  the  present  our  studies  in  respiration  have  concerned  the  various 
mechanisms  involved  in  bringing  about  a  constant  change  in  the  com- 
position of  the  alveolar  air.  We  must  now  consider  the  nature  of  the 
means  by  which  the  oxygen  is  conveyed  to  the  tissues  and  the  carbon  di- 
oxide removed  from  them. 

In  the  first  place,  it  is  important  to  note  that  it  is  not  for  purposes 
of  oxidation  in  the  blood  itself  that  the  02  is  required.  In  its  respiratory 
function  this  fluid  serves  as  a  transporting  agency  between  the  lungs 
and  the  tissues,  in  which  reside  the  furnaces  of  the  body  that  con- 
sume the  02  and  produce  the  C02.  This  does  not  imply  that  there  is  no 
oxidation  in  the  blood  itself;  indeed,  we  should  expect  a  certain  degree 
of  oxidation  because  of  the  fact  that  the  blood  contains  some  living 
cells — the  leucocytes.  It  is  scarcely  necessary  nowadays  to  offer  evi- 
dence for  the  foregoing  conclusion.  One  well-known  experimental  proof 
consists  in  replacing  the  blood  in  a  frog  with  physiological  saline  solution 
and  then  subjecting  the  frog  with  the  saline  in  its  blood  vessels  to  an 
atmosphere  of  pure  02,  when  it  will  be  found  that  the  animal  continues 
to  absorb  the  normal  amount  of  02  and  exhale  the  normal  amount  of 
C02.  It  respires  normally  without  any  blood  in  the  blood  vessels. 

In  order  that  this  transportation  of  gases  between  the  lungs  and  the 
tissues  may  be  efficiently  performed,,  the  blood  must  be  provided  with 
means  for  carrying  adequate  amounts  of  gases  to  supply  the  requirements 
of  the  tissues,  both  during  rest  and  during  their  varying  degrees  of 
activity.  Not  only,  therefore,  must  the  02  and  C02  capacity  of  the 
blood  be  very  considerable,  but  it  must  be  capable  of  very  rapid  adjust- 
ment from  time  to  time. 

Our  problem  naturally  resolves  itself  into  three  parts:  (1)  the  call 
of  the  tissues  for  oxygen  (Bar croft)  ;  or,  as  it  is  styled,  tissue  or  internal 
respiration;  (2)  the  mechanism  by  which  the  blood  transports  the  proper 
amounts  of  gases  to  meet  the  requirements  of  the  tissues;  and  (3)  the 
mechanism  by  which  the  blood  gases  are  exchanged  in  the  lungs — ex- 
ternal respiration.  For  convenience,  however,  we  shall  change  this  nat- 
ural order  and  consider  the  transportation  of  the  gases  first. 

391 


392  THE   RESPIRATION 

THE  TRANSPORTATION  OF  GASES  BY  THE  BLOOD 

The  Transportation  of  Oxygen 

It  is  plainly  not  by  mere  solution  in  the  plasma  of  the  blood  that  the 
transportation  of  02  occurs,  for  at  the  partial  pressure  of  this  gas  ex- 
isting in  the  alveolar  air  at  the  temperature  of  the  body  the  amount  that 
could  be  dissolved  in  the  blood  would  be  only  one-fortieth  of  that  which 
is  actually  found  to  be  present.  If  there  were  only  plasma  in  the  blood 
vessels,  it  would  require  a  volume  of  fluid  amounting  to  150  kilograms 
or  more  in  order  to  convey  the  necessary  amount  of  02  from  the  lungs 
to  the  tissues;  that  is,  the  contents  of  the  vascular  system  would  weigh 
twice  as  much  as  the  average  weight  of  a  man. 

The  substance  that  carries  the  02  in  the  blood  is  the  hemoglobin,  which 
may  be  described  as  a  highly  complex  iron  compound  of  protein  espe- 
cially evolved  for  the  purpose  of  transporting  02.  In  some  of  the  lower 
animals  other  compounds  exist  in  the  blood  for  this  purpose,  but  none 
of  them  is  to  be  compared  in  its  efficiency  with  hemoglobin.  They  are 
merely  poor  imitations  of  it. 

Regarding  the  conditions  under  which  hemoglobin  combines  with  or 
delivers  up  02,  the  first  question  that  presents  itself  is  whether  or  not 
the  reaction  is  a  strictly  chemical  one.  If  so,  a  definite  amount  of  02 
must  be  capable  of  combining  with  a  definite  amount  of  hemoglobin.  It 
is  impossible  to  secure  hemoglobin  of  sufficient  purity  to  test  this  rela- 
tionship directly  on  hemoglobin  itself,  so  that  we  must  test  it  indirectly 
by  examining  the  combining  equivalent  between  02  and  that  portion  of 
the  hemoglobin  molecule  upon  which  the  combining  power  depends.  This 
is  the  part  of  the  molecule  containing  iron.  Now,  if  we  compare  the 
amount  of  02  wrhich  hemoglobin  can  take  up  with  the  amount  of  iron 
present  in  the  hemoglobin,  we  shall  find  that  one  atom  of  iron  becomes 
combined  with  two  atoms  of  02.  Evidently,  then,  we  are  here  dealing 
with  a  definite  chemical  reaction  occurring  between  the  02  and  the  iron 
of  the  hematin  portion  of  the  hemoglobin.  This  relationship  is  known 
as  "the  specific  oxygen  capacity  of  hemoglobin.  " 

In  showing  that  the  union  of  02  and  hemoglobin  occurs  according  to 
chemical  laws,  we  throw  into  prominence  consideration  of  the  mechanism 
by  which  the  02,  combined  with  hemoglobin  in  the  blood,  is  rapidly  de- 
livered up  in  the  capillaries  so  as  to  supply  the  tissues  with  their  require- 
ment, and  is  then  as  rapidly  recombined  again  in  the  lungs.  Moreover, 
we  must  reconcile  the  idea  of  a  specific  02  capacity  with  the  well- 
known  observation  that  the  hemoglobin  in  the  circulation  may  be  united 
with  considerably  less  02  than  the  total  amount  possible.  In  other  words, 
we  must  recognize  that,  although  it  is  essentially  a  chemical  reaction, 


RESPIRATION    BEYOND    THE    LUNGS  393 

the  combination  of  02  with  hemoglobin  is  greatly  influenced  by  other 
factors,  and  that  it  is  these  that  are  likely  to  be  of  physiological  impor- 
tance. 

In  order  to  understand  the  conditions  under  which  hemoglobin  will 
take  up  and  give  off  02  in  the  animal  body,  we  must  study  the  combining 
power  of  hemoglobin  when  it  is  exposed  to  different  partial  pressures 
of  02  (for  laws  governing  this,  see  page  353).  In  the  blood,  the  ex- 
tremes of  the  partial  pressure  of  02  are  represented,  at  the  one  end,  by 
that  in  the  alveolar  air,  which  we  have  seen  to  be  about  100  mm.  Hg, 
and  at  the  other,  by  that  existing  in  the  tissues,  such  as  muscle,  which 
has  been  shown  to  be  not  more  than  19  or  20  mm.  Hg.  We  must  further 
bear  in  mind  that  the  02  in  its  passage  from  the  alveolar  air  to  the  hemo- 
globin and  from  the  hemoglobin  to  the  tissues,  is  transmitted  in  solution 
through  the  plasma;  that  is,  so  far  as  the  supply  of  02  to  the  tissue  cells 
is  concerned,  the  plasma  serves  as  the  immediate  source.  Since  the  tis- 
sues are  using  up  02  at  a  very  great  speed,  especially  when  active,  and 
are  thus  tending  to  lower  the  tension  of  02  in  the  plasma,  favorable  con- 
ditions have  to  be  created  whereby  the  hemoglobin  liberates  02  at  the 
same  rate  as  that  at  which  it  is  leaving  the  plasma.  In  brief,  it  is  the 
02  tension  of  the  plasma  in  the  tissue  capillaries  that  is  the  important' 
factor,  the  hemoglobin  merely  serving  as  a  storehouse,  which  delivers 
its  02  at  just  such  a  rate  as  to  maintain  the  plasma-oxygen  tension  at 
a  constant  level.  It  is  obviously  of  the  greatest  importance  that  we 
should  understand  how  this  mechanism  of  an  adequate  plasma-oxygen 
tension  is  maintained. 

Methods  of  Investigation. — We  must  remember  that  the  combination 
of  02  and  hemoglobin,  being  a  definite  chemical  reaction,  will  be  re- 
versible, and  must,  therefore,  obey  the  laws  of  mass  action  (see  page 
23)  according  to  the  equation:  Hb  -f-  02^±Hb02.  In  order  to  ascertain 
the  position  of  the  balance  of  this  equation  at  different  partial  pressures 
of  02, — that  is,  the  relative  quantities  of  oxy-  and  reduced  hemoglobin 
formed  in  a  solution  of  hemoglobin  when  this  is  shaken  with  02  at  differ- 
ent pressures, — we  may  proceed  as  follows:  A  few  c.c.  of  the  hemoglobin 
solution  are  placed  in  each  of  a  series  of  vessels  called  tonometers,  like 
those  shown  in  Fig.  134.  In  addition  to  the  hemoglobin  solution,  each 
tonometer  contains  a  mixture  of  nitrogen  and  02  in  different  propor- 
tions. Suppose  we  use  six  vessels  and  in  No.  1  have  pure  nitrogen;  in 
No.  2,  nitrogen  containing  5  mm.  partial  pressure  of  02;  in  No.  3,  10 
mm. ;  in  No.  4,  20 ;  in  No.  5,  50 ;  and  in  No.  6,  100.  We  now  rotate  the 
tonometers  in  a  water-bath  at  body  temperature  for  about  twenty  min- 
utes, so  that,  by  the  formation  of  a  thin  film  of  hemoglobin  solution  over 
the  walls  of  the  vessel,  perfect  equilibrium  between  the  atmosphere  and 


394  THE   RESPIRATION 

the  fluid  may  be  attained  (see  page  355).  A  measured  quantity  of  hemo- 
globin solution  (0.1  or  1.0  c.c.)  is  then  removed  from  each  tonometer 
and  placed,  together  with  some  very  dilute  ammonia  to  lake  the  blood, 
in  one  of  the  small  bottles  of  the  differential  manometer,  shown  in  Fig. 


Fig.    134. — Barcroft's  tonometer   for  determining  the   curve   of   absorption   of  oxygen   by    hemoglobin 
or  blood.      (From  Starling's  Physiology.) 

135.*  This  manometer  consists  in  principle  of  a  graduated  U-shaped 
tube  of  narrow  bore,  containing  clove  oil,  the  free  end  of  the  U-tube 
being  connected  with  small  bottles  provided  with  some  device  so  that 


Fig.    135. — Barcroft's   differential    blood    gas    manometer.      The    capillary    U-tube    contains    clove    oil. 
The  pockets  on  the  sides  of  the  blood  bottles  should  be  deeper.     For  manipulation  see  context. 

two  fluids  can  be  placed  in  each  of  them  but  kept  unmixed  until  the 
bottle  is  violently  shaken.  The  three-way  stopcock  between  the  small 
bottles  and  the  manometer  serves  to  permit  communication  of  the 
manometer  with  the  outside  air. 


*The  blood-gas  manometers  are  made  in  two  sizes  for  use  with   1   c.c.  and   0.1   c.c.   quantities  of 
blood,  respectively.     The  results  with  these  small  quantities  are  as  accurate  as  with  larger  amounts. 


RESPIRATION    BEYOND    THE    LUNGS 


395 


An  equal  quantity  of  hemoglobin  solution  that  has  been  saturated 
with  oxygen — i.  e.,  oxyhemoglobin — is  placed  in  the  bottle  on  the  other 
end  of  the  manometer  tube  from  that  containing  the  bottle  with  the  un- 
saturated  hemoglobin  solution.  The  bottles  having  been  attached  to 
the  manometer  with  the  stopcocks  open  to  the  outside,  the  apparatus 
is  placed  in  a  water-bath  until  the  temperature  conditions  are  constant. 
The  manometers  are  then  closed  to  the  outside  air  and  the  bottles  are 
shaken  in  order  that  the  hemoglobin  solution  that  is  unsaturated  with 
02  may  take  up  02  from  the  atmosphere  in  the  bottle  until  it  becomes 
saturated.  The  resulting  shrinkage  in  the  volume  of  the  atmosphere 
on  the  side  of  the  unknown  hemoglobin  solution  causes  the  clove  oil 


Fig.  136. — Barcroft  blood  gas  manometer.  This  form  can  be  used  either  as  a  differential 
manometer  (page  403)  or  for  direct  measurement  of  pressure.  For  the  latter  purpose  one  bottle 
is  removed  and  the  pressure  of  gas  generated  in  the  other  bottle  is  measured  by  the  height  to 
which  it  raises  the  clove  oil  in  the  distal  tube  of  the  manometer,  the  meniscus  in  the  proximal 
limb  being  readjusted  to  its  original  level  by  compression  with  the  brass  screw  of  the  rubber  tube 
shown  in  the  center. 

meniscus  to  move  towards  that  side,  the  degree  of  movement  being  pro- 
portional to  the  initial  unsaturation  of  the  hemoglobin.  The  manometer 
tubes  are  then  again  brought  into  communication  with  the  atmosphere 
so  that  the  meniscus  of  clove  oil  may  move  back  to  its  old  level,  and  the 
bottle  with  saturated  hemoglobin  is  removed  from  the  manometer  and  a 
drop  or  two  of  a  saturated  solution  of  potassium  ferricyanide  placed 
in  the  separate  compartment  of  the  bottle  without  allowing  it  to  mix 
with  the  hemoglobin.  The  bottle  is  then  reattached,  the  temperature 
conditions  readjusted,  the  manometer  closed  off  from  the  ouside  air, 
and  the  apparatus  again  shaken  so  that  the  ferricyanide  mixes  with  the 


396  THE   RESPIRATION 

hemoglobin  solution.  This  drives  off  all  the  02  from  the  oxyhemoglobin 
solution,  and,  therefore,  raises  the  pressure  in  the  atmosphere  of  that 
bottle  so  that  the  clove  oil  moves  to  the  opposite  side  of  the  manom- 
eter, the  degree  of  displacement  being  proportional  to  the  amount  of 
oxyhemoglobin. 

We  have  now  all  the  necessary  data  for  estimating  the  relative  amounts 
of  reduced  hemoglobin  in  the  hemoglobin  solution  as  removed  from  the 
tonometers,  for  it  is  plain  that  the  second  estimation,  as  described  above, 
tells  us  how  much  oxyhemoglobin  might  have  been  formed  had  all  the 
hemoglobin  been  saturated  and  the  first  one,  how  much  02  had  yet  to  be 
taken  up  by  the  original  hemoglobin  solution  to  produce  saturation. 

The  Dissociation  Curve. — The  next  step  is  to  plot  the  results  obtained 
from  the  various  hemoglobin  solutions  in  the  form  of  a  curve.  This  is 
known  as  the  dissociation  curve  of  "hemoglobin.  It  is  plotted  with  the 
relative  percentages  of  reduced  and  oxyhemoglobin  in  each  of  the  solu- 
tions along  the  ordinates,  and  the  partial  pressures  of  02  in  millimeters 
of  mercury  to  which  they  were  exposed  along  the  abscissae.  The  curve 
thus  drawn  is  exactly  of  the  same  shape  as  that  which  would  be  pro- 
duced if  we  were  to  place  the  tonometers  in  a  row  at  distances  from  one 
another  corresponding  to  the  partial  pressure  of  02  which  each  con- 
tained, and  then  to  mark  on  each  tonometer  the  relative  amounts  of 
reduced  and  oxyhemoglobin  found  in  the  solutions  after  shaking.  A 
line  joining  these  marks  on  the  tonometers  would  then  exactly  corre- 
spond to  the  curve  drawn  by  the  method  described  above.  This  will  be 
clear  from  the  accompanying  figure  from  Barcroft's  book  (Fig.  137). 

In  such  a  chart  the  space  below  the  curve  can  be  taken  to  represent 
the  percentage  of  oxyhemoglobin  (red  in  chart),  and  that  above  it  of 
reduced  hemoglobin  (blue  in  chart),  at  the  varying  partial  pressures  of 
02  which  are  indicated  along  the  abscissae  as  being  contained  in  the  at- 
mosphere of  the  tonometers,  and  which  must  be  proportional  to  the 
partial  pressure  of  02  in  the  solution  in  which  the  hemoglobin  is  dis- 
solved. 

Difference  between  Curves  of  Blood  and  Hemoglobin  Solutions. — The 
curve  obtained  from  pure  hemoglobin  solutions  is  very  far,  however, 
from  clearing  up  the  problem  as  to  how  the  blood  absorbs  and 
discharges  02.  On  the  contrary,  it  makes  this  problem  appear  all  the 
more  difficult,  for,  according  to  the  curve  (Fig.  138-Curve  A)  the  hemo- 
globin is  already  more  than  half  combined  with  02  at  a  partial  pressure 
of  this  gas  of  no  more  than  10  mm.  Hg,  which  means  that  in  the  low 
partial  pressure  of  02  existing  in  the  capillaries  the  oxyhemoglobin,  in- 
stead of  readily  yielding  up  its  load  of  02,  would  greedily  retain  prac- 
tically the  whole  of  it.  The  curve,  in  other  words,  would  satisfactorily 


20 


4 


100 
mm.  pressurt 


Percentage  saturation 
with  oxygen 


0      10      20      30      40      50       QO       70      80       90       100 

Oxygen  pressure 
mm. 


Fig.  137. — Upper  left  hand,  percentage  saturation  of  hemoglobin  with  oxygen  at  37°  C.  cor- 
responding to  oxygen  pressures  of  0,  10,  20,  40  and  100  mm.  of  oxygen,  respectively. 

Upper  right  hand,  the   same  spaced  with  the  oxygen  pressure  as  the  abscissae. 

Lower  figure,  dissociation  curve  representing  the  equilibrium  between  oxygen,  oxyhemoglobin 
(red)  and  reduced  hemoglobin  (purple).  (From  Joseph  Barcroft.) 


RESPIRATION    BEYOND    THE    LUNGS 


397 


explain  why  hemoglobin  should  readily  absorb  02  from  the  alveolar  air, 
but  would  fall  far  short  of  explaining  how  this  02  is  readily  released 
when  it  is  required  in  the  tissues.  Obviously  there  is  some  artificial  con- 
dition present  in  the  above  experiment  which  can  not  obtain  in  the  nat- 
ural environment  of  the  blood. 

Since  hemoglobin  takes  up  02  in  proportion  to  its  iron,  it  can  not  be 


10     ZO     30     W     30     60     70     80    <?0    100 

Fig.    138. — Average    dissociation    curves. 

Ordinates — Percentage  saturation  of  hemoglobin  with   oxygen. 

Abscissae — Tension    of   oxygen    in    mm.    of    mercury. 

Curve  A — Degree  of  saturation  of  pure  hemoglobin  solutions  at  varying  pressures. 

Curve  B — Disregard    this    curve. 

Curve  C — Effect   of   20  mm.    CO2   pressure   on  above  solution. 

Curve  D — The  saturation  curve  in  normal  blood  at  40  mm.  carbon  dioxide  pressure. 

because  of  changes  in  the  02  combining  part  of  the  hemoglobin  itself 
that  blood  and  pure  hemoglobin  solutions  have  dissimilar  dissociation 
curves,  but  rather  because  of  differences  in  the  environment  in  which  the 
hemoglobin  acts.  That  this  is  so  can  be  readily  shown  by  plotting  the 
dissociation  curve,  not  for  a  hemoglobin  solution,  but  for  blood  itself 
(D  in  Fig.  138).  The  results  are  very  different.  At  a  partial  pressure 
of  02  of  about  60  mm.  Hg — that  is,  a  lower  pressure  than  exists  in  the 


398 


THE   RESPIRATION 


lung  alveoli  (100  mm.) — the  blood  becomes  nearly  saturated  with  02, 
whereas  at  pressures  below  50  mm.  it  readily  loses  02,  so  that  at  10  mm. 
there  is  nearly  complete  reduction. 

The  question  is:  What  are  the  environmental  conditions  under  which 
the  hemoglobin  in  the  blood  so  alters  its  combining  power  for  02  as  to 
produce  such  a  difference  in  the  dissociation  curve?  By  experimenting 
with  hemoglobin  solutions,  three  such  factors  have  been  found  to  come 
into  play:  (1)  the  presence  of  inorganic  salts,  (2)  the  hydrogen-ion  con- 
centration (C02  tension)  of  the  solution,  and  (3)  the  temperature.  If 


Fig.    139. — Curve  to   show   the   degree    of   variations    occurring   in   the    Oa    dissociation   curve    for 

the    blood    of   man    in    atmospheres    containing    carbon    dioxide    in    the    same    percentage    as    present 

in  the  alveolar   air   of  the  individuals   examined.      Along  the   abscissae   are   given    the    pressures    of 

oxygen  in  mm.   Hg.     and  along  the  ordinates   the  percentage    saturation   of  the  blood   with   oxygen. 

.(From    Barcroft's   Respiratory   Function   of   the   Blood.) 

hemoglobin  is  dissolved  in  water  containing  the  various  salts  of  plasma 
in  the  same  proportion  as  in  blood  (artificial  plasma),  the  dissociation 
curve  will  be  found  to  change  so  as  to  resemble  that  of  blood  (Fig.  139). 
Since  the  plasmas  of  different  animals  contain  different  proportions  of 
salts,  the  artificial  plasma  required  to  secure  the  result  is  not  always  the 
same.  It  differs,  for  example,  for  the  dog  and  man.  Potassium  salts 
are  particularly  efficient  in  causing  hemoglobin  to  absorb  02.  The  in- 
fluence of  varying  hydrogen-ion  concentrations  of  the  solution  may 
be  conveniently  studied  by  adding  varying  percentages  of  C02  to  the 
gas  mixture  in  the  tonometers,  when  it  will  be  found  that  the  curve  be- 
comes lowered  in  proportion  to  the  amount  of  C02  present.  This  is  shown 
in  Fig.  140. 


RESPIRATION    BEYOND    THE   LUNGS 


399 


The  effect  of  temperature  on  the  dissociation  curve  is  twofold:  (1)  on 
the  rate  with  which  equilibrium  is  established  at  the  given  partial  pres- 
sure of  02,  and  (2)  on  the  position  of  the  curve;  the  lower  the  tempera- 
ture, the  higher  the  curve. 

The  Rate  of  Dissociation. — Though  it  is  now  clear  that  the  three  con- 
ditions— namely,  saline  content,  CH,  and  temperature — are  capable  of 
altering  the  dissociation  curve  of  a  pure  hemoglobin  solution  so  as  to 
make  it  correspond  with  that  of  blood,  this  does  not  entirely  solve  our 
problem,  for  we  have  yet  to  show  how  the  cooperation  of  these  forces 
renders  it  possible  for  the  rate  at  which  hemoglobin  takes  up  02  in 
the  lungs  to  correspond  exactly  with  that  at  which  it  gives  up  its  02 


70      80       90      100 


Fig.  140. — Dissociation  curves  of  human  blood,  exposed  to  0,  3,  20,  40  and  90  mm.  CO2.     Ordinate, 
percentage  saturation.     Abscissa,   oxygen   pressure.      (From   Joseph    Barcroft.) 

to  the  tissues.  To  study  this  problem  a  somewhat  different  kind  of 
experiment  must  be  undertaken.  The  hemoglobin  solution  is  placed  in 
a  tube  and  the  gas  mixture  slowly  bubbled  through  it,  samples  of  the 
solution  being  removed  at  intervals  for  analysis  in  the  differential  blood- 
gas  apparatus.  To  obtain  the  rate  of  oxidation,  a  mixture  of  N2  or  H2 
and  02  is  bubbled  through  the  blood  with  the  partial  pressure  of  the 
02  the  same  as  that  which  obtains  in  alveolar  air — namely,  about  95-100 
mm.  Hg;  and  to  obtain  the  rate  of  reduction  pure  N2  or  H2  gas  is  bub- 
bled through. 

The  rates  of  reduction  or  of  oxidation  as  thus  determined  are  then 
plotted  in  curves  constructed  with  the  percentage  saturation  of  the 
hemoglobin  on  the  ordinates  and  the  time  in  minutes  along  the  abscissae 
(Fig.  141).  Even  if  we  use  blood  in  this  experiment  and  therefore  make 


400 


THE   RESPIRATION 


certain  that  the  hemoglobin  is  acting  in  -the  presence  of  the  proper  pro- 
portion of  salts,  we  shall  find,  as  curve  A  shows,  that  at  room  temperature 
the  rate  of  oxidation  is  very  much  greater  than  the  rate  of  reduction. 
on  30  40  so 6Q TO go so TOO  Oxidation 


17-5°  C.  no  C09 


Reduction 


Oxidation 


37-5°  C.  no  C02 


Reduction 


80 
60 
40 
20 
0 

\" 

-^ 

Oxidation 

37-5°  C. 

+  40  mm.  pressure 
of  C02 

Reduction 

\ 

1 

\  / 

V 

C 

A 

/ 

\ 

/ 

\ 

/ 

\ 

/ 

^  —  < 

Fig.    141. — Curves   showing   relative   rates   of   oxidation    and   reduction   of  blood   as   influenced   by 
temperature  and  tension  of  CO2. 
Ordinates — Percentage  saturation. 
Abscissae. — Time    in    minutes. 
Reducing  gas,  hydrogen. 
Oxidizing  gas,  oxygen. 

A,  temperature    17.5°    C.,   with   no   CO2. 

B,  temperature   37.5°    C.,   with   no   CO2. 

C,  temperature   37.5°    C.,   but   the   O2   and   H    contained   40   mm.      Hg  pressure  of  CO2.      (From 
Joseph  Barcroft.) 

If  now  we  repeat  the  observation  at  a  temperature  of  37°  C.,  the  two 
curves  come  more  nearly  to  correspond,  but  still  the  rate  of  reduction  is 
slower  than  that  of  oxidation.  If  in  a  third  experiment,  besides  having 
proper  temperature  and  chemical  conditions,  we  produce  the  oxidation 


RESPIRATION    BEYOND    THE   LUNGS  401 

and  reduction  in  the  presence  of  a  partial  pressure  of  C02  of  40  mm., 
which  corresponds  to  that  of  the  arterial  blood,  we  shall  find  that  oxida- 
tion becomes  a  little  slower,  whereas  reduction  is  further  quickened. 
Indeed  the  two  curves,  as  seen  in  C  in  the  figure,  come  practically  to 
correspond,  indicating  that  the  environmental  conditions  under  which 
hemoglobin  combines  and  gives  off  02  in  the  blood  are  exactly  adjusted. 

One  word  more  with  regard  to  the  influence  of  CH.  Its  effect  in  flat- 
tening out  the  curve,  especially  at  the  lower  partial  pressures  of  02, 
indicates  that  when  a  high  CH  is  present,  the  blood  will  very  readily  part 
with  its  02  supply.  Now,  the  most  significant  application  of  this  fact 
is  that  high  concentrations  of  H  ion  will  occur  just  exactly  where  it 
will  be  of  benefit — namely,  in  the  capillaries  (because  of  the  C02  and 
lactic  acid  produced  by  the  tissues).  Some  doubt  has,  however,  recently 
been  thrown  on  the  importance  of  this  factor. 

Since,  as  we  have  seen,  hemoglobin  absorbs  02  according  to  chemical 
laws,  it  will  naturally  be  asked  not  only  why  the  dissociation  curve  flat- 
tens out  while  yet  maintaining  the  shape  of  a  right-angled  hyperbola, 
as  by  the  action  of  acids  or  an  increase  in  temperature,  but  also  why  it 
should  change  its  shape  when  salts  are  also  present.  The  explanation 
offered  by  Barcroft  and  his  pupils  is  that  the  changes  depend  on  the  fact 
that  since  hemoglobin  is  a  colloidal  substance,  its  molecules  undergo 
processes  of  aggregation  under  the  conditions  referred  to  above,  and 
therefore  cause  the  reaction  to  become  of  a  different  type  from  that 
represented  by  the  equation  Hb02  ^  Hb  +  02.  As  has  been  pointed  out 
by  Bayliss,  although  such  a  process  might  suffice  to  explain  the 
flattening  out  of  the  curve,  it  fails  to  explain  the  change  in  its  shape; 
for,  according  to  the  laws  of  mass  action,  such  a  change  could  occur 
only  if  molecules  of  a  different  type  came  to  take  part  in  the  reaction. 

Dissociation  Constant. — Notwithstanding  these  criticisms,  it  is  of  con- 
siderable practical  importance  to  know  that  an  equation  exists  from 
which  the  entire  dissociation  curve  can  be  plotted  by  making  only  one 
determination  of  the  relative  amounts  of  oxy-  and  reduced  hemoglobin 
at  a  particular  tension  or  partial  pressure  of  oxygen.  This  equation  is  as 

y  Kxn 

follows:  -JOQ-  =  -= —      n  ,  where  y  equals  the  percentage  saturation  of 

hemoglobin  with  02,  +  the  02  tension,  and  K  and  n  are  constants,  K 
being  the  equilibrium  constant  and  n  the  average  number  of  molecules 
of  hemoglobin  supposed  to  exist  in  each  aggregate. 

When  this  equation  is  applied  to  human  blood,  the  value  of  n  remains 
unchanged  and  is  given  as  2.5,  so  that  by  transposition  we  are  enabled 

to  find  the  value  of  K  as  follows:  K  = — -r^ .    If  we  find  the  value 

xn(100-y) 


402  THE   RESPIRATION 

of  K  by  measuring  the  relative  saturation  of  the  blood  with  02  at  one  pres- 
sure of  this  gas,  then  by  changing  the  value  of  x  to  correspond  to  other 
02  pressures,  we  can  find  all  positions  of  the  curve  for  a  given  sample  of 
blood. 

An  important  practical  application  of  this  method  is  found  in  the 
determination  of  the  (7H  of  blood,  for,  as  we  have  seen,  the  dissociation 
curve  becomes  lowered  in  proportion  to  the  concentration  of  hydrogen 
ions.  The  acidity  of  a  sample  of  blood  can  therefore  be  found  by  com- 
parison of  its  dissociation  curve,  as  plotted  from  the  values  found  for 
K,  with  that  of  normal  blood  to  which  known  quantities  of  acid  have 
been  added.  When  the  curves  correspond,  the  bloods  must  contain  the 
same  amounts  of  acid,  other  things  being  equal.  In  brief,  then,  the  re- 
action of  the  Uood  is  proportional  to  the  value  of  K.  When  this  is  low, 
it  indicates  that  the  blood  is  taking  up  an  abnormally  low  percentage 
of  its  possible  load  of  02  at  a  given  pressure  of  02,  and  that  the  acidity 
is  greater  than  normal ;  when  K  is  high,  for  the  same  reason  the  acidity 
must  be  low. 

In  determining  K  for  the  blood  as  it  exists  in  the  body,  it  is  necessary 
that  it  should  be  subjected  to  the  same  tension  of  C02  as  obtains  in  the 
blood  vessels.  K  will  then  be  proportional  to  the  CH  of  the  living  blood. 
This  condition  would  be  impossible  to  fulfil  in  drawn  samples  were  it 
not  for  the  fact  that  we  can  place  in  the  tonometer  an  atmosphere  con- 
taining the  same  partial  pressure  of  C02  as  is  found  in  the  alveolar  air. 
Since  this  value  varies  in  different  individuals,  it  must  be  separately 
ascertained  in  each  case  (see  page  361).  As  determined  with  these 
modifications,  K  has  been  found  to  vary  in  healthy  men  between 
0.000212  and  0.000363  (ten  individuals).  When  acid  substances  appear 
in  the  blood,  as  in  acidosis,  K  becomes  extremely  low;  thus,  in  one  case 
suffering  from  acidosis  with  dyspnea,  it  was  found  a  few  hours  before 
death  to  be  only  from  0.000082  to  0.00011.  It  is  said  to  be  raised  after 
taking  food  that  is  rich  in  alkali.* 


*When  K  is  found  to  be  normal,  the  blood  is  said  to  be  meseotic;  where    K  is  low,  it  is  said  to 
be  myonectic;  and  when  K  is  high  and  the  acidity  is  therefore  small,  it  is  said  to  be  pleonectic. 


CHAPTER  XLV 
RESPIRATION  BEYOND  THE  LUNGS— Cont'd 

THE  MEANS  BY  WHICH  THE  BLOOD  CARRIES  THE  GASES 

In  the  foregoing  account  of  the  physiology  of  the  blood  gases,  empha- 
sis is  placed  on  the  tension  under  which  the  gases  exist  rather  than  on 
the  total  amount  of  each  gas  present  in  the  blood.  This  has  been  done 
because  the  exchange  of  gases  between  alveolar  air  and  blood  and  be- 
tween blood  and  tissues  proceeds  according  to  the  laws  of  gas  diffusion, 
which  are  of  course  dependent  upon  differences  in  gas  pressure  or 
tension. 

Something  must  now  be  said  regarding  the  amount  of  the  gases.  This 
may  be  measured  either  by  physical  or  by  chemical  methods.  In  the 
former,  a  measured  quantity  of  blood  is  received  into  an  evacuated  glass 
vessel,  which  is  then  attached  to  a  mercury  pump,  by  which  the  gases 
are  sucked  out  of  the  blood  and  transferred,  by  suitable  manipulations 
of  stopcocks,  to  a  graduated  tube,  in  which  they  are  then  analyzed  by 
chemical  means.  The  principle  of  the  chemical  method  has  already  been 
described  in  connection  with  the  measurement  of  oxygen  in  hemoglobin 
solutions  (see  page  393).  A  measured  quantity  of  blood,  kept  free  from 
contact  with  the  air,  is  transferred  under  some  weak  ammonia  solution 
to  one  of  the  blood-gas  bottles  of  the  blood-gas  differential  manometer, 
and  a  few  drops  of  a  saturated  solution  of  potassium  ferricyanide  are 
placed  in  the  pocket  of  the  bottle.  After  the  blood  has  been  laked  and 
temperature  conditions  adjusted,  the  ferricyanide  is  mixed  with  the 
blood  solution,  thus  causing  the  02  to  be  quantitatively  displaced.  From 
the  increased  pressure  produced  in  the  manometer  the  amount  of  02  can 
readily  be  computed.  To  determine  the  C02  of  the  blood,  the  bottle  is 
now  removed  from  the  manometer  and  a  few  drops  of  a  saturated  solu- 
tion of  tartaric  acid  placed  in  the  pocket.  When  this  is  mixed  with  the 
deoxygenated  blood  mixture,  after  the  usual  adjustment  for  tempera- 
ture, the  pressure  caused  by  the  evolved  C02  is  recorded  and  the  amount 
present  calculated. 

The  results  of  the  analysis  are  expressed  as  the  number  of  cubic  centi- 
meters of  gas  present  in  100  c.c.  of  blood — the  volume  percentage,  as  it 
is  called.  The  following  are  approximate  percentage  values: 

403 


404  THE   RESPIRATION 

OXYGEN  CARBON   DIOXIDE  TOTAL  GAS 

Venous  blood  12  48  60 

Arterial   blood  20  40  60 

The  estimation  of  the  amounts  of  the  gases,  although  of  little  value 
in  connection  with  the  physiology  of  gas  exchange,  is  very  important  in 
supplying  information  regarding  the  respiratory  activities  of  the  various 
organs  and  tissues.  Just  as  we  determine  the  total  respiratory  exchange 
of  an  animal  by  measuring  the  differences  in  02  and  C02  in  inspired  and 
expired  air,  so  may  we  determine  the  local  respiratory  exchange  of  the 
tissues  by  analysis  of  the  gasses  in  blood  removed  from  the  artery  and 
vein  of  the  tissue.  It  should  be  clearly  understood,  however,  that  it  is 
not  the  percentage  but  the  total  amount  of  the  gases  that  must  be  con- 
sidered, and  that  it  is  therefore  necessary  to  know  the  volumes  of  blood- 
flow  as  well  as  the  percentage  of  the  gases.  Something  will  be  said  later 
of  the  results  of  such  investigations  (see  page  408). 

At  present  we  are  concerned  with  the  manner  in  which  the  gases  are 
carried  in  the  blood.  The  02,  as  we  have  seen  is  carried  by  the  hemo- 
globin, some  being  also  in  a  state  of  simple  solution  in  the  plasma.  The 
C02,  to  which  we  must  now  pay  attention  and  which  it  will  be  noted 
is  present  even  in  arterial  blood  in  considerably  greater  amount  than 
the  02,  is  carried  by  various  agencies,  the  relative  importance  of  each 
of  which  is  not  as  yet  clearly  understood.  A  most  important  feature 
of  the  mechanism  is  that  there  is  a  considerable  degree  of  interdependence 
between  the  carrying  agencies  for  C02  and  02,  an  increase  in  the  one 
causing  a  decrease  of  the  other.  By  comparison  of  the  dissociation  curve 
of  blood  for  oxygen  at  varying  pressures  of  C02  we  have  already  studied 
this  relationship  in  so  far  as  C02  influences  the  02-carrying  power  of 
blood.  By  adopting  the  same  method  but  in  the  reverse  way  we  may 
also  investigate  the  influence  of  varying  tensions  of  02  on  the  C02  carry- 
ing power. 

The  C02-Dissociation  Curve  of  Blood. — This  is  constructed  by  expos- 
ing defibrinated  blood  in  a  flask  at  body  temperature  to  atmospheres 
containing  known  percentages  of  C02  and  then  removing  samples  and 
analyzing  them  for  C02  in  Barcroft's  or  Van  Slyke's  apparatus.  The 
results  are  plotted  as  shown  in  Fig.  142  by  placing  the  tensions  (calculated 
from  the  percentages)  of  C02  in  mm.  Hg  on  the  abscissae  and  the  vol- 
umes per  cent  of  C02  absorbed  on  the  ordinates.  When  the  atmosphere 
with  which  the  C02  is  mixed  is  a  neutral  gas  such  as  hydrogen,  the  upper 
curve  (B)  is  obtained;  when  the  atmosphere  is  air,  the  lower  curve  (A). 
Clearly,  reduced  blood  can  carry  considerably  more  C02  at  all  pressures 
of  this  gas,  than  oxygenated  blood.  Disregarding  for  the  moment  the 
agency  by  which  the  C02  is  carried,  it  is  important  to  note  that  the 


RESPIRATION    BEYOND    THE    LUNGS 


405 


height  of  the  curve  at  any  given  tension  of  C02  varies  somewhat  for 
different  individuals,  but  not  in  proportion  to  the  tension  of  C02  in  the 
alveolar  air ;  that  is,  a  person  with  a  low  C02-dissociation  curve  may  have 
a  high  alveolar  C02-tension  and  vice  versa.  On  the  other  hand  in  a  given 
individual  if  the  one  of  these  be  lowered  by  some  physiological  condition, 
the  other  will  become  altered  in  the  same  direction.  Thus  in  muscular 
exercise  the  C02-dissociation  curve  and  the  alveolar  tension  of  C02  both 
decline. 

It  can  be  shown  that  it  is  the  degree  of  reduction  of  hemoglobin  which 
is  responsible  for  the  alteration  in  C02-carrying  power.     Thus,  the  dis- 


50 


yfr 


30         40 


50 


60         70 
vrv     rtvm. 


80 


90 


Fig.   142. — Curve  of  CO2  tension  in  blood.     For  description,  see  text.      (From   Christiansen,   Doug- 
las and  Haldane.) 

sociation  curve  is  the  same  whether  pure  oxygen  or  air  is  used  as  the 
diluting  gas.  Did  02  per  se  have  an  influence  these  results  should  be 
different.  Another  indication  that  it  is  the  amount  of  reduced  hemoglobin 
that  is  the  determining  factor  is  that  the  curve  is  the  same  in  the  presence 
of  coal  gas  as  in  that  of  oxygen. 

When  we  were  considering  the  unloading  of  02  from  the  blood  in  the 
tissues  we  saw  that  the  local  increase  in  C02-tension  must  encourage  it 
because  of  depression  of  the  dissociation  curve  for  02  (page  399).  Of  much 
greater  physiological  importance,  however,  is  the  opposite  relationship  be- 
tween the  unloading  of  C02  from  the  blood  in  the  lungs  and  the  increase 
in  oxyhemoglobin  due  to  the  oxygen  taken  up  from  the  alveoli.  This  will 


406  THE    RESPIRATION 

be  evident  by  studying  the  curves  in  Fig.  142  more  minutely.  Let  us 
suppose  that  all  of  the  18.1  volumes  per  cent  of  02  in  arterial  blood  be- 
comes used  up  in  the  tissues.  With  the  respiratory  quotient  of  0.8  (page 
582)  this  will  mean  that  15  c.c.  of  C02  are  carried  away  from  the  tissues  in 
every  100  c.c.  of  blood.  If  the  blood  when  it  gained  the  lungs  remained 
completely  unoxygenated  it  will  be  seen  by  examination  of  curve  B 
that  to  discharge  this  15  c.c.  C02,  the  C02-tension  would  have  to  fall 
through  40  mm.  e.g.,  from  80  mm.  to  40  mm.,  or  in  other  words,  the  al- 
veolar C02-tension  would  rise  to  this  extent.  But  we  know  by  actual 
measurement  of  alveolar  tension  that  no  such  change  occurs.  The  ex- 
planation is  that  the  absorbed  02  forms  oxyhemoglobin  so  that  to  find 
the  pressure  difference  necessary  to  drive  out  the  002  we  must  shift  to 
curve  A,  when  we  find  that  22  mm.  Hg.  difference  in  tension  is  sufficient 
to  expel  the  15  c.c.  of  C02,  as  is  shown  in  the  curve  by  the  straight  line 
joining  A  and  B.  Now  we  know  that  blood  only  yields  up  about  one- 
third  of  its  oxygen  during  a  circuit  of  the  circulation;  therefore,  since 
only  5  c.c.  of  C02  will  be  added  to  every  100  c.c.  of  blood,  the  necessary 
difference  in  tension  in  the  alveoli  will  require  to  be  only  a  little  over 

7  mm.  Hg.,  a  difference  which  is  not  far  removed  from  that  actually 
observed.    Even  when  the  pressure  of  C02  in  the  venous  blood  entering 
the  lungs  is  the  same,  or  indeed  even  somewhat  less  than  that  in  the 
alveolar  air,  some  of  the  C02  will  be  discharged  because  of  the  arterial- 
ization  of  the  blood.     In  normal  human  blood  equilibrated  with  C02  at 
a  partial  pressure  of  40  mm.  at  38°  C.  the  total  C02  varies  between  43 
and  55  vols.  per  cent  for  whole  blood  (Peters  and  Barr)85  and  it  is  about 

8  vols.  per  cent  higher  for  plasma  (Joffe  and  Poulton).86 

How  the  C02  is  Carried  in  the  Blood. — Most  of  the  carbon  dioxide 
is  carried  in  combination  with  alkali  which  is  set  free  for  this  purpose 
from  hemoglobin.  The  latter  is  therefore  a  carrier  of  C02  in  the  sense 
that  it  furnishes  the  necessary  alkali.  It  does  this  in  virtue  of  being 
a  weak  acid.  This  acidity  is  however  decidedly  greater  for  HbO  than 
for  Hb  so  that  as  02  leaves  the  blood  in  the  tissue  capillaries  and  HbO 
is  changed  into  Hb,  alkali  that  was  previously  in  combination  is  set  free 
and  can  combine  with  C02.  This  is  the  explanation  of  the  curve  in  Fig. 
142.  Even  although  no  reduction  of  HbO  to  Hb  should  occur,  an  in- 
creased tension  of  C02  in  the  blood  would  also  cause  some  alkali  to  be 
split  off  from  HbO  as  well  as  some  from  phosphates.  The  H2C03  fixed 
in  these  ways  must  pass  through  the  envelopes  of  the  corpuscles.  But, 
it  may  be  asked,  how  does  this  explain  fixation  of  C02  by  the  plasma 
alone?  This  occurs  because  the  hemoglobin  increases  the  alkali  of  the 
plasma  by  withdrawing  Cl  into  the  corpuscles  from  the  Nad  of  the 
plasma,  thereby  leaving  the  Na  to  form  NaHC03.  The  Cl  like  the 
H2C03  unites  in  the  corpuscles  with  the  alkali  set  free  from  Hb  and  HbO 
and  by  interchange  with  phosphates.  In  other  words,  when  the  tension 


RESPIRATION    BEYOND    THE   LUNGS  407 

of  C02  rises  in  the  plasma  both  H2C03  and  HC1  migrate  into  the  cor- 
puscles, leaving  less  H2C03  and  more  Na  in  the  plasma  and  tending 

TT    QQ 

therefore  to  hold  the  ratio  L?  at  its  normal  level  so  tnat  PH 
changes  only  to  a  slight  degree  (from  PH  7.35  in  arterial  blood  to  PH 
7.33  in  venous  blood).  Plasma  separated  from  corpuscles  is  therefore  a 
much  less  efficient  buffer  than  whole  blood.  If  the  blood  be  first  of  all 
equilibrated  with  varying  tensions  of  C02  and  the  plasma  then  sepa- 
rated, it  will  within  certain  limits  give  the  same  PH  as  blood  itself. 

To  go  into  the  various  experiments  upon  which  these  conclusions 
depend  would  take  us  far  beyond  the  limits  of  this  volume.  Excellent 
accounts  of  these  experiments  have  recently  been  given  by  D.  D.  Van 
Slyke81  and  C.  L.  Evans.82  In  a  general  way  it  may  be  said  that  the 
experiments  consist  in  determining  the  amounts  of  C02  taken  up  by 
exposing  blood  or  plasma  at  varying  partial  pressures  of  C02  in  a  tonom- 
eter as  shown  in  Fig.  134.  From  the  laws  of  solution  of  gases  and  the 
coefficient  of  solubility  of  C02  in  blood  (page  353)  it  is  then  possible  to 
calculate  by  the  formula  given  on  page  49  what  the  PH  must  be  at  vary- 
ing tensions  of  C02.  Haggard  and  Y.  Henderson83  have  contributed 
many  important  results  by  these  methods. 

Alterations  in  C02-Content  of  the  Blood  Plasma  in  Certain  Respiratory 
and  Circulatory  Diseases. — There  is  a  difference  of  three  to  eight  volumes 
per  cent  in  the  CO2-content  of  the  plasma  of  arterial  and  venous  blood  in 
man  during  complete  muscular  rest.  After  exercise,  such  as  walking, 
the  difference  becomes  much  greater  (12  to  15  per  cent).  The  average 
for  arterial  plasma  is  56  volumes  per  cent,  the  deviations  from  the  aver- 
age being  about  -  5  (R.  W.  Scott75). 

In  chronic  cardiac  disease  (rheumatic  myocarditis  and  valvulitis),  with- 
out vascular  or  renal  complication,  the  carbonate  of  the  plasma  of  both 
arterial  and  venous  blood  (taken  while  the  patient  is  at  rest)  is  very  de- 
cidedly below  the  normal,  the  arterial  C02  being  also  much  more  variable 
than  usual,  and  the  discrepancy  between  venous  and  arterial  bloods  more 
marked.  The  lowest  values  were  found  by  R.  W.  Scott  to  occur  in  cases 
in  which  dyspnea  was  a  marked  symptom,  which  indicates  that  the  cause 
for  the  low  C02  value  must  be  increased  alveolar  ventilation  due  to  excite- 
ment of  the  respiratory  center  by  inadequate  oxygenation  of  the  blood 
(anoxemia).  When  the  condition  is  treated  by  rest  in  bed  and  the  circula- 
tion becomes  restored  to  normal,  the  C02-content  of  the  arterial  blood  re- 
turns towards  the  normal. 

In  cases  of  chronic  pulmonary  emphysema  without  circulatory  or  renal 
complications  the  C02-content  of  arterial  and  of  venous  blood  plasma  is 
markedly  raised  (values  such  as  80.2  for  arterial  plasma  and  88.4  for 
venous  having  been  obtained).  These  patients  show  another  remark- 
able peculiarity,  namely  a  great  tolerance  towards  C02  in  the  inspired 


408 


THE    RESPIRATION 


air:  thus,  in  one  case,  inspiration  of  air  containing  11.4  per  cent  C02  only 
served  to  increase  the  minute  volume  of  air  breathed  from  10  to  14  liters, 
with  mild  symptoms  of  dizziness  and  nausea  (R.  W.  Scott).  In  a  normal 
person  a  much  lower  percentage  of  C02  would  increase  the  pulmonary 
ventilation  several  times  over  the  normal  and  the  symptoms  would  soon 
become  intolerable.  The  most  probable  explanation  for  the  existence 
of  these  conditions  is  that  the  interference  with  the  pulmonary  func- 
tion has  prevented  proper  removal  of  free  C02  from  the  blood,  to  com- 
bine with  which  the  alkali  has  increased  probably  by  diminution  in  its 
excretion  by  the  kidney.  The  increase  in  alkali  raises  the  buffer  action 
of  the  blood  for  C02.  Oxygenation  of  the  blood  is  also  interfered  with, 
causing  cyanosis. 

THE  OXYGEN  REQUIREMENT  OF  THE  TISSUES 

In  order  to  ascertain  the  average  02  requirement  of  the  different  tis- 
sues of  the  body,  it  is  necessary  to  adopt  as  a  standard  of  measurement 
the  amount  of  02  in  c.c.  absorbed  per  gram  of  tissue  per  minute.  To  ob- 
tain it  we  must  know:  (1)  the  weight  of  the  particular  organ  or  tissue 
under  investigation;  (2)  the  bloodflow  through  the  vessels  of  the  organ 
in  c.c.  per  minute;  and  (3)  the  different  percentages  of  02  in  the  arterial 
and  venous  blood  of  the  tissue.  It  would  be  beyond  the  scope  of  this 
book  to  review  in  any  detail  the  many  experimental  investigations  which 
have  been  undertaken  in  this  connection.  A  few  of  the  most  recent 
and  important  results  are  given  in  the  accompanying  table  from  Halli- 
burton's  Physiology: 


OEGAN 

CONDITION    OF    REST 

OXYGEN  USED 
PER    MINUTE 
PER  GRAM 
OF  ORGAN 

CONDITION  OF  ACTIVITY 

OXYGEN 
USED    PER 
MINUTE 
PER    GRAM 
OF    ORGAN 

Voluntary 

Nerves  cut.    Tone 

0.003   C.C. 

Tone  existing  in  rest 

0.006   C.C. 

muscle 

absent 

Gentle  contraction 

0.020  c.c. 

Active  contraction 

0.080  c.c. 

Unstriped 

Resting 

0.004  c.c. 

Contracting 

0.007  c.c. 

muscle 

Heart 

Very  slow  and 

0.007  c.c. 

Normal  contractions 

0.05  c.c. 

feeble  contractions 

• 

Very  active 

0.08  c.c. 

Submaxillary 

Nerves  cut 

0.03  c.c. 

Chorda  stimulations 

0.10  c.c. 

gland 

Pancreas 

Not  secreting 

0.03  c.c. 

Secretion  after  injec- 

0.10 c.c 

tion  of  secretin 

Kidney 

Scanty  secretion 

0.03  c.c. 

After  injection  of 

0.10  c.c. 

diuretic 

Intestines 

Not  absorbing 

0.02  c.c. 

Absorbing  peptone 

0.03  c.c. 

Liver 

In  fasting  animal 

0.01  to 

In  fed  animals 

0.03    to 

0.02  c.c. 

0.05  c.c. 

Suprarenal 

Normal 

0.045  c.c. 

gland 

RESPIRATION    BEYOND    THE    LUNGS  409 

In  the  order  of  their  oxygen  requirements,  or  the  coefficient  of  oxida- 
tion, as  it  is  called,  the  tissues  may  be  divided  into  four  groups ;  glandular, 
muscular,  connective,  and  nervous.  The  nervous  tissues  should  possibly 
stand  above  the  connective,  but  very  little  is  known  regarding  their 
oxygen  consumption,  although  it  appears  that  this  is  quite  low  (Hill  and 
Nabarro).  It  is  of  course  necessary  in  making  these  comparisons  to 
secure  the  coefficient  of  oxidation  both  when  the  tissue  is  at  rest  and 
when  it  is  thrown  into  varying  degrees  of  activity.  Special  attention 
has  been  devoted  to  the  requirements  of  skeletal  muscle,  heart  muscle 
and  the  salivary  glands. 

Skeletal  Muscle. — It  will  be  seen  from  the  table  that  a  resting  muscle 
while  still  connected  with  the  nervous  system  consumes  about  0.006  c.c. 
02  per  gram  per  minute;  a  small  amount  when  compared  with  other 
tissues.  The  consumption  increases  by  from  ten  to  fifteen  times  during 
muscular  exercise.  This  increase  depends  partly  on  increased  blood 
flow. 

As  a  type  of  the  experimental  method  by  which  these  values  are  ob- 
tained and  to  show  for  what  purpose  the  muscle  requires  the  extra  oxy- 
gen when  it  contracts  it  will  be  of  interest  to  consider  the  observations 
of  Verzar47.  This  worker  isolated  the  gastrocnemius  muscle  of  the  cat, 
and  without  disturbing  its  blood  supply  collected  samples  of  blood  by 
introducing  a  1  c.c.  pipette  into  a  branch  of  the  saphenous  vein.  Activ- 
ity was  induced  by  throwing  the  muscle  into  brief  tetanus  by  the  ap- 
plication of  an  electrical  stimulus  to  the  sciatic  nerve.  During  its  con- 
traction the  muscle  lifted  a  weight,  so  that  it  did  about  70  gram-centi- 
meters of  work  at  the  beginning  of  each  period  of  tetanus.  The  velocity 
of  bloodflow  was  determined  by  the  rate  at  which  the  blood  flowed  along 
the  pipette,  and  the  02-consumption,  by  the  difference  in  percentage  of 
02  in  the  venous  and  the  arterial  blood.  These  measurements  were  made: 
(1)  before  contraction,  (2)  during  contraction,  and  (3)  after  contraction. 
It  was  found  that  although  the  02  consumption  was  usually  somewhat 
greater  during  the  tetanus  than  during  rest,  the  most  outstanding  and 
significant  result  was  that  a,  great  increase  occurred  immediately  fol- 
lowing the  tetanus — that  is,  the  call  for  02  continues  for  some  time  after 
the  actual  work  has  been  performed.  This  result  shows  that  the  con- 
traction is  not  dependent  upon  oxidation,  but  that  the  oxidation  occurs 
mainly  after  the  contraction  is  over.  The  mechanism  involved  in  mus- 
cular contraction  can  not  therefore  be  analogous  with  that  by  which 
energy  is  liberated  in  a  steam  engine  by  the  oxidation  of  the  fuel. 

Interesting  results  corroborative  of  these  conclusions  have  been  se- 
cured by  observations  on  the  heat  production  of  isolated  muscles.  It 
was  found  that  heat  production  occurred  after  a  single  shock  to  the 


410  THE   RESPIRATION 

muscles,  not  only  during  the  contraction,  but  for  a  considerable  period 
after  it,  provided  02  was  present.  In  the  absence  of  02  this  recovery 
was  either  greatly  delayed  or  entirely  abolished.  Such  results  favor 
the  view  that  02  is  used  largely  in  the  processes  whereby  the  muscles, 
''like  an  engine  charging  an  accumulator,  synthetize  substances  con- 
taining a  considerable  amount  of  potential  energy,  which  again,  like  the 
accumulator,  it  discharges  when  appropriate  stimuli  are  applied" — (L. 
V.  Hill48).  One  immediately  thinks  of  lactic  acid  in  connection 
with  these  interesting  results,  for,  as  has  already  been  stated,  Hopkins 
and  Fletcher29  have  shown  that  this  acid  is  produced  in  the  absence  of 
02  in  excised  frog  muscles,  but  when  02  is  present,  it  is  either  not  pro- 
duced or,  if  so,  quickly  disappears. 

These  important  results  lead  to  the  further  question  as  to  whether 
the  increase  in  blood  flow  accompanying  activity  is  in  itself  sufficient  to 
account  for  the  increased  uptake  of  oxygen.  This  question  is  answered 
by  finding  whether  the  increase  in  total  oxygen  consumption  during  mus- 
cular exercise  (in  man)  is  proportional  to  the  increase  in  bloodflow  which 
can  be  determined  by  measurement  of  the  output  of  the  heart  (page 
216).  Krogh44  calls  the  ratio  between  the  two  the  coefficient  of  utilization, 
and  it  is  obtained  by  dividing  the  amount  of  oxygen  taken  up  from  one 
liter  of  blood  during  its  passage  round  the  body  by  the  oxygen  capacity 
of  the  blood  (per  liter).  The  former  value  is  ascertained  by  analysis  of 
the  respired  air  and  measurement  of  the  minute  volume  of  the  heart  (page 
218).  Thus,  suppose  270  c.c.  of  02  is  absorbed  by  the  body  in  one  minute 
and  the  minute-volume  of  the  heart  is  4.800  c.c.  (and  the  oxygen  capacity 

of  the  blood  18.5  per  cent)  then  *   0  =  56.25  and  — ^= —  =  0.3. 

4.O  loo 

The  coefficient  increases  markedly  during  exercise,  showing  that  other 
factors  besides  increased  blood  flow  come  into  play.  This  is  shown  in 
the  accompanying  tables. 

O2  CONSUMPTION      OUTPUT  OF  HEART     COEFFICIENT  OF 

C.  C.   PER  MIN.  LITERS   PER  MIN.  UTILIZATION 

1         Best                                                310                        .       5                                  0.30 
(a                                    1630                             17.05                             0.47 
_   g   jb 2089 19.65. 0.55 

The  unknown  factors  may  reside  in  the  blood  itself  or  in  the  tissues. 
In  the  former,  the  increase  in  CH  due  to  the  passage  of  acids  into  the 
blood  would  greatly  increase  the  rate  at  which  oxyhemoglobin  dissociates 
(see  Fig.  141)  this  being  further  assisted  by  the  slight  rise  in  temperature 
which  accompanies  the  contraction.  With  regard  to  the  view  that  there 
is  an  increased  avidity  of  the  tissues,  the  recent  work  of  Krogh,  referred 
to  elsewhere  (pages  252  and  414)  would  not  seem  to  lend  support. 


RESPIRATION    BEYOND    THE   LUNGS  411 

Heart  Muscle. — The  gaseous  exchange  of  the  heart  has  been  studied 
both  on  isolated  heart  preparations  and  by  examining  the  exchange 
in  the  lungs  of  a  combined  lung  and  heart  preparation.  The  most 
important  investigations  by  the  first  of  these  methods  are  those  of 
Eohde  (cf.  27).  By  altering  the  initial  pressure  it  was  found  that  the 
02  used  by  the  heart  depends  on  the  product  of  the  pulse  frequency  and 
the  maximal  increase  in  pressure  produced  by  each  cardiac  contraction; 

or,  in  the  form  of  an  equation :    ^     =  a  constant  quantity ;  where  Q  is 

the  oxygen  used,  T  the  maximal  increase  of  pressure  at  each  beat,  and  N 
the  frequency  of  the  pulse. 

It  should  be  pointed  out,  however,  that  constancy  in  the  product  of 
the  above  equation  does  not  hold  under  abnormal  conditions  of  the  heart- 
beat. For  example,  when  the  pressure  in  the  heart  is  very  high,  the 
amount  of  02  required  begins  to  go  up  out  of  proportion,  indicating  that 
the  heart  is  becoming  overtaxed — that  it  is  losing  its  efficiency.  The 
same  result  occurs  when  the  heart  is  dying,  and  when  depressing  drugs 
are  used,  such  as  chloral  hydrate,  potassium  cyanide,  veratrine,  etc. 
Some  other  drugs,  however,  such  as  epinephrine,  do  not  cause  altera- 
tion in  the  ratio,  nor  does  vagus  stimulation.  Of  course  when  the  vagus 
is  stimulated,  the  02  consumption  in  a  given  period  decreases  because 
the  heartbeats  are  slowed ;  but  the  absorption  of  02  is  not  increased  rela- 
tively to  the  slowing  of  the  heart. 

The  oxygen  consumption  of  the  heart  in  a  heart-lung  preparation  (page 
163)  has  been  investigated  particularly  by  Evans49  with  the  object  of  de- 
termining the  mechanical  efficiency'  of  the  heart.  This  involves  a  com- 
parison of  the  actual  mechanical  work  done  with  the  energy  expenditure 
calculated  on  the  basis  that  1  c.c.  02  consumed  =  2.07  kilo-grammeters 
of  work.  It  was  found  that  when  the  pulse-rate  is  constant  and  rapid 
(as  it  would  be  in  a  heart  deprived  of  nerve  control),  the  efficiency  be- 
came greater  as  the  venous  inflow  was  increased.  This  conforms  with  the 
principles  laid  down  elsewhere  concerning  the  so-called  law  of  the  heart 
(page  216).  There  is  every  reason  for  believing  that  alterations  in  pulse- 
rate  produced  through  the  nerve  control  would  also  influence  the  effi- 
ciency, that  is,  the  consumption  of  02  is  less  for  a  given  output  of  blood 
per  minute  when  maintained  by  a  slow  beat  than  by  a  fast  one.  In  the 
heart-lung  preparation  alteration  in  the  rate  by  changing  the  tempera- 
ture had  this  effect.  Under  the  most  favorable  conditions  the  mechanical 
efficiency  of  the  heart  was  found  to  be  28  per  cent,  which  is  greater  than 
that  reached  by  the  body  as  a  whole  under  the  most  favorable  conditions. 

Glands. — Most  work  has  naturally  been  done  on  the  most  accessible 
gland — the  submaxillary.  By  stimulating  the  secretory  nerve,  of  t&is 


412  THE   RESPIRATION 

gland  (the  chorda  tympani)  in  the  dog,  it  has  been  found  that,  whereas 
the  more  abundant  secretion  lasts  only  so  long  as  the  stimulus  is  ap- 
plied to  the  nerve,  the  02  consumption  is  increased  to  several  times  that 
of  rest,  and  remains  increased  for  a  considerable  period  after  the  stimulus 
has  been  removed.  Accompanying  the  increased  functional  activity 
there  is  a  very  marked  increase  in  bloodflow  due  to  vasodilatation,  which, 
in  part  at  least,  is  dependent  upon  the  secretion  into  the  blood  of  some 
substances  resulting  from  the  glandular  activities,  and  is  not  entirely 
due  to  the  action  of  vasodilator  nerve  fibers. 

Similar  results  have  been  obtained  in  the  case  of  the  pancreas  when 
excited  to  secrete  by  the  injection  of  secretin  (see  page  460).  Under 
such  conditions,  the  oxygen  consumption  has  been  observed  to  increase 
about  fourfold  and  to  be  accompanied  by  a  dilatation  of  the  gland. 

The  work  on  the  kidney  has  been  especially  interesting,  because  it 
has  been  found  that  increased  activity,  which  of  course  is  measured  by 
the  rate  of  urine  excretion,  is  not  always  accompanied  by  increased 
consumption  of  oxygen.  When  diuresis  is  caused  by  injecting  Ring- 
er's solution  into  the  circulation,  a  great  increase  in  urine  outflow  may 
occur  without  any  change  in  oxygen  consumption ;  whereas,  on  the  other 
hand,  when  a  diuretic  such  as  sodium  sulphate  or  caffeine  is  used,  the 
oxygen  consumption  increases  enormously. 

Regarding  the  other  tissues  and  organs,  the  02  consumption  of  the 
lungs  and  brain  appears  to  be  small.  It  is  a  very  significant  fact,  how- 
ever, that  the  higher  cerebral  centers  are  extremely  sensitive  to  depri- 
vation of  02. 

The  Blood. — In  the  blood  itself,  a  certain  amount  of  oxidation  goes 
on  because  of  the  presence  of  living  cells  such  as  the  blood  corpuscles. 
This  oxidation  becomes  considerable  in  the  blood  of  animals  rendered 
anemic  by  the  injection  of  phenyl  hydrazin.  A  thorough  investigation 
of  the  cause  of  this  greater  oxidation  has  shown  it  to  be  owing,  not  to 
an  increase  in  nucleated  erythrocytes,  but  to  the  presence  of  the  young 
unnucleated  red  blood  corpuscles,  which  appear  in  large  numbers  in  the 
blood  under  these  conditions.  A  similar  increase  in  blood  oxidation  oc- 
curs during  posthemorrhagic  anemia  the  rate  of  oxidation  running  paral- 
lel with  the  rate  of  regeneration  of  the  red  corpuscles. 

The  Mechanism  by  Which  the  Demands  of  the  Tissues  for 
Oxygen  Are  Met 

There  are  two  possible  methods  by  which  this  may  be  brought  about: 
(1)  by  a  change  in  the  CH  or  the  saline  constituents  or  the  temperature  of 
the  plasma,  so  that  the  hemoglobin  more  readily  delivers  up  its  load 


RESPIRATION   BEYOND   THE   LUNGS  413 

of  02;  and  (2)  by  an  increase  in  the  mass  movement  of  blood  through 
the  vessels  of  the  acting  tissue. 

Regarding  the  first  of  these  possibilities,  there  is  no  doubt  that  acids 
are  produced  during  metabolism  of  acting  tissues.  As  we  have  seen, 
when  muscles  contract  in  the  presence  of  an  abundance  of  02,  C02  is 
produced  in  large  amounts,  and  when  they  contract  in  a  deficiency  of  02, 
sarcolactic  acid.  In  the  submaxillary  gland,  too,  it  has  been  possible  to 
show  that  the  CH  of  the  venous  blood,  as  measured  by  the  value  of  K  of 
the  dissociation  curve  -of  hemoglobin,  becomes  distinctly  increased  dur- 
ing glandular  activity.  That  this  increase  in  CH  will  dislodge  02  we  have 
already  seen  (page  401). 

That  it  should  have  been  impossible  by  direct  methods  to  show  any 
change  in  CH  of  the  blood  as  a  whole  during  muscular  exercise  (cf.  page 
410)  does  not  necessarily  indicate  that  such  may  not  occur  in  the  capillary 
blood  of  the  muscles  themselves.  There  is  considerable  indirect  evi- 
dence that  CH  rises  in  the  blood  circulating  through  the  muscles.  This 
increased  acidity  will  greatly  facilitate  the  unloading  of  02  from  the 
blood;  not  so  much  because  it  depresses  the  level  of  the  dissociation 
curve  as  that  it  accelerates  the  rate  of  dissociation  (page  399).  This 
acceleration  will  be  further  encouraged  by  the  rise  in  temperature  of 
the  blood  (pages  409  and  433). 

In  connection  with  dilatation  of  the  blood  vessels  of  the  active  tis- 
sue it  is  most  important  to  bear  in  mind  that  this  may  occur  either 
in  the  arterioles  or  in  the  capillaries  or,  of  course,  in  both  together. 
Krogh42  has  conclusively  demonstrated  that  the  capillaries  of  muscles 
can  become  dilated  during  activity  quite  independently  of  dilatation 
of  their  contributory  arterioles  and  it  has  been  shown  by  Dale  and 
Richards43  that  histamine  causes  capillary  dilatation  accompanied  by 
arteriole  constriction.  The  application  of  this  discovery  in  the  patho- 
genesis  of  shock  has  already  been  referred  to  (page  307)  and  it  is  pos- 
sible that  histamine,  or  a  similar  substance,  may  be  the  cause  of  the 
capillary  dilatation  during  muscular  activity. 

But  before  such  an  hypothesis  can  be  entertained,  it  is  necessary  to 
show  that,  independently  of  nerve  impulses,  the  blood  vessels  of  an  acting 
organ  may  dilate.  The  best  evidence  has  been  secured  by  studying  the 
effects  of  stimulating  with  epinephrine  the  cervical  sympathetic  nerve  to 
the  submaxillary  gland  of  a  cat.  The  gland  cells  become  more  active, 
and  dilatation  of  the  artery  occurs,  although  on  blood  vessels  alone 
epinephrine  in  similar  dosage  produces  constriction.  Of  course  in  show- 
ing that  local  chemical  products  of  activity  serve  as  the  excitant  of  local 
dilatation,  we  do  not  mean  to  imply  that  the  vasodilator  fibers  going  to 
the  blood  vessels  are  of  no  use.  Indeed  we  know  that  such  fibers  do  be- 


414  THE  RESPIRATION 

come  active  in  the  case  of  a  salivary  gland  whose  cells  have  been  para- 
lyzed by  atropine,  but  it  is  a  significant  fact  that  this  dilatation  is  of  rela- 
tively short  duration,  whereas  that  produced  by  glandular  activity  lasts 
for  some  time.  The  suggestion  seems  therefore  not  out  of  place  that  un- 
der normal  conditions  the  initial  dilatation  of  an  acting  gland  may  be 
brought  about  through  nervous  stimuli,  but  the  later  dilatation  is  main- 
tained by  metabolic  products,  and  by  rise  in  temperature. 

It  is  probable  that  the  increased  blood  flow  acting  along  with  the 
accelerated  dissociation  of  oxyhemoglobin  is  adequate  to  account  for 
all  of  the  increased  consumption  of  oxygen  by  the  active  muscles.  The 
oxygen  simply  diffuses  into  the  muscle  fibers  from  the  blood  plasma. 
It  has  commonly  been  supposed  that  the  avidity  of  the  muscle  for  oxygen 
is  so  great  that  the  tension  within  the  fiber  immediately  falls  to  zero 
but  Krogh  has  brought  forward  evidence  to  show  that  this  is  not  neces- 
sarily the  case.  This  worker  has  shown,  by  microscopic  examination,  that 
the  capillaries  containing  blood  are  relatively  scanty  in  a  resting  muscle 
being,  however,  uniformly  distributed  around  the  fibers,  but  that  many 
additional  capillaries  become  filled  with  blood  and  make  their  appearance 
during  activity.  That  is  to  say  many  capillaries  that  are  empty  during 
rest  open  up  and  fill  with  blood  when  the  muscle  becomes  active.  He  has 
also  shown  by  mathematical  calculations  that  every  part  of  the  muscle 
fiber  must  be  readily  accessible  to  oxygen  molecules  conveyed  into  them 
purely  by  physical  processes. 


CHAPTER  XLVI 

THE   PHYSIOLOGY  OF  BREATHING  IN   RAREFIED   AND   COM- 
PRESSED AIR 

In  the  application  of  a  knowledge  of  the  physiology  of  respiration  to 
the  investigation  of  disease,  a  group  of  conditions  arises  in  which  con- 
siderable interference  with  physiological  mechanisms  occurs,  not  as  a  result 
of  disease,  but  of  changes  in  the  atmospheric  environment.  The  regula- 
tion of  the  functions  of  respiration  depends  very  largely  on  changes  in 
the  physical  and  chemical  properties  of  the  alveolar  air,  so  that  it  is  to 
be  expected  that  similar  changes  in  the  atmosphere  will  have  a  marked 
influence  on  the  respiratory  activity  and  on  the  general  well-being  of 
the  animal. 

Man  subjects  himself  to  the  influence  of  these  conditions  by  living 
at  high  altitudes  and  by  work  in  caissons  and  diving  suits.  Although  it 
has  been  necessary,  in  explaining  the  functions  of  the  respiratory  center, 
to  refer  in  previous  chapters  to  the  influence  of  deficiency  of  oxygen, 
it  is  important  that  we  pay  some  attention  to  the  subject  of  mountain 
sickness  as  a  whole,  because  of  the  more  lasting  physiological  alterations 
which  become  established  during  it.  We  will  then  consider  the  opposite 
condition  of  caisson  sickness  or  diver's  palsy. 

MOUNTAIN  SICKNESS 

This  condition  depends  primarily  on  disturbances  in  the  control  of  the 
respiratory  function,  and  it  is  on  account  of  the  useful  information  con- 
cerning the  nature  of  these  functions,  rather  than  because  of  the  so-called 
disease  itself,  that  so  much  attention  has  been  devoted  to  its  investiga- 
tion during  recent  years.  The  disturbances  produced  by  the  rarefied 
atmosphere  develop  rather  quickly,  but  after  some  time  they  gradually 
disappear,  indicating  that  the  organism  has  acclimated  itself — that  is, 
the  compensatory  mechanisms  have  come  into  play  to  bring  the  respira- 
tory control  back  to  normal.  When  animals  are  placed  in  pneumatic 
cabinets  from  which  some  of  the  air  is  pumped  out,  most  of  the  imme- 
diate symptoms  observed  in  mountain  sickness  occur,  but  it  is  usually 
impracticable  to  continue  the  observations  for  a  sufficient  length  of 
time  to  allow  the  compensating  mechanisms  to  develop. 

More  or  less  hyperpnea,  especially  on  exertion,  soon  appears  in  a 

415 


416  THE    RESPIRATION 

rarefied  atmosphere,  and  the  alveolar  C02  tension  assumes  a  value  con- 
siderably below  the  normal.  For  example,  at  sea  level  the  minute  vol- 
ume of  air  breathed  in  one  individual  was  10.4  liters,  and  the  alveolar 
C02  tension  39.6  mm.  Hg.  After  being  some  time  on  Pike's  Peak,  where 
the  barometer  registers  only  459  mm.  Hg,  Douglas26  found  the  minute 
volume  of  air  to  be  14.9  liters,  and  the  alveolar  C02  tension  27.1  mm.  Hg. 
At  first  sight  the  above  statement  may  seem  to  contradict  one  pre- 
viously made,  to  the  effect  that  the  alveolar  C02  tension  tends  to  remain 
constant  at  varying  barometric  pressures.  This  applies,  however,  to 
the  slight  variations  occurring  at  ordinary  elevations.  It  is  important 
to  consider  the  significance  of  these  changes  because  it  will  assist  us 
in  the  investigation  of  the  clinical  conditions  of  hyperpnea,  in  which 
likewise  a  diminished  C02  alveolar  tension  is  often  observed.  Mountain 
sickness  may  indeed  ~be  considered  as  an  intermediate  condition  between 
the  physiological  and  the  pathological. 

From  what  we  have  learned  we  should  expect  the  above  result  to  be 
dependent  upon  stimulation  of  the  respiratory  center  by  deficiency  of 
oxygen,  that  is  anoxemia  (page  374).  This  excitation  may  be  aggravated 
by  a  hyperexcitability  of  the  center  due  to  constant  irritation  of  the 
sensory  nerve  terminations  in  the  skin  by  a  greater  chemical  activity  of 
the  light  rays  at  high  altitudes.  The  erythema  of  the  skin  observed  at 
high  altitudes  is  cited  as  evidence  for  this  irritative  action  of  light  rays. 
A  similar  increase  in  respiratory  activity  has  been  observed  by  Lindhard63 
to  be  produced  by  light  baths.  This  author  believes  that  this  action 
of  light  is  the  main  cause  for  a  demonstrably  greater  excitability  of 
the  respiratory  center  during  summer  than  winter. 

The  increased  breathing  brings  about  a  blowing  off  of  C02  from  the 
blood  with  a  consequent  decrease  of  alveolar  C02-tension,  and  a  tend- 
ancy  to  alkalosis  (page  373)  as  a  result  of  which  the  kidney  excretes 
less  acid  and  ammonia  (page  381).  Until  this  compensation  is  fully 
effected  it  would  be  expected  that  PH  would  tend  to  be  raised  and  this 
has,  as  a  matter  of  fact,  been  demonstrated  by  the  calorimeter  method 
using  particular  care  to  see  that  the  blood  is  kept  at  a  tension  of  C(X 
equal  to  that  of  the  alveolar  air.  (Barcroft  et  al.)  Since  the  adjustment 
of  the  acid-base  equilibrium  by  means  of  alteration  in  the  acid  excretion 
by  the  kidneys  must  take  some  time  it  is  to  be  expected  that  the  alveolar 
C02  will  gradually  attain  its  new  levels  both  on  the  mountain  and  after 
returning  to  sea  level.  That  this  is  actually  the  case  is  shown  in 
Fig.  142-A. 

Thus,  on  Pike's  Peak,  where  the  barometric  pressure  is  459  mm.  Hg., 
the  C02-tension  after  an  initial  fall  took  about  seven  days  before  it  came 
to  its  permanent  level  for  that  barometric  pressure,  and  fourteen  days 
elapsed  after  descending  from  the  mountain  before  the  sea  level  tension 
had  been  regained. 


BREATHING   IN    RAREFIED    AND    COMPRESSED   AIR 


417 


The  anoxemia  acts  on  the  various  nerve  centers,  producing  symptoms 
which  vary  in  different  individuals  according  to  their  relative  susceptibili- 
ties. In  some,  the  digestive  centers  are  affected  and  nausea  and  vomiting  oc- 
cur; in  others,  the  higher  cerebral  centers  are  affected,  causing  depression 


TO 


COLORADO 
.5RR1ISLG5 


CDLOKAUO 
SPRINGS 


O7       G^      ^       00       CD 

o     o     o     o     o 


§5 


Fig.    142-A.— COa-tension   at   various   altitudes. 


The  horizontal  interrupted  lines  represent  the 
mean  normal  alveolar  CO2  and  O2  pressures  at  sea  level  (i.e.,  Oxford  and  New  Haven) ;  the  thick 
line,  alveolar  CO2  pressure;  and  the  thin  line,  alveolar  O2  pressure.  (From  Douglas,  Haldane, 
Henderson,  and  Schneider.) 

and  general  mental  apathy,  great  drowsiness,  muscular  weakness,  or  it  may 
be  mental  excitement  and  loss  of  self-control.    As  to  whether  it  is  the  anoxe- 


418  THE   RESPIRATION 

mia  itself  or  the  slight  degree  of  alkalosis  induced  by  the  lowered  C02- 
tension  that  is  the  cause  for  these  symptoms  cannot  at  present  be  said. 

The  susceptibility  of  different  individuals  also  varies  according  to  the 
amount  of  previous  experience  in  mountaineering  and  the  type  of  breath- 
ing. Much  of  the  value  of  previous  experience  and  training  depends  on 
the  ability  to  perform  muscular  effort  economically;  to  adjust  the  effort 
to  the  available  oxygen  supply  without  causing  aggravation  of  the  symp- 
toms of  anoxemia.  It  often  happens  that  no  symptoms  appear  so  long  as 
the  person  is  at  rest,  but  immediately  do  so  whenever  any  muscular 
effort  is  attempted. 

The  type  of  breathing  that  best  withstands  the  rarefied  air  is  slow  and 
deep,  rather  than  rapid  and  shallow.  The  reason  for  this  is  of  course 
that  much  more  of  the  outside  oxygen  gets  into  the  alveoli  in  the  former 
case  than  in  the  latter,  the  dead  space  being  practically  constant.  The 
following  figures  taken  from  observations  on  three  different  individuals 
will  illustrate  the  importance  of  this  factor. 


C.C.  PER 

NO.  OF  RES- 

HEIGHT IN  METERS 

RESPIRATION 

PIRATIONS 

AT  WHICH  SYMP- 

PER MINUTE 

TOMS  OCCURRED 

Subject  1 

270 

20 

3300 

"       2 

440 

14 

6000 

"        3 

700 

8 

6500 

(From  Halliburton.) 

After  living  for  some  time  in  the  rarefied  air  and  quite  independently 
of  training  in  the  efficient  performance  of  muscular  work,  adaptation 
occurs,  so  that  the  symptoms  pass  off.  The  essential  feature  of  this  adap- 
tation is  increased  absorption  of  02  into  the  blood.  For  many  years  it 
has  been  claimed  that  this  adaptation  was  due  chiefly  to  the  development 
of  a  secretory  activity  by  the  pulmonary  epithelium.  Oxygen  was 
thought  to  be  forced  into  the  blood  in  quantities  much  greater  than  would 
be  the  case  if  the  pulmonary  epithelium  acted  as  a  passive  membrane 
across  which  oxygen  moved  by  a  simple  process  of  diffusion.  As  a  result 
of  the  recent  development  of  the  method  of  arterial  puncture,  it  has  been 
shown  that  the  blood  of  men  thoroughly  acclimated  to  life  at  an  altitude 
of  14,000  feet  in  the  Andes,  when  drawn  directly  from  the  radial  artery 
without  exposure  to  air,  is  darkly  venous  in  color.  Analysis  shows  that  the 
tension  of  oxygen  in  it  is  no  greater  than  that  existing  in  the  alveolar  air, 
nor  is  the  quantity  of  oxygen  greater  than  would  be  taken  up  by  the 
blood  when  exposed  to  air  of  composition  similar  to  that  found  in  the 
alveoli  of  the  lungs.  In  view  of  these  facts  it  is  apparent  that  it  is 
unnecessary  to  assume  any  secretory  function  on  the  part  of  the  pul- 


BREATHING   IN   RAREFIED   AND    COMPRESSED    AIR  419 

monary  epithelium — the  simpler  process  of  physical  diffusion  is  sufficient 
to  account  for  the  facts. 

Three  mechanisms  are  known  to  be  responsible  for  increasing  the 
quantity  of  oxygen  in  the  blood:  (1)  increase  in  the  tension  of  oxygen 
in  the  alveolar  air;  (2)  an  increased  affinity  of  the  hemoglobin  for  oxygen; 
(3)  increase  in  the  erythrocytes  and  hemoglobin  of  the  blood. 

The  increased  alveolar  oxygen  tension  is  a  result  of  the  increase  in 
pulmonary  ventilation.  If  no  adaptation  occurred,  the  oxygen  tension 
at  10,000  feet  would  be  59  mm.  and  at  15,000  feet  33.8  mm.  Actual 
observations  on  men,  however,  gave  at  10,000  feet  a  tension  of  65  mm. 
and  at  15,000  feet  52  mm. 

The  increased  affinity  of  the  hemoglobin  for  oxygen  is  due  to  a  change 
in  the  composition  of  the  blood  the  exact  nature  of  which  is  as  yet  un- 
known. As  a  result  it  takes  up,  when  exposed  to  the  alveolar  air,  about 
5  per  cent  more  oxygen  than  would  be  the  case  in  the  absence  of  this 
compensation. 

These  compensations  are  not  sufficient  to  restore  the  blood  completely 
to  the  condition  found  at  sea  level.  They  bring  it  at  14,000  feet,  only  to 
81  or  91  per  cent  saturation  even  in  the  case  of  men  who  have  lived  for 
generations  at  this  altitude.  As  a  result  cyanosis  is  prevalent  among 
them,  and  clubbed  fingers,  such  as  may  accompany  chronic  cyanosis  in 
the  pathological  at  sea  level,  are  not  infrequent.  Yet  in  spite  of  the  per- 
sistent unsaturation  of  the  blood,  men  who  are  acclimated  to  these  alti- 
tudes can  accomplish  prolonged  and  severe  muscular  work  and  take 
pleasure  in  such  strenuous  diversions  as  dancing,  tennis  and  football. 

The  constantly  low  tension  of  02  in  the  plasma  causes  the  red  blood 
corpuscles  and  the  percentage  of  hemoglobin  to  become  markedly  in- 
creased after  residence  for  some  time  in  high  altitudes.  At  first  this  is 
due  to  a  concentration  of  the  blood  by  a  diminution  in  plasma,  but  grad- 
ually the  blood-forming  organs  become  excited  and  an  actual  increase 
in  the  total  amount  of  hemoglobin  occurs.  In  the  light  of  these  facts  it 
is  interesting  to  compare  the  average  number  of  red  corpuscles  in  the 
blood  of  inhabitants  of  different  altitudes. 


HEIGHT  ABOVE  SEA 
(METERS) 

RED  CORPUSCLES 
(PER  C.MM.  BLOOD) 

Christiania 
Zurich 
Davos 
Arosa 
Cordilleras 

0 
412 
1560 
1800 
4392 

4,970,000 
5,752,000 
6,551.000 
7,000,000 
8,000,000 

(From  Starling.) 


420  THE   RESPIRATION 

As  has  been  pointed  out  elsewhere  the  increase  in  the  percentage  of 
hemoglobin  starts  very  soon  after  the  rarefied  air  begins  to  be  breathed, 
and  in  confirmation  of  this  it  is  of  interest  to  note  that  even  at  relatively 
low  altitudes  Miss  Fitzgerald  found  that  changes  in  the  concentration 
of  blood  pigment  are  distinct.  The  purpose  of  these  changes  is  no  doubt 
that  there  may  be  a  larger  storehouse  of  oxygen  in  the  blood  from  which 
the  necessary  tension  may  be  maintained  in  the  plasma.  The  most  im- 
portant work  that  remains  to  be  done  in  mountain  sickness  is  measurement 
of  the  acid  and  ammonia  excretion  by  the  kidneys  so  as  to  see  in  how  far 
the  observations  made  in  pneumatic  cabinets  can  be  confirmed  (see  page 
381). 

COMPRESSED-AIR  SICKNESS;  CAISSON  DISEASE; 
DIVER'S  PALSY 

Divers  and  caisson  workers  are  susceptible  to  peculiar  symptoms. 
These  are  frequently  of  sufficient  severity  to  cause  death,  but  may  be  so 
mild  as  almost  to  escape  notice.  They  first  appear,  not  when  the  worker 
is  subjected  to  the  high  pressure,  but  after  he  has  come  back  to  atmos- 
pheric pressure.* 

While  in  the  compressed  air  the  worker  as  a  rule  suffers  no  discom- 
fort. A  stuffiness  may  be  felt  in  the  ears  and  temporary  giddiness ;  the 
respiration  and  pulse  rate  may  become  slow  and  frequency  of  micturition 
may  be  noticed,  but  none  of  the  symptoms  of  disease  appear  until  after 
the  caissonier  or  diver  has  been  decompressed  (after  he  has  returned  to 
atmospheric  pressure),  the  exact  time  of  their  onset  being  either  imme- 
diately after  decompression  or  at  the  end  of  several  hours.  The  worker 
may  have  returned  home  and  spent  the  evening  feeling  perfectly  well 
until  he  went  to  bed,  when  symptoms  supervened  which  may  include  mus- 
cular and  joint  pains,  vertigo,  embarrassed  breathing,  subcutaneous  em- 
physema and  hemorrhages,  pains  in  the  ears  and  deaf nessT" vomiting, 
perhaps  hemoptysis  and  epigastric  pain.  These  symptoms  usually  pass 
off  after  some  hours  but  the  arthralgia  and  myalgia  sometimes  persist 
for  a  considerable  time. 

In  the  more  severe  cases  the  first  symptom  is  severe  pain  in  the  mus- 
cles and  joints,  quickly  followed  by  motor  paralysis,  so  that  the  patient 
falls  and  is  likely  to  become  unconscious.  The  pulse  is  almost  imper- 
ceptible, the  respiration  is  labored,  sometimes  even  asphyxial,  the  face 


*A  caisson  is  a  steel  or  wooden  chamber  sunk  in  water  and  prevented  from  filling  by  ^means  of 
compressed  air.  For  the  passage  of  the  workmen  and  of  material,  into  and  out  of  the  caisson,  the 
latter  is  connected  with  a  second  smaller  chamber  fitted  with  air-locks  and  decompressing  cocks.  A 
diver  works  in  a  waterproof  suit,  the  head  being  enclosed  in  a  copper  helmet  connected  by  hose  with 
air  pumps.  Every  10  meters  or  33  feet  of  water  corresponds  to  one  atmosphere  pressure  (IS  pounds 
to  the  square  inch),  so  that  at  this  depth  the  total  air  pressure  in  a  caisson,  or  in  a  diver's  helmet, 
would  amount  to  30  pounds  to  the  square  inch,  that  is,  +  1  atmosphere. 


BREATHING   IN   RAREFIED    AND    COMPRESSED   AIR  421 

cyanosed,  and  the  surface  of  the  body  cold.  Many  of  the  cases  are  fatal  ; 
indeed,  death  may  be  almost  instantaneous.  Such  cases  are  common  in 
careless  diving  when  the  divers,  to  return  the  more  quickly,  screw  up  the 
outlet  valve  in  their  helmets  so  as  to  fill  their  suits  with  air,  which  car- 
ries them  to  the  surface,  where  they  decompress  themselves  by  opening 
the  valve. 

Autopsies  of  persons  dead  of  caisson  disease  have  shown,  as  a  rule, 
f  thp  viscera,  hemorrhages  in  the  spinal  cord  and 


brain,  and  ecchymoses  on  the  pleura  and  pericardium:  In  some  cases 
"mterlobar  emphysema  of  the  lungs  and  laceration  of  the  spinal  cord  and 
brain  have  been  noted. 

The  Cause  of  the  Symptoms 

The  cause  for  the  symptoms  is  not,  as  was  at  one  time  supposed,  that 
the  pressure  drives  the  blood  from  the  peripheral  into  the  deep  regions 
of  the  body,  including  the  nerve  centers.  Such  a  process  is  impossible, 
because  the  fluids  of  the  body  —  and  all  tissues,  even  the  bones,  are  full 
of  fluid  —  are  incompressible.  Pressure  applied  to  any  part  of  the  body 
will  be  immediately  distributed  equally  to  every  other  part.  If  this  were 
not  so,  life  would  be  impossible  during  any  variation  of  atmospheric  pres- 
sure. It  is  now  clearly  established  that  all  the  symptoms  of  caisson  disease 
are  due  to  decompression,  and  not,  in  the  slightest  degree,  to  the  mechan- 
ical effect  of  the  pressure  itself  (Paul  Bert,  Leonard  Hill  and  Macleod34). 

When  an  animal  is  under  pressure,  its  tissue  fluids  dissolve  a  large 
amount  of  gas.  They  absorb  it  in  obedience  to  the  law  of  solution  of  a 
gas  in  a  fluid,  which  states  that  the  amount  of  gas  dissolved  in  water  is 
directly  proportional  to  the  partial  pressure  of  that  gas  in  the  atmos- 
phere; at  two  atmospheric  pressures  twice  as  much  gas  will  pass  into 
solution  as  at  zero  pressure  (Dalton's  law).  So  long  as  the  gas  is  in 
simple  solution,  it  does  not  in  any  way  change  the  physical  condition  of 
the  blood  and  tissue  fluids.  If,  however,  the  animal  is  suddenly  decom- 
pressed (i.  e.,  the  pressure  of  air  surrounding  it  is  reduced  to  zero),  the 
dissolved  gas  will  be  so  quickly  thrown  out  of  solution  that  bubbles  of 
it  are  set  free.  These  bubbles  act  as  lair^emliQli,  sticking  in  the  pulmonic 
capillaries  or  blocking  up  a  terminarartery  in  the  brain;  or  they  may  be 
large  and  tear  the  capillary  wall  and  so  lead  to  hemorrhage.  If  these 
bubbles  are  produced  in  the  posterior  spinal  roots,  intense  pain  results; 
if  in  the  anterior,  motor  paralysis.  Frothing  of  the  blood  in  the  heart  im- 
pedes the  action  of  the  organ  and  death  soon  follows. 

The  following  experiments  furnish  proof  of  this  explanation:  A  frog 
was  placed  in  a  small  steel  chamber  connected  with  a  cylinder  of  com- 
pressed air  and  provided  with  two  windows  by  which  a  strong  arc  light 


422  THE   RESPIRATION 

could  be  passed  through  the  chamber.  The  web  of  the  foot  was  stretched 
on  a  wire  and  fixed  so  that  the  small  blood-vessels  could  be  seen  by  apply- 
ing a  microscope  to  the  outside  of  the  window.  After  carefully  observing 
the  circulation  of  the  blood  in  the  vessels  at  atmospheric  pressure,  a  posi- 
tive pressure,  amounting  in  some  experiments  to  +  50  atmospheres,  was 
introduced  but  no  effect  could  be  noted  on  the  circulating  blood.  By 
opening  a  tap  in  the  chamber,  decompression  to  zero  pressure  was  quickly 
effected  and,  immediately,  large  bubbles  were  seen  to  develop  in  the 
blood,  blocking  the  vessels  and  producing  stasis.  The  bubbles  were  de- 
rived from  the  gas  that  had  gone  into  solution  under  pressure.  On  re- 
applying  the  pressure  the  bubbles  of  gas  again  went  into  solution  and 
the  blood  circulated  normally.  When  the  pressure  was  subsequently  very 
gradually  lowered  to  zero,  the  circulation  went  on  undisturbed,  and  the 
frog  was  removed  from  the  chamber  in  normal  condition. 

The  process  involved  in  causing  caisson  disease  is  evidently  the  same  as 
that  which  can  be  observed  in  a  bottle  of  aerated  water;  if  the  cork  in 
such  a  bottle  is  drawn,  the  dissolved  gas  escapes  as  bubbles  and  effer- 
vescence results;  if  the  bottle  is  recorked,  the  gas  reenters  solution  and 
the  fluid  becomes  quiet.  If  a  pin  hole  is  made  in  the  cork,  the  gas  will 
gradually  escape  and  no  effervescence  will  result. 

Confirmatory  results  have  been  secured  by  observations  on  mammals. 
The  arterial  blood  pressure  of  rabbits  was  not  found  to  become  altered 
by  exposure  to  compressed  air,  and  various  animals  placed  in  a  large, 
strong  steel  chamber  at  pressures  far  in  excess  of  those  to  which  man 
ever  subjects  himself  did  not  show  any  symptoms  like  those  of  caisson 
sickness,  unless  the  pressure  was  suddenly  lowered.  Many  times  also,  if 
symptoms  had  appeared  they  could  be  removed  by  again  subjecting  the 
animals  to  the  compressed  air. 

Investigations  were  also  carried  out  to  determine  exactly  how  much 
gas  the  blood  of  an  animal  subjected  to  high  pressures  contains,  and  how 
long  it  takes  to  absorb  the  maximal  amount  of  gas  and  to  release  it.  It 
was  found  that  the  gases  that  increased  in  amount  were  nitrogen  and 
oxygen,  and  that  these  become  dissolved  in  the  blood  according  to  Dai- 
ton's  law. 

The  Prevention  of  the  Symptoms 

The  most  important  practical  application  of  these  observations  con- 
cerns the  length  of  time  required  for  the  saturation  and  desaturation  to 
occur,  for  the  results  serve  as  a  basis  upon  which  the  safe  regulation  of 
work  in  compressed  air  by  man  can  be  conducted.  The  most  significant 
outcome  of  the  above  experiments  from  this  standpoint  is  that  it  takes 
considerable  time  for  the  blood  to  absorb  its  full  quota  of  gas  at  a  given 


BREATHING   IN    RAREFIED    AND-  COMPRESSED    AIR  423 

atmospheric  pressure  and  to  liberate  it  again  when  the  animal  is  decom- 
pressed. The  cause  of  delay  is  that  the  tissue  fluids  other  than  the  blood 
take  much  longer  than  would  be  expected  to  reach  equilibrium  with  the 
partial  pressure  of  gas  in  the  blood  plasma. 

To  understand  why  this  delay  should  occur,  let  us  suppose  that  the 
only  gas  concerned  is  nitrogen.  As  the  pressure  rises,  the  blood  in  the 
capillaries  of  the  lungs  must  dissolve  nitrogen  in  proportion  to  the  pres- 
sure of  this  gas  in  the  alveoli;  the  blood  carries  the  dissolved  gas  to  the 
tissues  and  these  dissolve  it  until  the  pressure  is  again  equalized  between 
them  and  the  blood.  The  blood,  after  giving  up  its  excess  of  dissolved 
nitrogen,  returns  to  the  lungs  and  again  becomes  saturated  and  this  goes 
on  until  blood  and  tissue  have  become  saturated  with  gas  at  the  external 
pressure.  The  tissues  are  two-thirds  water  and  they  contain  (in  man) 
from  15  to  20  per  cent  of  fat.  Fat,  however,  dissolves  five  times  more 
nitrogen  than  water  (Vernon)  ;  consequently,  it  takes  longer  for  a  given 
volume  of  tissue  than  of  blood  to  become  saturated  at  a  given  pressure. 

The  blood  in  man  constitutes  one-twentieth  of  the  body  weight;  so 
that  if  the  tissues  were  all  liquid  they  would  dissolve  20  times  as  much 
nitrogen  as  the  blood.  On  account  of  the  fat  which  they  contain,  however, 
the  tissues  take  up  more  than  this  proportion — namely,  in  an  average 
man  about  35  times  more  than  the  blood.  All  the  blood  in  the  body  takes 
about  one  minute  to  complete  a  round  of  the  circulation,  so  that  in  this 
time,  after  being  suddenly  subjected  to  an  increased  pressure — assuming 
that  the  blood  circulates  equally  throughout  the  body — the  tissues  will 
be  one-thirty-fifth  saturated;  in  the  next  minute  another  thirty-fifth  of 
thirty-four  thirty-fifths  will  be  saturated,  and  so  on.  After  five  minutes 
the  body  will  be  about  22  per  cent,  and  in  25  minutes  about  one-half, 
saturated;  but  it  will  take  about  two  hours  before  saturation  is  complete. 
These  calculations  assume  that  the  blood  is  evenly  distributed  through- 
out the  body;  but  this  is  not  the  case,  for  its  mass  movement  varies 
considerably  in  different  parts,  being  much  greater  in  the  active  muscles 
and  in  the  glands  than  in  passive  structures,  such  as  fat.  These  less  vas- 
cular parts  will  therefore  lag  behind  the  others  in  taking  up  their  full 
quota  of  gas,  and  therefore  prolong  the  time  necessary  for  complete 
saturation  of  the  body  as  a  whole. 

We  see  therefore  that,  after  some  time  in  compressed  air,  the  blood 
and  active  tissues  will  be  saturated  and  contain  volumes  of  dissolved 
gas  in  proportion  to  their  relative  bulks ;  the  fat,  although  not  saturated, 
will  yet  contain  up  to  five  times  more  gas  than  an  equal  volume  of 
blood,  and  the  passive  tissues  will  be  incompletely  saturated. 

These  considerations  regarding  the  saturation  of  the  different  parts 
of  the  body  apply  also  to  its  desaturation.  Suppose,  for  example,  that 


424  THE   RESPIRATION 

the  external  pressure  is  suddenly  lowered:  the  blood,  on  leaving  the 
lungs,  will  contain  no  excess  of  gas;  when  it  reaches  the  tissues  it  will 
remove  gas  until  the  pressure  is  equalized,  discharge  this  into  the  alveoli 
and  return  again  for  more.  Other  things  being  equal,  it  will  take  the 
same  number  of  minutes  to  desaturate  that  it  took  to  saturate,  and  the 
parts  of  the  body  that  will  lag  behind  the  others,  in  being  desaturated, 
are  those  with  a  sluggish  circulation. 

When  the  mass  movement  of  the  blood  is  increased  by  muscular  exer- 
cise, the  rate  of  saturation  and  desaturation  with  nitrogen  is  increased 
in  proportion.  During  active  work  the  increase  in  movement  of  the 
blood  may  be  four  or  five  times  over  the  normal,  so  that  the  tissues  of 
the  caisson  worker  become  much  more  quickly  desaturated  during  decom- 
pression than  the  above  figures  would  lead  one  to  expect. 

Application  of  Foregoing  Laws  in  Practice 

With  regard  to  the  application  of  these  principles  in  the  decompression  of  caisson 
workers,  it  is  impracticable  to  occupy  as  much  time  as  it  takes  to  saturate  the  body 
even  at  comparatively  low  pressures.  If  the  great  dangers  attending  work  in  com- 
pressed air  are  to  be  avoided,  we  must  either  insist  on  very  gradual  decompression 
or  we  must  show  how  the  dissolved  gases  may  be  got  rid  of  by  some  modification  in 
the  decompression  procedure.  With  this  object  in  view,  we  must  determine  what 
difference  of  pressure  may  be  allowed  between  the  external  air  and  the  body  without 
the  formation  of  bubbles.  Actual  experience  shows  that  there  is  no  risk  of  bubble- 
formation,  however  quick  the  decompression,  after  exposure  to  + 15  pounds  pressure 
(i.  e.,  2  atmospheres  absolute).  "Now,  the  volume  of  gas  capable  of  being  liberated 
on  decompression  to  any  given  pressure  is  the  same,  if  the  relative  diminution  of 
pressure  is  the  same" — (Haldane35).  On  reduction  from  4  to  2  atmospheres,  the  same 
volume  of  gas  will  tend  to  be  liberated  as  on  reduction  from  2  to  1  atmospheres — that 
is  to  say,  no  bubbles  will  form.  The  practical  conclusion  is  "that  the  absolute  air 
pressure  can  always  be  reduced  to  half  the  absolute  pressure  at  which  the  tissues  are 
saturated  without  risk."  Thus,  after  saturation  at  90  pounds  absolute  pressure  (+5 
atmospheres),  a  man  can  be  immediately  decompressed  to  45  pounds  (+2  atmospheres) 
in  a  few  minutes  without  risk,  but  from  this  point  on  the  decompression  must  be 
conducted  slowly,  so  as  to  insure  that  the  nitrogen  pressure  in  the  tissues  is  never 
more  than  twice  the  air  pressure.  The  great  advantage  of  this  method  is  that  it  makes 
the  greatest  possible  use  of  difference  of  pressure  between  tissues  and  blood  in  order 
to  get  rid  of  the  gas  that  these  contain. 

-  When  the  decompression  from  the  start  is  gradual,  the  desaturation  of  the  tissues 
'will  progressively  lag  behind  that  of  the  blood,  and  the  tendency  to  the  liberation  of 
m-ee  gas  will  become  greater.  In  such  a  case  the  decompression  is  far  too  slow  at  first 
kind  far  too  rapid  later.  Theoretically,  therefore,  the  decompression  should  be  rapid 
at  first  and  very  slow  later. 

Before  recommending  the  adoption  of  this  principle  of  stage  decompression  in 
caisson  work,  Haldane  and  his  coworkers  made  numerous  observations  on  the  incidence 
of  decompression  symptoms  in  laboratory  animals.  They  assert  that  the  stage  method 
is  decidedly  safer  than  the  uniform  method,  the  advantage  being  particularly  after 
short  exposures.  On  the  other  hand,  Leonard  Hill  could  make  out  no  definite  advan- 
tage for  the  stage  method.  The  two  methods  have  also  been  compared  in  actual  caisson 


BREATHING   IN   RAREFIED   AND    COMPRESSED   AIR  425 

work  at  the  Elbe  Tunnel,  where  the  pressure  was  +  2  atmospheres.  Very  little  advan- 
tage could  be  demonstrated  for  the  stage  as  compared  with  the  uniform  method  at  this 
comparatively  low  pressure.  The  general  conclusion  which  we  may  draw  is  that  the 
stage  method  should  be  employed,  although  it  is  not  to  be  expected  that  it  will  ab- 
solutely insure  absence  of  decompression  symptoms.  Of  course  the  great  advantage 
of  the  stage  method  is  the  saving  of  time,  making  it  possible  to  persuade  the  workmen 
to  adopt  it. 

There  are  two  other  factors  that  are  to  be  considered  in  hastening  the  desaturation 
of  the  tissues;  these  are  muscular  exercise,  and  the  breathing  of  an  indifferent  gas. 

It  is  clear,  from  what  has  already  been  said,  that  the  gas  dissolved  in  the  tissues 
will  become  removed  in  proportion  to  the  mass  movement  of  the  blood,  and  it  is  prob- 
ably true  that  muscular  exercise,  performed  in  the  decompression  chamber,  is  of  as 
great  importance  in  preventing  the  subsequent  development  of  symptoms  as  a  much 
prolonged  decompression.  In  a  man  at  rest,  the  circulation  through  the  central  nervous 
system  and  the  viscera  is  constantly  influenced  by  the  pumping  action  of  the  respiratory 
movements,  but  in  the  capillaries  of  the  muscles,  joints,  fat,  etc.,  this  influence  is  not 
felt  and  the  blood  flows  more  slowly.  It  is  consequently  in  these  parts  that  bubble 
formation  is  likely  to  occur,  especially  some  time  after  decompression.  The  bubbles 
cause  the  neuralgic  pains — the  "bends"  and  " screws "  so  well  known  to  caisson 
workers.  f  These  could  no  doubt  be  entirely  prevented  by  muscular  exercise  and  massage 
of  the  limbs  during  decompression.  In  illustration  of  these  facts  the  following  experi- 
ment by  Greenwood  may  be  cited:  During  decompression  from  +75  pounds  pressure  in  95 
minutes  "  Greenwood  flexed  and  extended  all  the  limb  joints  at  frequent  intervals, 
with  the  exception  of  the  knees.  Subsequently  pain  and  stiffness  were  experienced  in 
t*he  knees  and  nowhere  else."  In  another  experiment  the  knees  also  were  flexed  and 
no  pain  was  felt. 

But  even  in  the  parts  with  active  circulation,  the  gas  in  the  tissues  may  lag  con- 
siderably behind  that  in  the  blood,  although  the  decompression  has  been  properly 
controlled.  This  has  been  shown  by  Leonard  Hill  in  the  case  of  the  kidney.  The 
" tissue"  gas  in  this  case  can  be  taken  as  the  gas  dissolved  in  the  urine,  by  analyzing 
which,  therefore,  at  different  stages  of  decompression,  the  excess  of  nitrogen  over  what 
it  should  be  at  the  external  pressure,  can  be  ascertained.  On  decompression  from  4-30 
pounds  by  two  stages  to  zero,  a  considerable  super-saturation  was  found  to  exist.  The 
excess  of  nitrogen  can,  however,  be  cleared  out  of  the  kidneys  rapidly  and  completely 
by  breathing  oxygen,  which  should  therefore  be  administered  during  decompression  in 
cases  where  great  care  has  to  be  exercised  (Leonard  Hill). 

"When  symptoms  do  appear,  they  can,  in  most  cases,  be  relieved  by  recompression, 
and  all  modern  caisson  works  are  provided  with  a  special  chamber  for  this  purpose. 
We  need  scarcely  say  anything  about  this  treatment  here,  as  its  value  is  so  well  known. 
Suffice  it  to  say  that,  although  it  is  most  likely  to  afford  relief  when  applied  as  soon  as 
possible  after  the  appearance  of  the  symptoms,  yet  it  is  often  efficacious  when  applied 
several  days  after  their  onset. 

Quite  apart  from  the  dangers  of  decompression,  it  must  of  course  be  remembered 
that  the  working  conditions  in  a  caisson  are  somewhat  different  from  those  at  atmos- 
pheric pressure,  as  the  air,  owing  to  its  compression,  is  warmer  and  is  loaded  to  satura- 
tion point  with  moisture.  This  hot,  wet  air  interferes  with  the  heat-regulating 
mechanism  of  the  body,  making  hard  muscular  work  very  uncomfortable  because  of  the 
tendency  of  the  body  temperature  to  rise.  The  reaction  of  the  body  against  this 
tendency  to  hyperthermia  consists  in  dilatation  of  the  superficial  capillaries  and  in- 
creased heart  action. 

When  such  working  conditions  are  repeated  day  by  day,  the  appetite  is  likely  to 


426  THE   RESPIRATION 

fail,  partly  because  of  the  tendency  of  the  body  to  suppress  the  activity  of  the  metabolic 
processes,  so  as  to  keep  down  heat  production,  and  partly,  no  doubt,  because  the  di- 
gestive processes  are  working  below  par  on  account  of  there  being  less  blood  circulating 
through  the  visceral  blood  vessels,  it  having  been  sent  to  the  surface  of  the  body  to 
be  cooled  off.  The  worker  therefore  tends  to  take  less  food,  his  metabolism  becomes 
depressed,  and  his  factors  of  safety  against  bacterial  infections  become  lessened. 

The  risk  of  the  appearance  of  symptoms  on  decompression  is  also  greater  when  the 
air  in  the  caisson  has  been  moist  and  hot,  for  the  heart  has  been  overworking  to  main- 
tain the  bloodflow  in  the  dilated  vessels;  it  gets  fatigued  and  is  consequently  unable 
to  maintain,  during  decompression,  a  rate  of  bloodflow  that  is  adequate  for  carrying 
the  gas-saturated  blood  to  the  lungs,  where  the  excess  of  gas  becomes  dissipated. 

The  criterion  of  proper  working  conditions  in  the  caisson  is  therefore  the  wet-bulb 
temperature.  This  should  stand  below  75  °F.  To  maintain  this  condition  it  is  necessary 
to  ventilate  the  caisson,  preferably  with  air  that  has  been  cooled  by  cold-water  radiators ; 
ir  any  case,  the  ventilation  should  be  adequate  to  keep  down  the  wet-bulb  temperature. 
The  increased  expense  of  ventilation  with  cooled  air  would  soon  be  balanced  by  the 
greater  working  efficiency  of  the  men.  Constant  circulation  of  the  air  in  the  caissons 
by  means  of  fans  assists  also  in  improving  the  conditions,  for  it  helps  to  increase 
dissipation  of  heat  from  the  body. 


CHAPTER  XL VII 

THE  ADAPTATIONS  OF  THE  CIRCULATORY  AND  RESPIRATORY 
SYSTEMS  DURING  MUSCULAR  EXERCISE 

There  is  probably  no  field  of  physiological  research  in  which  more 
important  results  have  been  obtained  during  the  past  few  years  than  in 
that  pertaining  to  the  effects  of  muscular  exercise  on  the  bodily  func- 
tions. The  adaptations  in  the  circulation  are  particularly  important 
because  they  can  be  properly  carried  out  only  when  this  system  is  in 
perfect  working  order,  so  that  a  study  of  them  affords  us  a  most  valuable 
method  for  estimating  the  reserve  power  of  the  heart  and  the  efficiency 
of  the  peripheral  circulation.  We  shall  first  of  all  consider  the  adjust- 
ments of  the  circulatory  and  respiratory  systems  that  accompany  muscu- 
lar exercise  and  then  proceed  to  see  how  the  knowledge  may  be  used  in 
clinical  diagnosis. 

The   Circulatory   Changes  Accompanying  Muscular  Exercise* 

During  activity  the  muscles  require  many  times  more  blood  than  dur- 
ing rest.  When  the  activity  is  widespread  the  greater  blood  supply  is 
provided  by  increased  heart  action  accompanied  by  dilatation  of  the 
muscular  arterioles  and  capillaries  and  constriction  of  those  of  the 
splanchnic  area  so  that  the  entire  available  blood  supply  of  the  body  is 
made  to  circulate  more  rapidly. 

If  we  take  as  a  measure  of  the  extent  of  muscular  activity,  the  con- 
sumption of  oxygen,  it  has  been  found  that  this  runs  practically  parallel 
with  the  output  of  the  heart  and  with  the  volume  of  air  breathed.  The 
output  of  the  heart  varies  between  3  and  6  liters  per  minute,  in  the  resting 
individual;  during  moderate  muscular  work  it  becomes  8  or  9  liters,  and 
during  very  heavy  work  it  may  rise  to  20  liters  or  more  (Krogh). 

When  the  activity  is  confined  to  a  limited  group  of  muscles,  the  in- 
creased blood  supply  is  mainly  provided  by  a  local  dilatation  of  the 
blood  vessels  of  the  active  muscles  accompanied  by  a  reciprocal  constric- 
tion of  those  inactive  parts.  Under  these  conditions  there  may  therefore 
be  no  quickening  of  the  bloodflow  as  a  whole.  In  order  that  this  accurate 
adjustment  of  blood  supply  to  tissue  demands  may  be  promptly  and  ade- 
quately brought  about,  all  available  types  of  coordinating  mechanism  are 

*This  chapter  is  placed  here  rather  than   following  circulation  because  of  the  interdependence  of 
e    circulatory    and    respiratory    adjustments. 

427 


428  THE   RESPIRATION 

called  into  play ;  that  is  to  say,  mechanical,  nervous  and  hormone  factors 
cooperate  to  an  extent  which  is  dependent  upon  the  type  of  work  being 
performed. 

Besides  the  changes  in  pulse  rate  and  blood  pressure  which  are  evi- 
dently designed  to  supply  more  blood  to  the  acting  muscles,  changes 
dependent  upon  a  secondary  effect  of  the  muscular  movements  have  also 
to  be  considered.  Although  the  various  factors  work  together  and  are 
more  or  less  interdependent,  the  final  effect  can  be  understood  only  after 
we  have  studied  the  relative  influence  of  each  separately. 

The  Mechanical  Factor. — It  is  particularly  with  regard  to  this  factor 
that  the  circulatory  changes  may  be  an  unavoidable  consequence  of, 
rather  than  a  useful  adjustment  to,  the  muscular  effort.  The  effects  vary 
with  the  type  of  exercise  performed.  In  repeatedly  lifting  and  lowering 
dumbbells  from  the  floor  to  above  the  head,  the  contracting  muscles  of 
the  back  and  extremities  and  of  the  abdomen  compress  the  veins  and 
cause  the  blood  to  flow  more  rapidly  into  the  heart,  so  that  the  arterial 
pressure  suddenty  rises.  So  long  as  this  compression  exists,  the  veins 
remain  relatively  empty  and  the  arteries  overfilled,  but  whenever  it 
ceases  and  the  muscles  relax,  the  veins  fill  up  again  and  the  arterial  pres- 
sure markedly  falls,  until  the  extra  space  in  the  veins  has  been  occupied 
by  blood.  It  is  for  this,  reason  that  the  arterial  blood  pressure  is  always 
found  to  be  little,  if  any,  above  normal  when  taken  within  a  few  seconds 
after  such  exercise.  It  subsequently  rises  because  the  other  factors 
responsible  for  the  increased  pressure  (quick  heart  and  arteriole  constric- 
tion) are  still  in  operation  at  the  time  the  veins  again  become  filled  with 
blood.  The  purely  mechanical  influence  outlasts  the  exercise  for  a  com- 
paratively short  time,  whereas  the  nervous  and  hormone  influences  con- 
tinue acting.  This  interpretation  is  supported  by  the  observation  that 
the  fall  of  blood  pressure  is  greater  when  the  subject  is  left  standing 
after  a  given  amount  of  dumbbell  exercise  than  when  he  is  allowed  to  sit 
with  his  elbows  resting  on  his  knees.  In  the  standing  position  the  pres- 
sure on  the  abdominal  veins  is  less  and  the  hydrostatic  effect  of  gravity 
causes  more  blood  to  collect  in  the  large  veins  (Cotton,  Rapport  and 
Lewis36).  Being  purely  mechanical  in  its  causation,  the  preliminary  fall 
following  dumbbell  exercise  can  always  be  demonstrated  if  the  observa- 
tions are  made  at  close  enough  intervals  of  time. 

The  mechanical  response  of  the  circulation  to  exercise  acts  therefore 
through  the  rate  of  filling  of  the  right  heart  with  blood,  and  if  this  organ  is 
in  a  healthy  condition,  it  will  respond  to  the  greater  inflow  by  correspond- 
ingly increased  discharge.  Like  every  other  physiological  mechanism,  the 
heart,  therefore,  works  with  a  large  factor  of  safety — a  reserve  power — and 
it  is  the  rate  of  venous  filling  that  determines  how  much  of  this  reserve  must 


CHANGES   ACCOMPANYING    MUSCULAR   EXERCISE  429 

be  called  upon  to  maintain  the  circulation.  In  isolated  heart-lung  prep- 
arations Starling  and  his  coworkers  have  very  clearly  demonstrated  the 
close  dependence  of  cardiac  output  upon  rate  of  venous  filling  and  the 
enormous  range  through  which  the  systolic  discharge  can  be  made  to 
vary  by  altering  this  factor.  As  explained  elsewhere  (page  441),  when  the 
reserve  power  of  the  heart  is  lessened,  the  rise  in  blood  pressure  following 
exercise  is  longer  in  attaining  its  maximum,  which  is  set  at  a  higher  level 
and  persists  for  a  longer  time.  Observation  of  the  extent  of  these  changes 
furnishes  a  most  useful  functional  test  of  cardiac  efficiency. 

Other  mechanical  factors  that  augment  the  cardiac  output  depend  on 
the  increased  respiratory  movements.  During  each  respiration  the  in- 
crease in  capacity  in  the  thorax  causes  both  an  opening  up  of  the  thin- 
walled  veins,  so  that  blood  is  aspirated  towards  them  from  the  extra- 
thoracic  venous  system,  and  a  dilatation  of  the  blood  vessels  of  the  lungs, 
so  that  the  blood  finds  its  way  from  right  to  left  heart  more  readily. 
Although  this  dilatation  will  at  first  tend  to  cause  more  blood  to  collect 
in  the  intrathoracic  vessels  and  less  to  be  pumped  out  of  them,  the  expira- 
tory act  when  it  supervenes  will,  by  compressing  the  veins,  cause  the 
extra  blood  to  be  expelled  into  the  left  ventricle  and  thence  into  the 
arteries.  It  is  obvious  that  increased  depth  and  frequency  of  the  respira- 
tory movements  will  accelerate  the  bloodflow  and  tend  to  raise  the  arte- 
rial blood  pressure. 

The  above  factors  will  come  into  play  during  most  kinds  of  muscular 
exercise  such  as  walking,  running,  or  swinging  dumbbells,  etc.  There 
are  certain  types  of  muscular  effort,  however,  in  which  the  mechanical 
factors  produce  decidedly  disturbing  effects  on  the  circulation.  During 
a  sustained  effort  as,  for  example,  in  pulling  against  a  resistance  or  in 
attempting  to  lift  a  heavy  load,  the  respirations  are  suspended,  often  after 
a  deep  inspiration,  and  the  contracted  abdominal  muscles  press  the  dia- 
phragm up  into  the  thoracic  cavity.  After  a  preliminary  squeezing  out 
of  blood  first  of  all  from  the  veins  of  the  abdomen  into  the  thorax  and 
then  from  those  of  the  latter  into  the  systemic  arteries,  with  a  consequent 
rise  in  arterial  pressure,  there  comes  to  be  a  damming  back  of  blood  into 
the  peripheral  veins,  causing  them  to  swell  and,  if  continued,  marked 
cyanosis  may  develop.  When  such  efforts  are  maintained  for  long,  the 
arterial  pressure  begins  to  fall,  and  this  fall  is  very  pronounced  indeed 
at  the  end  of  the  effort,  because,  the  compression  being  removed  from  the 
abdominal  and  thoracic  veins,  these  open  up  and  form  a  large  unfilled 
blood  reservoir. 

A  similar  mechanism  comes  into  play  during  expulsive  acts  such  as 
defecation,  parturition,  etc.  In  these  the  glottis  is  closed,  usually  after 
a  preliminary  inspiration,  and  a  powerful  expiratory  movement  is  per- 


430  THE    RESPIRATION 

formed,  with  the  consequence  that  the  intrathoracic  and  intraabdominal 
pressures  rise  considerably,  greatly  augmenting  the  systolic  discharge 
and  causing  the  blood  pressure  to  rise.  Because  of  the  obstruction  to 
the  bloodflow  in  the  large  veins  of  the  abdomen  and  thorax,  however, 
the  later  effect  of  the  effort  is  to  diminish  the  systolic  discharge,  but  the 
fall  in  blood  pressure  which  this  would  be  expected  to  occasion  is  masked. 
The  pressure  remains  high  because  other  factors  increasing  the  peripheral 
resistance  come  into  play.  The  fall  in  blood  pressure  following  these  acts 
may  be  very  marked  indeed.  It  may  be  so  marked  that  fainting  occurs 
because  of  curtailment  of  intracranial  circulation.  Similar  mechanical 
effects  are  produced  in  the  acts  of  coughing,  sneezing,  etc. 

The  capacity  of  the  veins  varies  considerably  with  the  position  of  the 
body,  and  it  is  in  order  that  we  may  cause  alterations  in  this  capacity 
and  therefore  encourage  a  more  rapid  bloodflow  that  we  stretch  the  body 
after  sitting  for  some  time  in  a  cramped  position. 

The  Nervous  Factor. — The  activity  of  the  vagosympathetic,  vasomotor 
and  respiratory  centers  becomes  greatly  altered  during  muscular  effort. 
In  the  earlier  stages  the  alteration  depends  on  nervous  impulses  trans- 
mitted to  the  centers,  but  later  it  also  depends  on  changes  in  composition 
and  temperature  of  the  blood  flowing  through  them — the  hormone  factor. 
The  stimuli  which  first  act  on  the  centers  are  derived  from  the  cerebral 
cortex.  They  are  believed  to  irradiate  on  to  the  medullary  centers  from 
the  motor  pathways  along  which  impulses  are  passing,  on  their  way  down 
from  the  cortex  to  the  spinal  cord.  The  most  weighty  evidence  favoring 
this  belief  is  that  increase  in  the  rate  of  the  pulse  and  respirations  may 
occur  at  the  moment  a  muscular  effort  is  attempted,  before  there  is  any 
time  for  hormones  to  become  developed,  or  for  reflexes  from  the  muscles 
themselves  to  be  set  up.  Moreover,  the  degree  of  alteration  of  the  me- 
dullary centers  is  not  at  first  proportional  to  the  actual  amount  of  work 
done ;  if  a  person  expects  that  much  effort  will  be  required  to  do  a  piece 
of  work,  the  pulse  and  respirations  will  increase  immediately  he  starts 
the  work,  even  although  this,  after  all,  is  trivial.  These  impulses  are, 
however,  incapable  of  stimulating  the  respiratory  center  unless  the  C02- 
tension  of  the  blood  is  normal.  After  forced  breathing,  for  example, 
muscular  effort  does  not  cause  increased  breathing.  During  the  progress 
of  the  work  the  cortical  influences  continue  to  act  on  the  centers  which 
now  are  said  to  be  also  affected  by  afferent  impulses  from  the  periphery, 
as  well  as  by  hormones.  These  afferent  impulses  acting  on  the  pulse  rate 
are  supposed  by  Bainbridge  to  come  from  the  wall  of  the  ventricle  where 
they  are  set  up  by  the  diastolic  tension  due  to  venous  inflow.  It  is 
difficult  to  reconcile  this  view  with  the  slowing  of  the  pulse  that  occurs 
in  asphyxial  and  epinephrine  hypertension  (page  774). 


CHANGES    ACCOMPANYING    MUSCULAR    EXERCISE  431 

The  Hormone  Factor. — We  have  to  consider  first  the  nature  of  the 
hormone,  and  secondly  the  mode  of  its  action. 

The  Nature  of  the  Hormones. — The  most  important  hormone  is  car- 
bonic acid,  but  when  the  exercise  is  strenuous  and  continued,  or  from 
the  very  start  is  of  such  a  nature  that  it  uses  up  oxygen  more  quickly 
than  the  blood  can  supply  it  to  the  muscles,  lactic  acid  also  appears. 
It  is  probable  also  that  depression  of  the  tension  of  oxygen  in  the  blood 
supplying  the  medullary  respiratory  centers  is  in  itself  an  important  cause 
for  their  excitation.  Evidence  for  these  statements  can  readily  be  supplied 
in  man  by  analysis  of  the  expired  air  (for  carbon  dioxide)  and  of  the  urine 
(for  lactic  acid)  before  and  during  muscular  work.  The  carbonic  and  lactic 
acids  are  believed  by  many  to  act  by  causing  an  increase  in  the  H-ion  concen- 
tration of  the  blood.  There  is,  however,  no  direct  proof  for  this  belief,  al- 
though it  has  been  shown  by  determination  of  the  tension  of  C02  in  the 
alveolar  air  and  calculation  therefrom  of  the  PH  of  the  blood,  that  a 
decrease  of  0.02  occurs.  (Campbell,  Douglas  and  Hobson39).  Bareroft27 
by  measuring  the  dissociation  constant  of  his  own  blood  (see  page  401) 
before  and  after  climbing  1,000  feet  in  half  an  hour,  estimated  that  PH 
changed  from  7.29  to  7.09.  It  is  possible,  however,  that  these  estimations 
are  unreliable  since  they  may  not  have  included  all  the  factors  that  are 
involved. 

Another  view  is  that  the  effective  hormone  is  an  increase  in  the  free  car- 
bonic acid  itself  (see  page  368).  In  the  earlier  stages  of  muscular  work, 
the  greater  production  of  C02  by  the  active  muscles  would  raise  the 
tension  of  this  gas  in  the  plasma,  and  later,  especially  when  the  work 
was  strenuous,  lactic  acid  would  also  come  into  play  and  decompose  the 
NaHC03  of  the  blood,  so  as  to  liberate  C02.  As  the  NaHC03  (buffer  sub- 
stance) became  gradually  used  up,  a  relatively  greater  and  greater  pro- 
portion of  C02  would  come  to  exist  in  a  free  state  in  the  plasma,  so  that 
its  stimulating  effect  became  progressively  greater. 

One  serious  difficulty  in  accepting  the  free  C02  as  the  exciting  hormone 
of  the  nerve  centers  during  muscular  exercise  depends  on  the  observation 
that  the  alveolar  C02  after  some  time  is  lower  than  normal.  If  we  ac- 
cept Haldane's  teaching  that  there  is  accurate  correspondence  between 
the  tensions  of  C02  in  arterial  blood  and  alveolar  air,  not  only  during 
rest,  but  also  during  muscular  activity,  then  obviously  we  must  discard 
the  C02  hypothesis.  But  this  assumption  is  unwarranted,  for  Leonard 
Hill  and  Flack46  have  shown  quite  clearly  both  in  experimental  animals 
and  in  man  that  equilibrium  between  the  blood  and  alveolar  tensions  of 
C02  may  fail  to  occur.  When  blood  with  excess  of  C02  is  injected  into  the 
jugular  vein  of  dogs,  the  respiratory  center  is  stimulated,  as  shown  by 
the  increased  breathing,  which  indicates  that  the  OCX-rich  blood  must 


432  THE   RESPIRATION 

have  passed  through  the  lungs  without  all  of  the  excess  of  C02  being  re- 
moved from  it.  Hill  believes  that  the  diffusion  of  C02  out  of  the  blood 
into  the  alveolar  air  may  be  depressed  in  muscular  exercise,  and  that 
this,  rather  than  the  appearance  of  lactic  acid  in  the  blood,  is  responsi- 
ble for  the  low  C02  tensions  usually  found  present  as  illustrated  by  the 
results  given  in  the  table  on  page  336.  He  points  out  in  support  of 
this  view  that  a  person  after  exercise  can  hold  his  breath  for  a  much 
shorter  time  than  is  usual,  and  the  C02  meanwhile  mounts  in  the  alveo- 
lar air  very  rapidly. 

In  view  of  the  fact  that  the  respiratory  center  also  becomes  excited 
when  there  is  a  lowering  of  the  tension  of  oxygen  in  the  plasma  (page 
374)  a  contributory  cause  for  its  maintained  stimulation  during  exer- 
cise may  depend  on  the  great  demands  of  the  active  muscles  for  this 
gas.  In  its  passage  through  the  lungs  the  blood  under  these  circumstances 
may  not  succeed  in  taking  on  its  full  load  of  oxygen.  That  such  is 
the  case  during  muscular  exercise  has  been  suggested  by  Barcroft. 

It  is  well  known  that  an  animal  under  emotional  stress  may  perform  an 
amount  of  muscular  work  that  is  much  greater  than  the  usual,  and  Can- 
non has  brought  forward  evidence  to  show  that  this  may  be  associated  with 
an  increase  in  the  concentration  of  adrenin  in  the  blood.  The  adrenin  as- 
sists in  facilitating  the  action  of  the  autonomic  nervous  system  and  perhaps 
by  improving  muscular  contraction  (see  page  778). 

The  Effects  of  the  Hormone. — These  may  be  classified  as  follows:  (1) 
strictly  local  effects  on  the  muscles  themselves;  (2)  effects  on  the  heart; 
and  (3)  effects  on  the  nerve  centers.  The  local  production  of  acids  in 
the  muscles  will  cause  dilatation  of  the  arterioles,  for  it  has  been  shown 
by  various  observers  that  acids  cause  relaxation  of  vascular  muscle. 
Independently  of  changes  in  the  arterioles,  the  capillaries  themselves  are 
also  altered  in  tone  during  muscular  activity  (see  page  252).  For  the 
maintenance  of  capillary  tone  an  adequate  supply  of  oxygen  is  essential 
so  that  when  this  is  rapidly  used  up  by  exercise  capillary  dilatation 
occurs.  This  is  no  doubt  further  assisted  by  the  appearance  of  the  blood 
of  certain  products  of  the  metabolism  of  the  muscles.  These  are  proba- 
bly in  part  related  to  histamine  (-see  page  307)  and  in  part  are  acids, 
such  as  C02  and  lactic.  The  effects  produced  by  changes  in  H-ion  con- 
centration of  the  blood  on  the  heart  have  been  particularly  studied  by 
Starling  and  Patterson,38  who,  working  on  isolated  heart-lung  prepara- 
tions, have  shown  that  the  heart  relaxes  more  and  more  and  discharges 
less  blood  as  the  H-ion  concentration  of  the  perfusion  fluid  is  increased 
by  adding  C02  to  the  air  ventilating  the  lungs. 

It  is  unlikely  that  CH  in  the  blood  is  raised  to  the  extent  of  causing 
these  changes  in  the  heart  during  muscular  exercise.  It  is  possible,  how- 


CHANGES   ACCOMPANYING    MUSCULAR   EXERCISE  433 

ever,  that  sufficient  change  occurs  in  the  heart  to  cause  dilatation  of 
the  coronary  arteries,  and  thus  improve  the  bloodflow  (page  267).  It 
should  be  pointed  out  here,  however,  that  a  much  more  important  factor 
determining  the  coronary  bloodflow  is  the  pressure  in  the  aorta.  When 
this  is  lower  than  90  mm.  adequate  circulation  in  the  coronary  arteries  is 
difficult  to  maintain  even  though  these  vessels  be  dilated  to  the  full. 
Above  90  mm.  slight  further  elevations  in  aortic  blood  pressure  cause 
disproportionate  increase  in  coronary  flow.  The  blood  supply  of  the 
heart  itself  depends  much  more  upon  arterial  blood  pressure  than  upon 
any  other  factor  (Markwalder  and  Starling40).  Indeed  the  heart  is  not 
the  only  organ  in  which  a  similar  relationship  between  blood  pressure 
and  bloodflow  exists.  The  same  is  true  for  glands,  for  Gesell41  has  found 
that  a  trivial  fall  in  general  pressure  causes  a  marked  .curtailment  in 
bloodflow. 

The  known  influence  of  changes  in  H-ion  concentration  of  the  blood  on 
the  vasomotor  centers  is  difficult  to  correlate  with  the  changes  which  ac- 
tually occur  in  muscular  exercise.  There  is  no  doubt  that  an  increase  in 
CH  stimulates  the  vasoconstrictor  centers,  not  only  of  the  medulla,  but 
also  although  much  more  feebly,  of  the  spinal  cord,  but  this  action,  if 
it  occurs  during  exercise,  must  be  confined  to  the  splanchnic  area,  where 
it  would  have  the  effect  of  bringing  about  a  redistribution  of  the  total 
available  blood  by  expressing  it  from  the  viscera  and  sending  it  to  the 
active  muscles. 

The  effect  of  increased  H-ion  concentration  on  the  vagus  center  must 
be  insignificant.  It  is  commonly  believed  that  it  would  cause  not  what  is 
actually  observed,  a  quickening,  but  rather  a  slowing  of  the  heart  rate. 
But  even  this  is  doubtful.  If  increase  in  the  H-ion  concentration  does 
affect  the  heart  during  muscular  exercise,  it  must  act  by  inhibiting  the 
vagus  tone,  which  is  opposite  to  the  action  which  it  is  usually  believed 
to  have. 

The  activity  of  the  respiratory  center  is  of  course  excited  by  in- 
crease in  H-ion  concentration  (page  352)  and  the  resulting  greater  ac- 
tivity of  the  respiratory  pump  will  cause  important  changes  in  the  cir- 
culation. To  this  extent  alterations  in  CH  of  the  blood  will  assist  in 
bringing  about  a  greater  mass  movement  of  blood  during  muscular  ex- 
ercise. 

In  this  connection  we  must  consider  the  effect  of  change  in  the  tem- 
perature of  the  blood.  The  extent  of  this  rise  in  temperature  apart  from 
the  amount  of  exercise  depends  on  several  factors  such  as  the  cooling 
effect  of  the  environment,  the  amount  of  subcutaneous  fat,  and  whether 
or  not  the  person  is  in  training.  By  observations  on  the  temperature  of 
the  urine  in  a  group  of  soldiers  Pembrey  found  that  a  march  of  seven 


434  THE  RESPIRATION 

miles  caused  an  average  rise  of  0.8°  F.  on  a  cool  day,  and  of  1.4°  F.  on 
a  hot  day.     The  temperature  returns  to  normal  very  quickly  after  the 
exercise,  and  while  it  is  raised  there  is  by  no  means  the  upset  in  the 
bodily  functions  that  is  observed  in  fever.     For  one  thing,  the  metab- 
olism in  the  two  cases  is  quite  different;  in  fever,  protein  catabolism  is 
abnormally  great,  whereas  in  muscular  exercise  this  is  not  the   case, 
oxidation  of  carbohydrates  and  fat  being  the  source  of  the  energy.     It 
j  is  very  likely  that  rise  in  blood  temperature  is  in  part  responsible  for 
jthe  acceleration  of  the  heart  that  occurs  during  exercise,  and  for  in- 
/  creased  excitability  of  the  medullary  nerve  centers.    It  probably  also  as- 
sists in  hurrying  the  oxidative  changes  in  the  active  muscles,  and,  by 
lessening  the  affinity  of  hemoglobin  for  oxygen,  facilitates  the  liberation 
of  this  gas  to  the  plasma. 


CHAPTER  XL VIII 

THE  ADAPTATIONS  OF  THE  CIRCULATORY  AND  RESPIRATORY 
MECHANISMS  DURING  MUSCULAR  EXERCISE  (Cont'd) 

THE  EFFECT  OF  MUSCULAR  EXERCISE  ON  THE 
COMPOSITION  OF  THE  ALVEOLAR  AIR 

During  muscular  exercise  the  pulmonic  ventilation  increases  to  an 
extraordinary  extent.  At  rest  an  average  man  respires  6  to  8  liters  of 
air  per  minute,  but  during  walking  on  the  level  at  the  rate  of  5  kilometers 
an  hour,  this  figure  may  increase  to  about  20  liters. 

The  first  investigations  as  to  the  cause  of  the  relationship  between  muscular  activity 
and  pulmonic  ventilation  were  made  by  animal  experiments  in  which  tetanus  of  the 
muscles  of  the  hind  limbs  was  produced  by  electric  stimulation  of  the  spinal  cord.  The 
problem  was  to  find  out  what  serves  as  the  means  of  correlation  (nerve  reflex  or  hor- 
mone control)  between  the  muscular  activity  and  the  respiratory  activity.  By  cutting 
the  spinal  cord  above  the  point  of  stimulation,  it  was  found  that  the  tetanus  was  still 
accompanied  by  hyperpnea.  On  the  other  hand,  when  the  spinal  cord  was  left  intact 
but  the  blood  vessels  of  the  limb  were  ligated,  no  hyperpnea  followed  the  tetanus. 
Evidently  therefore  the  pathway  of  communication  is  the  blood. 

The  next  step  was  to  seek  in  the  blood  for  the  substance  or  hormone  that  acted  as 
the  respiratory  excitant,  and  naturally  the  first  possibility  considered  was  a  change  in 
the  gases  of  the  blood,  either  a  deficiency  of  O  or  an  increase  in  CO  .  Direct  exami- 
nation of  the  blood  for  the  quantity  of  these  gases,  however,  yielded  results  which 
were  quite  contrary  to  such  an  hypothesis.  It  was  found  that  the  percentage  of  O2, 
if  anything,  was  slightly  increased,  and  that  of  the  CO2,  if  anything,  diminished. 
Moreover,  when  the  expired  air  was  analyzed  during  the  hyperpnea,  the  percentage 
of  CO2  contained  in  it  was  distinctly  below  the  normal  average,  and  the  percentage  of 
0,  above  it.  Evidently,  therefore,  the  amount  of  gases  in  the  blood  has  nothing  to  do 
with  the  excitation  of  the  respiratory  center,  and  the  conclusion  drawn  by  the  earlier 
investigators  was  to  the  effect  that  the  exciting  substance  carried  from  the  active 
muscles  to  the  respiratory  center  must  be  some  unusual  metabolic  product,  possibly 
the  lactic  acid  produced  by  contraction. 

It  was  further  found,  by  examination  of  the  respiratory  quotient,  that  an  excess  of 
C0g  was  being  expired  during  the  work  and  immediately  after  it,  but  that  this  was 
subsequently  followed  by  a  much  lower  quotient,  indicating  that  CO  was  being  re- 
tained. Such  a  result  would  be  in  conformity  with  the  view  that  an  acid  such  as  lactic 
is  discharged  into  the  blood,  on  the  carbonates  of  which  it  would  act  as  explained  on 
page  372.  Breathing  in  and  out  of  a  small  rubber  bag  causes  the  same  alterations 
in  the  respiratory  quotient  (see  page  582). 

That  lactic  acid  is  actually  produced  by  contracting  muscle  could  not,  however,  be 
shown  by  all  investigators,  and  it  was  not  until  some  years  later  that  Fletcher  and 
Hopkins29  clearly  demonstrated  the  conditions  under  which  it  may  appear  in  active 

435 


436 


THE   RESPIRATION 


isolated  muscle.  These  observers  found  that  lactic  acid  is  produced  in  excised  muscles 
only  when  the  muscular  contraction  occurs  in  a  deficiency  of  O  .  When  it  occurs  in 
an  adequate  supply  of  O2,  CO2  instead  of  lactic  acid  is  produced. 

Much  light  has  been  thrown  on  the  physiology  of  muscular  exercise 
by  studying  the  alveolar  C02  tension  and  the  respiratory  quotient.  The 
results  of  such  observations  are  given  in  the  accompanying  table. 


(1) 

(2) 

(3) 

(4) 

(5) 

O2  used 

CO2  pro- 

B.Q. 

CO2in 

Total  alveolar 

in  c.c. 

duced  in  c.c. 

vol.  CO2 

alveolar 

ventilation  in 

per  min. 

per  min. 

vol.  O2 

air 

liters  per  min. 

1.  During  rest,  standing        328 

264 

0.804 

5.70 

5.80 

2.  Walking  at  the  rate  of 

3  kilometers  per  hour     780 

662 

0.849 

6.04 

13.6 

3.  Walking  at  the  rate  of 

5  kilometers  per  hour  1065 

922 

0.866 

6.10 

18.8 

4.  Walking  at  the  rate  of 

6  kilometers  per.  hour  1595 

1398 

0.876 

6.36 

27.6 

5.  Walking  at  the  rate  of 

7  kilometers  per  hour  2005 

1788 

0.891 

6.20 

35.6 

6.  Walking  at  the  rate  of 

8  kilometers  per  hour  2543 

2386 

0.938 

6.10 

48.2 

In  the  first  column  is  given  the  02  used  in  c.c.  per  minute.  Among  other 
things  these  figures  indicate  the  actual  amount  of  work  done.  In  the 
second  column  is  given  the  C02  production  in  c.c.  per  minute.  By  divid- 
ing the  figures  of  the  second  column  by  those  of  the  first,  we  obtain  the 
figures  of  the  third  column,  representing  the  respiratory  quotient.  The 
fourth  column  gives  the  C02  content  of  the  alveolar  air,  and  the  last 
column  the  total  alveolar  ventilation  in  liters  per  minute. 

Taking  for  the  present  the  figures  in  the  first  and  fourth  columns  it  will 
be  noted  that,  as  the  muscular  work  increases  up  to  a  total  consumption  of 
about  1600  c.c.  of  02  per  minute,  the  C02  percentage  in  the  alveolar  air 
steadily  increases.  The  question  arises,  does  the  alveolar  ventilation 
increase  in  proportion  to  the  increase  in  C02  tension?  If  it  does  so, 
increase  in  G02  tension  in  the  blood  can  be  held  solely  responsible  for 
the  hyperpnea  (i.  e.,  a  pure  C02  acidosis) ;  whereas  if  the  hyperpnea  is 
greater  than  can  be  accounted  for  by  the  increase  in  C02  tension,  other 
factors  must  be  acting  to  excite  the  respiratory  center.  By  making  this 
same  individual  breathe  atmospheres  containing  different  percentages  of 
C02  it  was  found  that  to  produce  a  doubling  of  the  alveolar  ventilation  it 
required  an  increase  amounting  to  0.33  per  cent  of  an  atmosphere  of  C02 
in  the  alveolar  air  (see  also  page  366).  When  we  examine  the  above 
figures  during  muscular  exercise,  however,  we  find  that  a  rise  in  alveolar 
C02  from  5.70  to  6.36  (i.  e.,  0.66  per  cent)  caused  the  alveolar  ventilation 
to  increase  by  considerably  more  than  four  times,  whereas  had  it  been 


CHANGES   ACCOMPANYING   MUSCULAR   EXERCISE  437 

entirely  due  to  an  increase  in  C02,  it  should  not  have  been  more  than 
three  times  as  much.  Evidently  therefore,  some  other  factor  than  C02-ten- 
sion  must  have  been  responsible  for  the  increased  respiratory  activity.  This 
conclusion  is  further  confirmed  by  examination  of  the  alveolar  C02 
during  very  strenuous  muscular  effort,  when  a  relative  decrease  in  the 
C02  percentage  becomes  apparent. 

If  it  is  true  that  the  exciting  agency  has  been  only  partly  dependent  on 
an  increase  in  the  C02-tension  of  the  blood,  we  should  expect  that  imme- 
diately after  discontinuing  the  muscular  exercise  the  C02-tension  of  the 
alveolar  air  would  fall  to  a  level  distinctly  below  normal,  that  it  would 
only  slowly  recover  thereafter,  and  that  further  exercise  before  the  re- 
covery had  occurred  would  produce  a  less  marked  increase  in  alveolar 
C02.  These  results  we  should  expect  because  the  store  of  C02  in  the  body 
must  have  been  depleted  by  the  hyperpnea.  By  actual  experiment  these 
suppositions  have  been  found  to  be  correct,  as  is  shown  in  the  following 
table. 


TIME  AFTER  DISCONTINUING  ALVEOLAR  C02  TENSION 

A  BRIEF  PERIOD  OF  IN  MM.  HG 

MUSCULAR  EXERCISE 


1st  Period: 

10" 

49.2 

3'  0" 

35.4 

6'  30" 

35.3 

12'  30" 

35.8 

2nd  Period: 

10" 

38.9 

3'  0" 

33-7 

6'  30" 

34.4 

3rd  Period: 

10" 

36.9 

3'  0" 

34.4 

8'  30" 

32.4 

18'  30" 

33.7 

24'  0" 

36.2 

Normal  resting: 

39.0 

(Douglas.) 

In  this  table  the  figures  of  Period  1  represent  the  alveolar  C02 
tension  in  mm.  Hg.  immediately  following  a  period  of  strenuous  work. 
The  figures  in  Period  2  are  for  the  same  individual  again  performing 
the  same  amount  of  work  with,  however,  only  a  short  period  of  rest  in- 
tervening, and  the  figures  of  the  third  period  are  a  repetition  of  the  same 
conditions.  It  will  be  observed  that  the  muscular  exercise  at  first  raised 
the  alveolar  tension  of  C02  from  the  normal  of  39  mm.  to  49.2  mm.,  but 
that  in  three  minutes  after  the  work  had  been  discontinued  the  tension 
was  considerably  below  the  normal.  During  the  second  period  of  mus- 
cular exercise  the  C02  in  the  alveolar  air  collected  immediately  after  the 
effort  did  not  increase  above  the  normal  level,  and  in  the  third  period 
the  increase  was  still  less. 

The  other  factors  besides  increase  in  C02-tension  may  be  appearance  of 


438  THE   RESPIRATION 

acids,  such  as  lactic,  decrease  in  the  oxygen  tension  of  the  plasma  and 
irradiation  of  impulses  on  the  respiratory  center  from  the  cerebrospinal 
pathways  in  the  medulla. 

Direct  evidence  that  lactic  acid  is  formed  during  strenuous  muscular 
exercise  in  man  has  been  furnished  by  Ryffel.30  Blood  removed  from  a 
person  immediately  after  running  at  full  speed  for  about  three  minutes 
contained  70.8  milligrams  of  lactic  acid  per  100  c.c.  of  blood,  the  normal 
amount  being  12.5  milligrams.  Much  of  the  lactic  acid  accumulating  in 
the  blood  is  no  doubt  got  rid  of  by  oxidation,  but  a  large  part  of  it  is 
also  excreted  by  the  urine,  in  which  it  was  found  by  Ryffel  in  consider- 
able amount  after  strenuous  muscular  exertion. 

The  accumulation  of  lactic  acid  in  the  blood  must  tend  to  raise  CH  as 
well  as  to  increase  the  C02-tension  by  decomposing  bicarbonates. 

With  regard  to  the  stimulation  of  the  respiratory  center  by  irradia- 
tion, it  is  altogether  likely  that  this  can  only  occur  provided  that  the 
excitability  of  the  center  is  being  maintained  at  a  certain  level  through  the 
existence  of  a  proper  degree  of  hormone  stimulation,  that  is,  by  a  proper 
CH  or  C02-tension. 

Finally,  let  us  consider  for  a  moment  the  behavior  of  the  respiratory 
'quotient.  This  ratio  rises  early  in  the  muscle  work  (Table  on  page  436), 
indicating  that  more  C02  is  being  excreted  than  02  absorbed.  After  the 
work  is  discontinued,  it  usually  falls  below  the  normal  because  of  retention 
of  C02  to  take  the  place  of  that  removed  by  the  hyperpnea  excited  by 
the  other  factors  than  increase  in  C02-tension.  A  similar  fall  in  the  res- 
piratory quotient  may  sometimes  occur  during  muscular  exercise,  if  this 
is  continued  for  a  long  time. 

Second- Wind 

When  strenuous  exercise  is  maintained,  it  is  usually  the  case  that  the 
breathlessness,  which  is  severe  soon  after  the  start,  more  or  less  gradually 
passes  away,  and  the  person  feels  better  able  to  continue  the  effort.  He 
gets  his  "second- wind."  Not  only  does  the  breathing  become  easier,  but 
any  cardiac  distress  that  may  have  been  present  is  likely  to  disappear, 
and  usually  sweating  sets  in.  The  pulse  rate  does  not  change.  It  is 
difficult  to  explain  the  cause  for  the  phenomenon,  but  a  clue  is  afforded 
by  the  discovery  made  by  Pembrey  and  Cooke6*  that  the  percentage 
of  C02  in  the  alveolar  air  is  less  after  the  second-wind  has  been  ac- 
quired than  it  was  before  it.  This  probably  indicates  that  something 
has  occurred  to  cause  a  lowering  of  CH  of  the  blood  supplying  the  res- 
piratory center,*  and  it  becomes  of  interest  to  speculate  as  to  the  nature 

*It  is  highly  improbable  that  the  lessened  breathing  could  be  due  to  a  lowering  of  the  excitability 
of  the  center. 


CHANGES   ACCOMPANYING   MUSCULAR   EXERCISE  439 

of  the  adjustment  which  might  be  responsible  for  this.  Since  we  know 
that  lactic  acid  is  produced  in  vigorous  exercise  at  such  a  rate  that  it 
accumulates  in  the  blood,  but  that  it  does  not  do  so  when  the  oxygen  sup- 
ply to  the  muscles  is  commensurate  with  the  rate  of  production  of  the 
acid,  it  is  likely  that  "second-wind"  p.ojnp.irlfts  with  a  rp.arl^nstment  of 
the  chemical  processes  in  the  muscles  leading  to  a  more  thorough  elim- 
ination* of  this  metabolic  product.  The  readjustment  may  depend,  first, 
on  an  increase  in_temperature  in  the  muscles,  stimulating  the  chemical 
processes,  and  secondly,  on  increased  bloodflow  due  to  the  opening  up 
of  capillaries.  The  appearance  of  sweating  is  another  effect  of  the  rising 
temperature.  Beside  the  more  adequate  elimination  of  lactic  acid,  it  is 
also  possible  that  changes  occur  in  the  blood,  increasing  its  alkaline  re- 
serve by  migration  of  basic  radicles  into  the  plasma  from  the  erythro- 

cytes  £nd  tissues  (see  page  40).     This  will,  of  course,  enable  the  plasma 

TT  r*(~\ 
to  take  up  more  acid  without  change  of  the  normal  ratio 


The  Influence  of  Oxygen  Inhalations  on  the  Effects  of  Muscular  Exercise 

The  most  important  work  in  this  connection  is  that  of  Leonard  Hill 
and  his  pupils46  who  have  found  that  the  inhalation  of  pure  oxygen  for 
a  few  minutes  renders  a  person  capable  of  greater  exertion,  and  decidedly 
lessons  the  degree  of  breathlessness  and  the  various  symptoms  of  cardiac 
distress.  That  the  improvement  of  the  circulation  does  actually  occur 
is  indicated  objectively,  by  the  fact  that  the  pulse  is  slower,  and  the 
blood  pressure  higher  for  a  given  degree  of  exercise  after  oxygen  than 
without  it.  Symptoms  of  cerebral  anemia  such  as  dizziness,  blurring  of 
vision,  etc.,  are  also  much  less  common  during  very  strenuous  work,  if 
oxygen  has  been  inspired  prior  to  the  effort.  There  are  at  least  two 
ways  by  which  the  excess  of  oxygen  may  bring  about  these  effects:  either 
it  becomes  stored  and  prevents  incompletely  oxidized  acids  from  accu- 
mulating or  retards  a  fall  in  02-tension,  or  it  increases  the  power  of  the 
blood  to  carry  away  the  oxidation  products  (C02).  Regarding  the  sec- 
ond possibility  it  is  now  well  known  that  increase  in  oxygen  in  the  blood 
lowers  the  dissociation  curve  for  C02  because  the  oxygen  displaces  C02  from 
hemoglobin  (page  404).  The  preliminary  inhalations  of  02  will  drive  out 
C02  from  the  blood  and  therefore  make  more  room,  as  it  were  for  the  extra 
load  of  this  gas  which  the  blood  must  carry  during  exercise.  Experimental 
evidence  that  these  changes  actually  occur  is  afforded  by  measurement  of 
the  breaking  point  when  the  breath  is  held,  that  is  the  time  during  which 
the  breath  can  be  held  before  an  irresistible  stimulus  to  breathe  is  expe- 
rienced. After  inhalation  of  oxygen  the  breaking  point  is  materially  pro- 
longed because  the  oxygen,  by  removing  C02  from  the  hemoglobin,  has 
enabled  it  to  take  up  more  of  the  gas  while  the  breath  was  held. 


440 


THE   RESPIRATION 


The  value  of  oxygen  inhalations  is  most  marked  in  the  early  stages  of 
great  exertion,  rather  than  later,  and  it  is  no  doubt  particularly  by 
maintaining  the  vigor  of  the  heart  beat,  that  it  acts.  From  what  has 
been  said  in  the  foregoing  paragraphs  of  this  chapter,  it  must  be  clear 
that  the  limitations  to  muscular  work  are  set  by  the  ability  of  the  heart 
to  maintain  a  circulation  rate  that  is  proportionate  to  the  demands  of 
the  muscles  for  oxygen,  and  the  output  of  the  heart  depends  on  the  oxy- 
gen carried  to  it  by  its  blood  supply.  It  is  probable  also  that  the  heart 
does  not  require  to  perform  as  much  work  in  order  to  maintain  an  ade- 
quate oxygen  supply  to  the  tissues  when  these  can  use  some  of  the  ex- 
cess stored  in  them,  if  such  storage  occurs.  In  this  way  its  expenditure 
of  energy  will  be  conserved. 

The  After-effects  of  Exercise 

Much  attention  has  been  given  in  recent  years  to  the  study  of  the 
after-effects  of  exercise,  because  of  the  valuable  information  concern- 
ing the  reserve  power  of  the  heart  which  can  thereby  be  obtained.  In  a 
normal  person  the  blood  pressure  and  pulse  rate,  as  we  have  seen,  are 
both  materially  raised  during  the  exercise,  but  they  promptly  return 
to  normal  after  it  is  terminated,  unless  the  exercise  has  been  both  severe 
and  prolonged,  when  the  pulse  rate  may  decline  fairly  rapidly  at  first, 
but  later  only  slowly,  so  that  it  still  remains  excessive  even  after  an 
hour.  This  delay  in  return  to  the  normal  pulse  rate  is  possibly  asso- 
ciated with  the  prolonged  increase  in  energy  metabolism,  which  a  bout 
of  strenuous  exercise  always  stimulates  (Benedict  and  Cathcart65).  In 
order  to  standardize  methods  for  testing  these  effects  in  the  clinic, 
Cotton,  Rapport  and  Lewis36  have  adopted  the  practice  of  causing  the 
patients  to  lift  dumbbells  of  20  Ib.  weight  from  the  floor  to  the  shoulders 
at  a  rate  of  every  2  seconds  for  periods  of  time  varying  between  20  and 
80  seconds.  The  pulse  rate  and  blood  pressure  are  taken  immediately 
before  and  at  varying  periods  after  the  exercise,  and  the  results  are 
tabulated  as  shown  in  the  accompanying  table. 


WORK 

PULSE 

SYSTOLIC    BLOOD    PRESSURE 

Lifts     20     Ib.     dumb- 
bells   every    2    see. 
for: 

Before 

Maximum 

After 
Time  re- 
quired    to 
fall      to 

Before 

Maximum 

After 
Time  re- 
quired    to 
fall      to 

normal 

normal 

80  sees. 

78 

170 

280+ 

121 

162 

230 

60     " 

72 

127+ 

280+ 

119 

145 

220 

40     « 

74 

118 

160 

116 

137 

120 

20     " 

80 

112 

60 

119 

128 

50 

CHANGES   ACCOMPANYING    MUSCULAR   EXERCISE  441 

The  respiratory  rate  after  such  exercise  usually  returns  to  normal 
earlier  than  the  pulse,  but  the  percentage  of  alveolar  C02,  which  is 
raised  shortly  after  the  beginning  of  the  exercise  and  depressed  imme- 
diately after  its  termination,  (page  436),  may  continue  subnormal  for 
the  best  part  of  an  hour.  The  occurrence  of  normal  breathing  with  a 
subnormal  alveolar  tension  of  C02  indicates  that  a  state  of  so-called 
compensated  acidosis  (page  39)  must  exist.  When  the  exercise  is 
more  prolonged,  the  alveolar  C02  may  remain  subnormal  for  hours.  If 
the  exercise  is  sufficient  to  raise  the  body  temperature,  this  usually 
returns  to  normal  in  about  an  hour,  and  may  even  become  subnormal  for 
a  time. 

Effort  Syndrome 

In  a  perfectly  healthy  person  violent  exertion,  or  a  course  of  athletic 
training,  leaves  no  harmful  effects.  If  the  heart  be  unequal  to  the  strain, 
however,  a  lessened  capacity  to  perform  muscular  work  may  become 
established  and  may  persist  for  weeks  or  months.  Its  lessened  capacity 
is  shown  by  the  fact  that  the  changes  in  blood  pressure,  in  pulse  rate  and 
in  breathing  are  greater  and  last  after  the  exercise  for  a  much  longer 
time  than  they  ought  to.  Distressing  subjective  symptoms  such  as  giddi- 
ness, palpitation,  breathlessness  and  precordial  pain  are  also  brought 
on  even  by  moderate  effort.  The  condition  in  which  exercise  has  these 
unfavorable  results  has  been  called  "irritable  heart,"  or  "effort  syn- 
drome," and  it  is  important  to  remember  that  the  symptoms  may  be 
entirely  absent  while  the  person  is  at  rest  and  only  appear  when  muscular 
exercise  is  attempted.  There  has  been  considerable  debate  as  to  the 
etiological  factors  involved  in  this  condition,  some  maintaining  that  these 
are  dependent  on  a  hyperexcitability  of  the  central  nervous  system, 
while  others  believe  that  they  are  due  to  toxic  products,  either  bacterial, 
or  derived  from  some  faulty  metabolism.  (Lewis66.)  There  does  not 
appear  to  be  any  justification  for  the  hypothesis  that  the  condition  may 
depend  on  prolonged  lowering  of  the  alkaline  reserve  of  the  blood  (Bain- 
bridge). 

It  seems  probable  that  it  is  the  cardiac  function  that  is  fundamentally 
upset  in  this  condition.  Because  of  toxic  processes  the  supply  of  oxy- 
gen to  the  cardiac  muscle  does  not  adapt  itself  to  the  extra  strain  put 
upon  it,  so  that  the  heart  fails  to  beat  powerfully  enough  to  maintain 
sufficient  blood  supply  to  the  tissues,  especially  the  nerve  centers.  The 
latter  then  also  suffer  from  lack  of  oxygen,  and  the  whole  complicated 
mechanism  of  adjustment  of  the  body  to  the  extra  demands  fails 
to  be  properly  coordinated.  In  support  of  this  view  it  is  note- 
worthy that  the  cardiac  muscle  is  very  susceptible  to  bacterial  and  other 


442  THE  RESPIRATION 

toxins,  and  that  evidence  of  preexisting  infectious  disease  is  very  common 
in  those  suffering  from  effort  syndrome  (Lewis).  It  is  also  interesting, 
as  Bainbridge  points  out,  that  "as  regards  their  response  to  exercise  a 
man  suffering  from  effort  syndrome  bears  almost  the  same  relation  to 
a  healthy  untrained  man  that  the  latter  does  to  a  trained  man."  Since 
training  affects  the  cardiac  function,  primarily,  the  above  analogy 
would  lend  support  to  the  view  that  the  cause  for  effort  syndrome  is  a 
great  depression  in  cardiac  function.  Under  suitable  treatment, — rest 
followed  by  exercises  that  are  graded  to  the  capacity  of  the  individual, — 
the  condition  of  effort  syndrome  often  disappears  (remedial  dilatation), 
but  sometimes  this  is  not  the  case,  and  the  heart  remains  permanently 
dilated  (irremedial  dilatation)  ("over  stress"  of  the  heart).  It  has 
been  assumed  by  clinical  investigators  that  in  the  latter  group  of  cases 
the  cardiac  muscle  fibers  have  become  mechanically  stretched  beyond 
their  limits  of  elasticity  by  the  exertion  which  was  responsible  for  the 
establishment  of  the  effort  syndrome. 

It  has  been  shown  by  Wearn  and  Sturgis76  that  intramuscular  injec- 
tions of  0.5  c.c.  1-1000  epinephrin  in  normal  men  cause  only  a  slight  rise 
in  blood  pressure  and  pulse  rate,  and  only  transient  and  trivial  subjec- 
tive symptoms.  In  those  suffering  from  the  condition  known  as  irrita- 
ble heart, or  effort  syndrome,  however,  the  blood  pressure  rises  decidedly 
(by  more  than  25  mm.),  the  pulse  accelerates  (by  about  26  beats  per 
minute)  and  marked  objective  symptoms  of  tremor,  pallor  or  flushing, 
sweating,  etc.,  are  noted  soon  after  the  injection  is  made  (in  about  12 
minutes).  The  patient  also  complains  of  great  discomfort.  It  has  also 
been  found  by  Tompkins,  Sturgis  and  Wearn*  that  these  injections  in- 
crease the  basal  metabolism,  the  pulmonary  ventilation  and  the  respiratory 
quotient  in  patients  with  irritable  heart  to  a  greater  extent  than  in  normal 
persons. 


*Tompkins,  E.  H.,  Sturgis,  C.  C,  and  Wearn,  J.  T.:     Ibid.,  1919,  xxiv,  269. 


CHAPTER  XLIX 

OXYGEN  UNSATURATION  OP  THE  BLOOD.   CYANOSIS  THE 
THERAPEUTIC  VALUE  OF  OXYGEN 

OXYGEN  UNSATURATION  OF  THE  BLOOD 

The  blood  leaving  the  lungs,  i.  e.,  arterial  blood,  is  95  per  cent  satu- 
rated with  oxygen.  Its  oxygen  unsaturation  is  therefore  said  to  amount 
to  5  per  cent.  The  venous  blood  is,  of  course,  unsaturated  with  oxygen 
to  a  greater  degree,  which  varies  between  22.7  and  3.3  per  cent,  depend- 
ing on  the  activity  of  the  tissues.* 

The  blood  is  transferred  under  albolene  to  prevent  contact  with  air, 
and  is  mixed  with  neutral  oxalate.  Samples  are  analysed  immediately 
for  the  percentage  of  oxygen  actually  present.  Another  sample  is  re- 
moved from  under  the  albolene  and  saturated  with  oxygen  by  exposing 
it  to  air,  after  which  it  is  also  analysed.  The  analyses  are  performed  by 
the  method  of  Van  Slyke.  Suppose  it  is  found  that  the  venous  blood 
gives  14  per  cent  02  and  the  total  02  capacity  is  20,  then  the  venous 
oxygen  unsaturation  is  30  per  cent.  The  hemoglobin  content  may  also  be 
used  to  determine  the  total  02  capacity. 

The  determinations  can  also  be  made  by  using  the  differential  manometer  of  Bar- 
croft  (page  395).  In  this  case  a  sample  of  the  blood  is  removed  by  means  of  a  pipette 
from  the  albolene  and  discharged  under  weak  ammonia  water  in  the  bottle  of  the  dif- 
ferential manometer.  After  allowing  for  temperature  changes  the  bottle  is  shaken, 
which  causes  the  blood  to  become  laked  and  saturated  with  oxygen,  which  it  takes  from 
the  confined  atmosphere  in  the  bottle  and  manometer.  This  causes  shrinkage,  the  de- 
gree of  which  is  noted  on  the  manometer.  After  readjusting  the  levels  in  the  manom- 
eter a  few  drops  of  a  saturated  solution  of  potassium  ferricyanide  is  then  mixed  with 
the  laked  blood  (without  opening  the  bottle,  see  page  403).  This  expels  the  O2  and 
creates  a  pressure  which  is  measured  in  the  manometer.  The  ratio  between  the  first 
and  second  readings  equals  the  unsaturation  of  the  blood,  and  the  second  reading,  mul- 
tiplied by  a  factor  for  the  apparatus,  gives  the  oxygen  content,  t 

Suppose  the  shrinkage  of  the  manometer  in  the  first  operation  is  25  mm.  and  the 
positive  pressure  in  the  second,  is  150,  and  the  factor  for  the  instrument  is  0.13,  then, 

100  x  25 
the  percentage  unsaturation  is  —        *"     =  16.6  per  cent  and  the  total  O2  capacity  19.5 

_LuU 
per  cent  (150x0.13). 

*The  sample  of  arterial  blood  is  collected  by  the  method  of  Hurter,  which  is  described  in  suf- 
ficient detail  by  Stadie;68  the  venous  blood  must  be  collected  without  causing  stasis. 

fThe  method  is  that  described  by  Barcroft  for  obtaining  data  from  which  the  dissociation  curve 
may  be  plotted  (page  396).  It  will  be  found  described  in  simplified  form  in  the  Tour.  Lab.  and 
Clin.  Med.,  1919,  iv,  No.  9. 

443 


444  THE   RESPIRATION 

Much  important  information  is  being  collected  concerning  these  values 
in  various  abnormal  conditions.  When  the  percentage  of  hemoglobin  is 
increased  or  decreased  the  oxygen  consumption  by  the  tissues  remains 
within  the  normal  limits  unless  the  percentage  of  hemoglobin  is  reduced 
below  30.  Thus  Lundsgaard67  found  in  a  polycythemic  patient  with  33.4 
volumes  per  cent  oxygen  capacity  (corresponding  to  181  per  cent 
hemoglobin)  a  venous  02  content  of  28  vols.  per  cent,  giving  a  differ- 
ence of  5.4  vols.  per  cent  or  16.1  per  cent  unsaturation ;  and  in  an  anemic 
patient  with  only  6.7  vols.  per  cent  oxygen  capacity  (36  per  cent  hemo- 
globin) he  found  the  venous  oxygen  to  be  1.5,  a  difference  of  5.2  vols. 
per  cent  or.  77.6  per  cent  unsaturation.  This  result  is  significant,  since 
it  shows  that  the  tissues  are  efficiently  oxygenated  whether  or  no  the 
arterial  blood  carries  a  great  reserve  or  no  reserve  at  all  of  oxygen. 
When  the  arterial  oxygen  falls  below  the  minimum  (which  is  about  30  per 
cent  hemoglobin),  the  bloodflow  must  become  increased  in  order  to  sup- 
ply the  tissues  with  the  normal  amount  of  oxygen.  The  observations  on 
the  mass  movement  of  the  blood  in  the  hands  and  the  viscera  referred 
to  elsewhere  in  this  volume  (page  208)  are  of  interest  in  this  connection. 

Cyanosis. — Before  considering  the  fundamental  causes  for  cyanosis  it 
is  important  to  note  that  a  condition  not  unlike  it  may  be  due  to  marked 
polycythemia  (erythrosis  or  false  cyanosis).  In  this  condition  the  oxy- 
gen unsaturation  of  the  venous  blood  is  normal.  Cyanosis  itself  is  prob- 
ably always  due  to  an  excessive  degree  of  oxygen  unsaturation  of  the 
blood,  although  sometimes,  as  in  poisoningT^T certain  drugs/Tris  caused 
by  conversion  of  oxyhemoglobin  into  methemoglobin.  The  unsaturation 
may  be  due  to  excessive  reduction  of  the  blood  in  the  tissues,  in  which 
case  the  arterial  blood  remains  normal,  or  it  may  depend  on  inadequate 
aeration  of  the  blood  in  the  lungs  when  both  venous  and  arterial  blood 
will  give  high  unsaturation  values. 

Excessive  reduction  in  the  tissues  may  result  either  from  increased 
activity,  as  in  vigorous  muscular  exercise,  or  from  a  sluggish  circula- 
tion, so  that,  although  the  rate  of  reduction  itself  is  not  altered,  the  blood 
loses  too  much  of  its  oxygen.  This  sluggish  state  of  the  capillary  circu- 
lation may  be  due  to  venous  obstruction,  to  independent  dilatation  of 
the  capillaries  (see  page  252),  or  to  a  slow  circulation  time  of  the  blood 
as  a  whole.  Faulty  aeration  of  the  blood  in  the  lungs  may  be  the  result 
of  interference  with  the  ventilation  of  the  alveoli  from  pneumonia, 
bronchitis,  edema,  etc.,  or  it  may  be  due  to  disturbances  in  the  lesser 
circulation,  as  in  valvular  or  congenital  heart  disease. 

Lundsgaard67  has  furnished  some  interesting  figures  to  show  the  de- 
gree to  which  the  unsaturation  of  the  venous  blood  must  occur  to  cause 
cyanosis.  The  practical  value  which  such  information  has  already  af- 


OXYGEN   UNSATURATION   OF    THE   BLOOD  445 

forded  in  following  the  treatment  of  pneumonia  indicates  the  lines  along 
which  future  progress  is  likely  to  take  place. 

THE  THERAPEUTIC  VALUE  OF  OXYGEN 

There  is  no  therapeutic  measure  that  is  less  efficiently  put  into  prac- 
tice than  the  administration  of  oxygen,  and  as  a  consequence,  most  phy- 
sicians have  little  faith  in  its  value.  There  are  several  reasons  for  this 
state  of  affairs:  in  the  first  place,  the  physiological  mechanism  by  which 
added  oxygen  could  assist  in  the  respiratory  functions  is  not  understood ; 
in  the  second,  an  insufficient  amount  of  the  gas  is  usually  given  and  in 
the  third,  it  is  usually  given  too  late.  On  the  other  hand,  when  oxygen 
is  properly  administered  in  suitable  cases  before  the  patient  has  become 
moribund,  much  evidence  has  accumulated  to  show  that  very  great  bene- 
fit indeed  results  from  the  treatment,  and  as  far  as  can  be  told  a  fatal 
termination  is  often  averted. 

Theoretical  Considerations. — In  order  to  understand  the  physiological 
principles  involved  in  this  treatment,  it  is  important  to  remember  that 
although  forty  to  fifty  times  as  much  oxygen  is  combined  with  hemo- 
globin as  is  in  simple  solution  in  the  blood  plasma,  yet  it  is  the  latter 
which  really  diffuses  into  the  tissues.  The  pressure  of  oxygen  in  the 
plasma,  in  other  words,  the  diffusion  pressure  of  oxygen,  is  the  deter- 
mining factor  in  causing  it  to  permeate  the  tissues,  and  whenever  this 
pressure  begins  to  fall  under  normal  conditions,  more  is  added  to  the 
plasma  by  dissociation  from  the  oxyhemoglobin  of  the  corpuscles.  The 
plasma  retails  the  oxygen  to  the  tissues,  and  the  corpuscles  are  the 
wholesale  warehouses  from  which  the  plasma  replenishes  its  stock.  The 
unloading  of  oxygen  from  the  oxyhemoglobin  to  the  plasma  is  assisted 
by  various  chemical  changes  that  take  place  while  the  blood  is  in  the 
capillaries.  From  these  considerations  it  follows  that  an  efficient  sup- 
ply of  oxygen  to  the  tissues  could  be  maintained  without  any  hemoglobin 
if  we  were  to  put  an  excess  of  the  gas  into  simple  solution  in  the  plasma ; 
that  is,  if  enough  were  forced  into  solution  in  the  plasma  in  the  lungs  so 
that  the  tissue  requirements  could  be  met  without  any  local  addition 
from  oxyhemoglobin.  Two  experiments  may  be  quoted  to  show  that  it  is 
possible  to  fulfil  these  conditions. 

1.  After  replacing  all  the  blood  from  the  blood  vessels  of  a  frog  by 
artificial  plasma  (Ringer's  solution)   the  animal  can  be  kept  alive  for 
days  in  a  vessel  containing   pure  oxygen    (i.  e.,   five  times  the   amount 
present  in  air)  and  during  this  time  the  rate  of  02  consumption  and  C02 
production  are  practically  the  same  as  normally. 

2.  Animals  (mice)  exposed  to  air  containing  more  than  0.5  per  cent  of 


446  THE   RESPIRATION 

carbon  monoxide  (contained  in  coal  gas)  soon  become  moribund,  because 
the  oxygen  carrying  power  of  the  hemoglobin  is  entirely  abolished  by  the 
formation  of  carboxy  hemoglobin.  If  the  animals  are  now  transferred 
to  pure  oxygen  under  two  atmospheres  pressure  (i.  e.,  10  times  the 
amount  in  air)  they  quickly  recover. 

Both  experiments  show  clearly  that  if  we  succeed  in  getting  sufficient 
oxygen  into  simple  solution  in  the  plasma,  the  oxyhemoglobin  is  not  nec- 
essary to  supply  the  tissues  with  this  gas. 

It  is  evident,  therefore,  that  oxygen  administration  can  be  of  no  avail 
in  poisoning  by  coal  gas,  or  any  other  substance,  which  destroys  the 
02-carrying  power  of  hemoglobin,  unless  it  is  forced  into  the  alveoli  so 
as  greatly  to  increase  the  partial  pressure.* 

In  pulmonary  edema,  in  " gassed"  cases,  in  bronchitis,  and  in  decom- 
pensated  cardiac  cases,  oxygen  is  also  of  undoubted  value,  when  it  is 
properly  administered.  Many  cases  of  pneumonia  are  also  benefited  by 
such  treatment,  but  there  are  others  in  which  the  heart  is  so  profoundly 
affected  by  toxic  substances  that  oxygen  may  perhaps  be  of  little  use. 
Evidence  of  this  benefit  is  afforded  by  the  easier  and  deeper  breathing, 
the  slowing  of  the  pulse,  the  disappearance  of  cyanosis  and  the  greater 
ease  and  comfort  experienced  by  the  patient.  Not  only  do  these  effects 
persist  as  long  as  the  gas  is  given,  and  thereby  serve  to  tide  over  a  crisis 
and  permit  the  natural  defensive  agencies  of  the  body  more  successfully 
to  combat  the  abnormal  condition,  but  they  often  outlast  the  administra- 
tion. 

Quantitative  evidence  that  in  pneumonia  the  arterial  blood  is  improp- 
erly saturated  with  oxygen  in  proportion  to  the  degree  of  cyanosis,  and 
therefore  of  the  condition  of  the  patient,  has  been  furnished  by  Stadie.68 
In  a  normal  person  the  arterial  blood  carries  95  per  cent  of  its  full  load 
of  oxygen,  but  in  pneumonia  only  a  little  over  80  per  cent.  Meakins72 
has  confirmed  these  findings,  and  has  added  most  important  observations 
on  the  effect  of  oxygen  inhalations  by  the  Haldane  method.  In  a  case 
of  pneumonia  the  oxygen  unsaturation  on  the  eighth  day  of  the  disease 
was  17.9  per  cent.  After  two  hours  of  oxygen  treatment  (at  a  rate  of 
delivery  of  2.5  liters  02  per  minute)  the  unsaturation  percentage  fell 
to  9.08,  and  after  18  hours  (at  1  liter  per  minute)  it  was  9.0.  The 
02  was  then  discontinued  and  in  4  hours  the  unsaturation  percentage 
had  risen  to  15.5.  It  fell  subsequently  to  3.05  after  24  hours,  during 
which  3  liters  02  per  minute  was  administered.  Shortly  after  this  the 
crisis  occurred.  Similar  results  were  obtained  in  a  case  of  chronic  bron- 
chitis, and  even  in  normal  men  it  was  found  that  inspiration  of  3  liters 

'Hemoglobin  becomes  converted  into  methemoglobin  and  incapable  of  carrying  labile  O2  in  vari- 
ous types  of  poisoning,  e.  g.,  acetanilide,  nitrobenzol. 


OXYGEN   UNSATURATION   OF   THE   BLOOD  447 

of  02  per  minute  for  100  minutes  changed  the  arterial  blood  from  4.4  per 
cent  unsaturation  to  1.87  per  cent.  To  explain  exactly  how  the  oxygen 
acts  in  this  group  of  cases  several  possibilities  must  be  considered.  In 
the  first  place  we  must  suppose  that  the  respiratory  membrane  has  become 
greatly  reduced  in  extent  because  the  alveoli  in  certain  parts  of  the  lungs, 
have  become  more  or  less  filled  with  fluid  or  exudate.  Under  these  cir- 
cumstances the  blood  circulating  in  the  vessels  of  the  affected  portion 
of  lung  cannot  be  reached  by  a  sufficient  amount  of  oxygen  to  saturate 
its  hemoglobin  fully,  because  there  is  an  inadequate  diffusion  pressure  of 
oxygen  to  penetrate  the  thick  layer  of  fluid  between  the  alveolar  air 
and  blood.  When  the  exudation  completely  fills  the  alveoli  the  blood 
ceases  to  circulate  through  the  capillaries  of  the  affected  part,  so  that 
all  the  blood  is  passing  through  the  capillaries  of  healthy  parts.  This 
explains  why  the  arterial  blood  may  remain  of  a  bright  red  color  in  cases 
where  there  is  entire  consolidation  or  collapse  of  considerable  areas 
of  lung.  So  long  as  the  hemoglobin  is  not  fully  saturated  the  tension 
of  oxygen  in  the  plasma  must  become  very  low  and  little  can  be  avail- 
able for  the  tissues  when  the  blood  arrives  at  them.  When  excess  oxy- 
gen is  breathed  the  amount  which  goes  into  solution  in  the  fluid  will 
become  proportionately  raised  so  that  there  will  .be  a  much  better  chance 
for  a  sufficient  amount  to  reach  the  plasma,  so  as  to  saturate  the  hemo- 
globin and  create  a  proper  tension  in  the  plasma. 

The  blood  which  leaves  the  lungs  as  a  whole  is  a  mixture  of  blood, 
still  more  or  less  venous  from  the  blocked  portions,  and  of  arterial  blood 
from  the  healthy  portions,  and  it  may  be  considered  that  the  mixture  is 
just  on  the  border  line  of  being  adequate  to  supply  the  oxygen  require- 
ments of  the  tissues  and  nerve  centers — otherwise  the  animal  could 
not  live.  A  very  little  improvement  in  the  oxygen  supply  will  therefore 
suffice  to  turn  the  tide  and  it  is  possible  that  this  may  reach  it  by  diffu- 
sion through  the  fluid  that  has  collected  in  the  alveoli.  By  increasing 
the  pressure  of  oxygen  in  the  inspired  air,  more  will  become  dissolved 
in  the  fluid  (by  Henry's  law,  page  353)  so  that  the  pressure  gradient  from 
air  to  blood  through  the  fluid  will  become  steeper.  But  another  fac- 
tor must  be  considered,  namely,  that  the  increased  partial  pressure  in 
the  healthy  alveoli  has  caused  more  02  to  go  into  simple  solution  in  the 
plasma  of  the  blood  circulating  in  these  portions,  and  although  this 
cannot  cause  the  hemoglobin  of  the  blood  to  carry  away  any  greater 
load  of  the  gas,  yet  when  this  blood  is  mixed  with  that  from  the  patho- 

*The  coefficient  of  solubility  of  oxygen  in  water  at  20°  C.  is  0.34.,  i.  e.,  0.34  c.c.  O2  will  diffuse 
through  Ifi  (.001  mm.)  of  water  in  1  minute  when  1  sq.  cm.  of  the  water  is  exposed  to  1  atmosphere 
of  the  gas.  (Krogh,  A.73).  The  amount  which  will  diffuse  through  fluid  is  proportional  to  the 
thickness  of  the  layer  of  fluid. 


448  THE   RESPIRATION 

logical  lobes,  the  dissolved  oxygen  will  assist  in  bringing  the  hemoglobin 
up  to  its  proper  degree  of  saturation  with  oxygen. 

It  has  been  imagined  by  some  that  it  is  useless  to  give  oxygen  because 
the  dissociation  curve  of  the  blood  at  varying  pressures  of  the  gas  (page 
396)  shows  even  after  reducing  the  partial  pressure  of  oxygen  to  one  half 
that  obtaining  in  normal  alveolar  air,  the  blood  still  takes  up  80  per  cent 
of  its  full  load.  It  is  argued  that  it  is  therefore  futile  to  attempt  to 
increase  the  oxygen  carried  by  the  blood  by  raising  the  partial  pressure 
in  the  air  which  is  inspired  into  the  still  healthy  alveoli.  From  what 
has  been  said  above,  however,  it  is  clear  that  this  viewpoint  does  not 
take  into  account  two  important  effects  which  follow  when  the  partial 
pressure  of  the  oxygen  is  increased,  namely,  that  under  this  condition 
oxygen  diffuses  much  more  rapidly  through  the  fluid  in  the  pathological 
portions  of  the  lung,  and  at  the  same  time  that  more  goes  into  simple 
solution  in  the  plasma  that  is  circulating  in  the  healthy  portions. 

Principles  in  Method  of  Administration. — The  success  of  any  treat- 
ment with_Qxygen  must  depend  on  several  factors,  the  most  important 
of  which  are:  (1)  to  get  as  much  of  the  gas  into  the  alveoli  as  possible; 
to  start  the  treatment  early  before  irreparable  damage  has  been  done 
because  of  anoxemia ;  and  (87  to  maintain  the  administration  until  cyanosis 
disappears.  With  regard  to  the  first  of  these  factors,  it  has  sometimes 
been  thought  that  there  is  an  element  of  danger  in  giving  too  much 
oxygen.  This  depends  on  the  observations  made  by  several  investiga- 
tors that  animals  that  have  been  caused  to  live  in  more  than  one  atmos- 
phere of  the  pure  gas  for  some  time  develop  symptoms  of  pulmonary 
irritation,  leading  on  to  pneumonia.  Even  by  the  best  methods  of  ad- 
ministration, however,  not  more  than  85  per  cent  of  the  gas  can  be  got 
into  the  alveoli  and  it  takes  three  or  four  days  for  this  percentage  to 
cause  pneumonia,  even  in  small  animals.  (Lorrain  Smith.)  Karsner 
has  also  shown  that  there  is  no  danger  in  administration  of  pure  oxygen, 
even  for  long  periods  of  time. 

The  importance  of  early  administration  is  evident  when  we  realize 
that  the  damage  of  oxygen  deficiency  on  the  nerve  centers  and  the  tis- 
sues usually  develops  insidiously,  and  that  once  started  the  damage 
must  lead  to  a  progressive  deterioration  of  the  vital  functions  of  the 
body.  The  respiratory  center  is  among  the  first  to  suffer  from  the  anox- 
emia. The  result  is  shallow  and  rapid  breathing.  Such  breathing  does 
not,  however,  properly  ventilate  the  alveoli  (page  418),  so  that  the  anox- 
emia becomes  aggravated,  and  a  vicious  respiratory  circle  becomes  es- 
tablished. The  defensive  agencies  of  the  body  against  toxins  and  bac- 
teria are  also  depressed  by  the  anoxemia  so  that  resistance  to  the  fur- 
ther progress  of  the  disease  is  deteriorated.  It  is  also  posible  that  pro- 


OXYGEN    UXS  ATI  "RATION    OF    THE    BLOOD  449 

longed  oxygen  deficiency,  or  it  may  be  some  toxic  substance  appearing 
in  the  blood  as  a  result,  renders  the  hemoglobin  less  capable  of  carrying 
oxygen  by  changing  some  of  it  into  methemoglobin.  It  is  at  least  sig- 
nificant that  this  compound  is  formed  in  animals  after  massive  injections 
of  streptococci  (Peabody7*).  The  maintenance  of  an  adequate  tension 
of  oxygen  in  the  plasma,  by  administration  of  oxygen  by  the  lungs, 
may  retard  the  development  of  toxic  substances. 

For   similar   reasons,    the    administration   should   be   maintained    until 
all  signs  of  deficient  oxidation  are  removed,  the  best  index  of  this  being 
the  color  of  the  face.    So  long  as  there  is  any  anoxemia  this  is  of  a  char- 
acteristic pale  ashen  hue,  different  from  that  of  ordinar}'  capillary  con 
gestion. 

t      Methods  of  Administration. — It  may  be  said  at  once  that  the  common 

I  clinical  practice   of  placing  a  funnel   connected   with  an   oxygen  tank 

|^in  front  of  the  patient's  face  is  worse  than  useless.    At  the  rate  at  which 

the  oxygen  is  usually  applied  by  this  method,  it  is  inconceivable  how 

any  measurable  increase  in  the  percentage  of  oxj^gen  in  the  alveolar 

air  could  be  attained,  and  if  enough  gas  is  turned  on  really  to  have  some 

influence,  the  waste  due  to  diffusion  into  the  air  is  prohibitive. 

Where  no  special  apparatus  is  obtainable  for  the  administration,  the 
best  -method  is  to  pass  a  wide  gum  elastic  catheter  into  one  nostril, 
through  which  the  gas,  after  bubbling  through  water  in  a  flask,  is 
passed  as  quickly  as  is  comfortable  for  the  patient.  The  method  is  ren- 
dered much  more  efficient  if  the  open  nostril  is  closed  by  the  attendant 
during  each  inspiratory  act.  Dr.  Rudolf  and  I  have  found  by  this  lat- 
ter method  that  the  concentration  of  oxygen  in  the  alveolar  air  can  be 
raised  to  35  per  cent,  With  the  opposite  nostril  open,  this  percentage 
was  much  less. 

When  special  appliances  are  available,  a  choice  may  be  made  between 
a  face  mask,  such  as  that  devised  for  the  purpose  by  J.  S.  Haldane,70  and 
which  was  extensively  used  in  the  treatment  of  gassed  men,  or  an  anes- 
thetic mask  may  be  employed.  The  oxygen  is  discharged  from  a  cylin- 
der of  the  gas,  (provided  with  a  reducing  valve)  through  tubing  con- 
nected with  a  T-piece.  To  one  limb  of  the  T  a  small  rubber  bag  is  at- 
tached, and  the  other  is  furnished  with  a  small  mica  valve  and  ends 
in  the  face  mask.  The  valve  does  not  open  on  expiration,  so  that  oxy- 
gen only  collects  in  the  bag,  and  it  is  inhaled  on  inspiration.  The  ap- 
pliance is  simple  and  saves  oxygen,  but  patients  not  infrequently  ob- 
ject to  covering  up  of  the  face  with  the  mask. 

A  very  satisfactory  method  is  that  of  S.  J.  Meltzer,71  in  which  a  flat 
metal  tube  (hollow  tongue  depressor)  is  connected  by  wide  rubber  tub- 
ing to  a  very  easily  manipulated  respiratory  valve,  beyond  which  is  a 


450  THE   RESPIRATION 

strong  rubber  bag  attached  to  the  rubber  tubing  coming  from  an  oxygen 
cylinder.  When  the  valve  is  in  the  inspiratory  position,  the  gas  passes 
through  the  bag  into  the  tongue  depressor;  when  in  the  expiratory 
position  it  fills  the  bag  and  none  gets  beyond  the  valve.  The  tongue 
depressor  is  inserted  in  the  mouth  not  much  farther  than  the  middle  of 
the  tongue,  so  that  there  may  be  no  gagging  or  other  discomfort,  and 
the  lips  are  kept  closed.  The  valve  is  manipulated  by  the  attendant 
about  10  to  12  times  a  minute. 

By  this  method,  with  the  nose  clamped,  we  have  been  able  to  raise 
the  percentage  of  oxygen  in  the  alveolar  air  to  eighty-five. 

Of  course  by  far  the  most  satisfactory  method  is  to  place  the  patient 
\in  a  respiratory  cabinet  filled  with  oxygen.  Such  cabinets  are  being 
pied  in  England,  and  there  is  no  doubt  that  they  will  soon  come  into 


xtensive 


RESPIRATION  REFERENCES 

(Monographs) 

Bainbridge,  F.  A.  :     The  Physiology  of  Muscular  Exercise  (Monographs  on  Physiology) 

Longmans,  Green  &  Co.,  London,  1919. 
Barcroft,  J.:     The  Respiratory  Function  of  the  Blood,  University  Press,  Cambridge, 

Borrutau,  H.:  Nagel's  Handbuch  der  Physiologic,  1905,  i,  29. 

Douglas,  C.  G.:     Die  Regulation  der  Atmung  beim  Menschen,  Ergebnisse  der  Physiol- 

ogic, 1914,  p.  338. 
Hill,    Leonard:      Caisson    Sickness,    International   Medical    Monographs,    E.    Arnold, 

London,  1912. 
Keith,  Arthur:     The  Mechanism  of  Respiration  in  Man,  Further  Advances  in  Physi- 

ology, E.  Arnold,  London,  1909. 
Schenck,  F.:     Innervation  der  Atmung,  Ergebnisse  der  Physiologic,  1908,  p.  65. 

(Original  Articles) 

iKeith,  Arthur:     Cf.  Further  Advances. 

^Hoover,  C.  F.:    Arch.  Int.  Med.,  1913,  xii,  214;  ibid.,  1917,  xx,  701. 

s 


F.  S.,  Guenther,  A.  E.,  and  Meleney,  H.  F.:  Am.  Jour.  Physiol.,  1916,  xl,  446. 
*Meltzer,  S.  J.:    Jour.  Physiol.,  1892,  xiii,  218. 

sHaldane,  J.  S.,  and  Priestley,  J.  G.:     Jour.  Physiol.,  1905,  xxxii,  225. 
Haldane  and  Douglas:     Ibid.,  1913,  xlv,  235. 
eHenderson,  Y.,  Chillingworth  and  Whitney:  Am.  Jour.  Physiol.,   1915,  xxxviii,  1. 

Henderson  and  Morriss:     Jour.  Biol.  Chem.,  1917,  xxx,  217. 
7Krogh,  A.,  and  Lindhard:     Jour.  Physiol.,  1913,  xlvii,  30;  ibid.,  1917,  li,  59. 
sPearce,  R.  G.:     Am.  Jour.  Physiol.,  1917,  xliii,  73;  ibid.,  1917,  xliv,  369. 
sSiebeck,  R.:     Skand.  Arch.  f.  Physiol.,  1911,  xxv,  87;  Carter,  E.  P.:     Jour.  Exper. 

Med.,  1914,  xx,  21. 

loPeabody,  F.  W.,  and  Wentworth,  J.  A.:     Arch.  Int.  Med.,  1917,  xx,  443. 
"Lewis,  T.:     Jour.  Physiol.,  1908,  xxxiv,  213,  233. 
izPorter,  W.  T.:     Jour.  Physiol.,  1895,  xvii,  455. 
isChristiansen  and  Haldane,  J.:     Jour.  Physiol.,  1914,'  xlviii,  272. 

i<Boothby,  W.  M.,  and  Berry,  F.  B.:      Am.   Jour.   Physiol.,   1915,   xxxvii,  433;   also 
Boothby,  W.  M.,  and  Shamoff,  V.  N.:     Ibid.,  p.  418. 


OXYGEN   UNSATURATION   OF   THE   BLOOD  451 

isAlcock,  N.  H.,  and  Seemann,  J. :     Jour.  Physiol.,  1905,  xxxii,  30. 

i«Scott,  F.  H.:    Jour.  Physiol.,  1908,  xxxvii,  301. 

"Stewart,  G.  N.,  and  Pike,  F.  H.:     Jour.  Physiol.,  1907,  xx,  61. 

iTaCoombs,  H.  C.,  and  Pike,  F.  H. :     Proc.  Soc.  Exper.  Biol.  Med.,  1918,  xv,  55. 

isKrogh,  A.:     Skand.  Arch.  f.  Physiol.,   1910,  xxiii,  248 ;   and  A.  Krogh  with  Marie 

Krogh,  ibid.,  179. 

isHaldane,  J.  S.,  and  Priestley,  J.  G.:     Jour.  Physiol.,  1905,  xxxii,  225. 
2oScott,  B.  W.:    Am.  Jour.  Physiol.,  1917,  xliv,  196. 

2iNewburg,  Means,  and  Porter,  W.  T.  :  Jour.  Exper.  Med.,  1916,  xxiv,  583. 
"Hasselbalch,  K.  A.,  and  Lundsgaard,  Chr.:     Biochem.  Ztschr.,  1912,  xxxviii,  77,  and 

Skand.  Arch.  f.  Physiol.,  1912,  xxvii,  13. 

23Hooker,  D.  B.,  Wilson,  D.  W.,  and  Connett,  H.:     Am.  Jour.  Physiol.,  1917,  xliii,  357. 
24Campbell,  J.  M.  H.,  Douglas,  C.  G.,  and  Hobson,  F.  G.:     Jour.  Physiol.,  1914,  xlviii, 

303. 
2sLindhard,  J.:    Jour.  Physiol.,  1911,  xxxviii,  337;  Haldane,  J.  S.,  and  Douglas,  C.  G.: 

Ibid.,  1913,  xlvi. 

26Douglas,   C.   G. :     Art,   Ergebnisse  der  Physiologic,  see   Monographs. 
27Barcroft,  J.:    see  Bespiratory  Function  of  Blood. 
28M41roy,  T.  H.:     Quart.  Jour.  Physiol.,  1913,  vi,  373. 
29Fletcher,  W.  M.,  and  Hopkins,  F.  G. :     Jour.  Physiol.,  1907,  xxxv,  247 ;  also  Fletcher, 

W.  M.:     Jour.  Physiol.,  1913,  xlvii,  361. 

soByffel,  J.  H.:     Proc.  Physiol.  Soc.  in  Jour.  Physiol.,  1909,  xxxix,  29. 
siPembrey,  M.  S.,  and  Allen,  B.  W. :     Jour.  Physiol.,  1909,  xxxii,  18. 
32Buckmaster,  G.  A.:     Jour.  Physiol.,  1917,  li,  105. 
ssDouglas,  C.  G.,  Haldane,  J.  S.,  Henderson,  Y.,  and  Schneider,  E.  C.:     Phil.   Trans. 

Boy.  Soc.,  1913,  203,  B,  185. 
3'4Hill,  Leonard,  Macleod,  J.  J.   B.:     Jour.  Physiol.,  1903,  xxix,   507;    Hill,  Leonard, 

Greenwood,  M.,  Flack,  M.,  etc.:     see  Hill's  Caisson  Sickness. 
snHaldane,  J.   S. :     Deep  Water   Diving,   Committee   of   the  Admiralty    (British),  see 

Hill's  Caisson  Sickness. 

scCotton,  T.  F.,  Bapport,  and  Lewis,  T.:     Heart,  1917,  vi,  269. 
3711111,  Leonard,  and  Macleod,  J.  J.  B. :     Jour.  Physiol.,  1908,  xxxvii,  77. 
38patterson,  S.  W.,  Piper,  H.,  and  Starling,  E.  H.:     Jour.  Physiol.,  1914,  xlviii,  465. 
ssCampbell,  J.  M.  H.,  Douglas,  C.  G.,  and  Hobson,  F.  G. :     Jour.  Physiol.,  1914,  xlvi,  301. 
4oMarkwalder  and  Starling:     Jour.  Physiol.,  1913,  xlvii,  275. 
4iGesell,  B.:     Proc.  Am.  Physiol.  Soc.,  Am.  Jour.  Physiol.,  1918,  xlv. 
42Krogh,  A.:     Jour.  Physiol.,  1919,  Hi,  pp.  409,  457. 
43Dale,  H.  H.,  Bichards,  A.  N.:     Jour.  Physiol.,  1918,  Hi,  110. 
44Rrogh,  A.:     Skand.  Arch.  f.  Physiol.,  1912,  xxvii,  126. 
45Lindhard,  J.:     Arch.  f.  d.  ges.  Physiol.    (Pfliiger)   1915,  clxi,  233. 
46Hill,  Leonard,  and  Flack,  M.:     Jour.  Physiol,  1910,  xl,  347. 
47Verzar,  F.:     Jour.  Physiol.,  1912,  xliv,  243. 

4sffill,  A.  V.:  Jour.  Physiol.,  1911,  xlii,  1;  ibid.,  1913,  xlvi,  435. 
4»Evans,  C.  L.:  Jour.  Physiol.,  1912,  xlv,  213;  ibid.,  1918,  Hi,  6. 
soWest,  H.  F.:  Arch.  Int.  Med.,  1920,  xxv,  306. 

siLundsgaard,  C.,  and  Van  Slyke,  D.  D. :     Jour.  Exper.  Med.,  1918,  xxvii,  65. 
52Dreyer,  G.:     Lancet,  1919,  August,  227. 
"Schaffer,  E.  S.:     Quart.  Jour.  Physiol.,  1919,  xii,  231. 

54Lacquer,  E.,  and  Verzar.  F.:     Arch.  f.  d.  ges.  Physiol.   (Pfliiger),  1912,  cxliii,  395. 
ssBona,  P.,  and  Neukirch,  P.:     Arch.  f.  d.  ges.   Physiol.    (Pfliiger),   1912,   cxlviii,   273. 
se Jacobs,  M.  H.:     Am.  Jour.  Physiol.,  1920,  li,  321. 
"Ellis,  M.  M.:     Am.  Jour.  Physiol.,  1919,  1,  267. 
ssLutz,  B.  B.,  and  Schneider,  E.  C.:     Ibid.,  1919,  1,  228. 

^Haldane,  J.  S.,  Kellas,  A.  M.,  and  Kennaway,  E.  L.:     Jour.  Physiol.,  1919,  Hii,  181. 
eoHasselbach,  K.  A.,  and  Lindhard,  J. :     Bi  ochem.  Ztschr.,  1915,  pp.  1  and  48. 
siHaldane,  J.  S.,  Meakins,  J.  C.,  and  Priestley,  J.  G. :     Jour.  Physiol.,  1919,  Hi,  433. 
*Bayliss,  W.  M.:     Jour.  Physiol.,  1919,  Hii,  162. 
esLindhard,  J.:     Skand.  Archiv.  f.  Physiol.,  1912,  xxvi,  289,  and  Jour.  Physiol.,  1911, 

xlii,  337. 
64Pembrey,  M.  S.,  and  Cook,  F.:     Proc.  Physiol.  Soc.,  1908,  in  Jour.  Physiol.,  xxxvii, 

p.  xli. 
65Benedict,  F.  G.,  and  Cathcart,  E.  P. :     Beport  187  Carnegie  Institution  of  Washington. 


452  TIII-:  RESPIRATION 

""Lewis,  T.:  Special  Eeport  Series  No.  8  issued  by  Medical  Research  Committee  Lon- 
don, 1917. 

"Lundsgaard,  C.:  Jour.  Biol.  Chem.,  1918,  xxxiii,  133;  and  Jour.  Exper.  Med.,  1918, 
xxvii,  pp.  179,  199,  219;  Ibid.,  1919,  xxx,  pp.  147,  258,  269  and  295. 

esStadie,  W.  C.:     Jour.  Exper.  Med.,  1919,  xxx,  215. 

«»Van  Slyke,  D.  D.:     Jour.  Biol.  Chem.,  1918,  xxxiii,  127. 

"oHaldane,  J.  S.:     Brit.  Med.  Jour.,  1919,  July,  p.  64. 

nMeltzer,  S.  J.:     Jour.  Am.  Med.  Assn.,  1917,  Ixix,  1150. 

•  2Meakins,  J.  C.:     Brit.  Med.  Jour.,  March  1920,  p.  324. 
-sKrogh,  A.:     Jour.  Physiol.,  1919,  Hi,  391. 
wPeabody,  F.  W.:     Jour.  Exper.  Med.,  1913,  xviii,  1. 

75gcott,  R.  W.:     Proc.  Soc.  Exper.  Biol.  and  Med.,  1919,  xvii,  pp.  18,  19  and  2.1. 
reWearn,  J.  T.,  and  Sturgis,  C.  C. :     Arch.  Int.  Med.,  1919,  xxiv,  247. 
"T'Collip,  J.  B.:     Jour.  Physiol.,  1920,  liv,  58. 
7sJacobs,  M.  W.:     Am.  Jour.  Physiol.,  1921. 

•  9Collip,  J.  B.,  and  Backus,  P.  L.:     Ibid.,  1920,  li,  568. 
soGrant,  S.  B.,  and  Goldman,  A.:     Ibid.,  1920,  lii,  209. 
si  Van  Slyke,  D.  D.:     Physiol.  Rev.,  1921,  i,  141. 
s2Evans,  .C.  Lovatt:     Jour.  Physiol.,  1921,  Iv,  160. 

s^Haggard  and  Henderson,  Y.:     Jour.  Biol.  Chem.,  1920,  xliv  and  xlv. 
84Rarcroft,  J.,  Roughton  and  Shoji:     Jour.  Physiol.,  .1921,  Iv,  371. 
sspeters,  J.  P.,  and  Barr,  D.  P.:     Jour.  Biol.  Chem.,  1921,  xlv,  489. 
sejoffe,  J.,  and  Poulton,  E.  P.:     Jour.  Physiol.,  1920,  liv,  129. 
87 Van  Slyke,  D.  D.:     Jour.  Biol.  Chem.,  1921,  xlviii,  153. 


PART  V 
DIGESTION 


CHAPTER  L 

GENERAL  PHYSIOLOGY  OF  THE  DIGESTIVE  GLANDS 

The  function  of  digestion  is  to  bring  the  food  into  such  a  condition 
that  it  can  be  absorbed  through  the  intestinal  epithelium  into  the  blood 
and  lymph.  Carbohydrates  are  broken  down  as  far  as  monosaccharides ; 
neutral  fats  are  split  into  fatty  acids  and  glycerine;  and  proteins  are 
broken  down  into  the  amino  acids.  The  agencies  which  effect  these 
decompositions  are  the  digestive  enzymes,  or  ferments,  contained  in  the 
various  digestive  fluids  or  juices.  The  digestive  juices  are  produced  by 
glands,  which  are  most  numerous  in  the  upper  levels  of  the  gastro- 
intestinal tract,  the  lower  levels  having  as  their  main  function  that  of 
absorption  of  the  digested  products.  In  order  that  the  masses  of  food 
may  be  kept  in  a  state  of  proper  consistency,  and  that  they  may  move 
readily  along  the  digestive  canal,  numerous,  mucous  glands  are  also 
scattered  along  the  whole  extent  of  the  canal.  Some  of  the  digestive 
glands,  such  as  the  main  salivary  glands,  the  pancreas,  and  the  liver, 
discharge  their  secretions  into  the  digestive  canal  by  special  ducts, 
Avhereas  others,  such  as  the  isolated  salivary  gland  follicles  in  the  mouth, 
the  gastric  glands  and  the  crypts  of  Lieberkiihn  in  the  intestine,  do  not 
have  an  anatomically  distinct  duct,  but  discharge  their  secretions  directly 
into  the  digestive  tube. 

It  will  be  convenient  to  consider,  first  of  all,  certain  properties  that  are 
common  to  the  digestive  glands,  and  then,  the  conditions  under  which 
each  gland  functionates  during  digestion. 


MICROSCOPIC  CHANGES  DURING  ACTIVITY 

Structurally  the  active  part  of  the  glands,  represented  by  the  acinus 
or  tubule,  is  composed  of  a  basement  membrane  lined  internally  with  the 
secreting  epithelium.  Outside  the  basal  membrane  are  the  lymph  spaces 
and  blood  capillaries.  After  the  gland  has  been  at  rest,  the  cells  become 

453 


454 


DIGESTION 


filled  with  granules  or  small  globules,  which  are  often  so  numerous  as 
almost  entirely  to  obliterate  the  nucleus.  When  the  gland  becomes  active, 
on  the  other  hand,  the  granules  or  globules  leave  the  cells,  except  for  a 
few  which  remain  toward  the  lumen  border.  (Figs.  143  and  144.) 


Fig.    143. — Cells  of  parotid   gland   showing  zymogen  granules:    A,   after  prolonged   rest;   B,   after  a 
moderate   secretion;    C,   after  prolonged   secretion.      (From   Langley.) 

These  observations  indicate  that  the  granular  or  globular  material  must 
represent  part  at  least  of  the  secretion  of  the  glands.  Sometimes,  even 
before  they  are  extruded,  the  granules  become  changed  into  some  differ- 
ent material,  as  is  indicated  by  the  fact  that  they  stain  differently  from 


B. 


Fig.  144.  —  Parotid  gland  of  rabbit  in  varying  states  of  activity  examined  in  fresh  state.  The 
upper  left-hand  acini  are  resting.  The  upper  right-hand  acini  are  from  a  gland  stimulated  to 
activity  by  injecting  pilocarpine,  and  the  two  lower  acini  from  one  after  stimulation  of  its  sym- 
pathetic nerve.  (After 


those  of  the  resting  gland.  It  must  not  be  thought,  however,  that  an 
extrusion  of  granules  necessarily  accompanies  secretory  activity,  for 
under  certain  conditions  a  copious  secretion  of  water  and  inorganic  salts, 
as  well  as  a  certain  amount  of  organic  material,  may  be  produced  with- 


PHYSIOLOGY   OF   THE   DIGESTIVE   GLANDS  455 

out  any  change  in  the  arrangement  of  the  granules.  In  such  cases  it  has 
been  observed,  as  in  the  pancreas,  that  fine  channels  develop  in  the 
protoplasm  of  the  cell  (see  page  464). 

From  this  histological  evidence  it  would  appear  that  the  gland  cell 
during  rest  is  endowed  with  the  property  of  building  up  out  of  the  pro- 
toplasm, as  granules  or  globules,  the  material  which  is  to  serve  as  one  of 
the  main  organic  constituents  of  the  secretion.  It  is  commonly  believed 
that  this  is  the  precursor  of  the  active  ferment  of  the  secretion ;  hence  its 
name,  zymogen.  It  has  been  shown  that  the  process  of  separation  of  the 
zymogen  granules  starts  around  the  nucleus  with  the  production  of  a 
basophile  substance,  which  in  hardened  specimens  sometimes  takes  the 
form  of  filaments.  From  this  basophilic  ergastoplasm,  as  it  is  called,  the. 
granules  are  gradually  formed,  and  then  for  some  time  continue  to 
undergo  slight  further  changes,  as  is  evidenced  by  the  fact  that  the 
staining  reaction  of  those  near  the  base  of  the  cells  differs  from  that  of 
those  at  the  free  margin.  When  the  gland  cell  is  excited  to  secrete, 
the  granules  before  being  extruded,  as  noted  above,  often  undergo  a 
definite  change,  becoming  swollen  and  more  globular  in  shape. 

MECHANISM  OF  SECRETION 

These  microscopic  studies  merely  tell  us  that  active  changes,  associated 
with  the  production  and  liberation  of  certain  of  the  constituents  of  its 
secretion,  are  occurring  in  the  gland  cell,  but  they  throw  no  light  on  the 
mechanism  whereby  the  gland  cells  secrete  water  and  inorganic  salts. 
This  may  be  dependent,  to  a  certain  extent  at  least,  on  differences  in 
osmotic  pressure  (see  page  11).  A  possible  explanation  of  the  flow  of 
water  is  as  follows:  If  a  watery  solution  of  some  osmotically  active  sub- 
stance is  put  in  a  tube,  which  is  closed  at  one  end  by  a  membrane 
impermeable  to  this  substance  and  at  the  other  by  one  permeable  to  it, 
and  the  tube  immersed  in  water,  a  continuous  current  will  be 
found  to  issue  from  the  permeable  end  so  long  as  there  remains  any 
osmotically  active  substance  in  the  tube.  If  we  assume,  then,  that  the 
membranes  at  the  two  ends  of  the  secreting  cell  are  of  such  a  nature  that 
the  one  next  the  basement  membrane  is  impermeable  to  some  osmotically 
active  substance  manufactured  by  the  cell,  and  the  other  toward  the 
lumen  is  permeable,  it  will  be  clear  that,  so  long  as  this  substance 
exists  in  the  cell,  it  will  attract  water  from  the  blood,  and  the  water 
together  with  the  osmotically  active  substance  will  be  discharged  into 
the  lumen. 

It  is  possible  that  when  anything  excites  the  cell  to  secretory  activity, 
such  as  a  nerve  impulse  or  hormone,  it  does  so  by  causing  a  change  in 


456  DIGESTION 

the  permeability  of  the  lumen  border  of  the  cell.  This  change  in  permea- 
bility may  be  dependent  upon  alterations  in  surface  tension  brought 
about  by  the  migration  of  electrolytes  to  the  border.  That  such  a  migra- 
tion of  electrolytes  does  actually  occur  has  been  demonstrated  by  A.  B. 
Macallum6  who  developed  a  microchemical  test  for  potassium,  by  the  use 
of  which  he  was  able  to  show  that  this  electrolyte  accumulates  at  the  lumen 
border  of  the  cell  during  secretory  activity,  that  is,  at  the  border  of  the 
cell  through  which  the  secretion  takes  place.  Potassium  may  be  taken 
as  a  prototype  of  electrolytes  in  general.  In  the  epithelium  of  the  small 
intestine,  where  the  current  goes  in  the  opposite  direction  to  that  in 
gland  cells,  the  accumulation  of  potassium  occurs  at  the  portion  of  the 
cell  next  the  basement  membrane. 

Other  observers  believe  that,  when  the  gland  becomes  more  active,  the 
molecules  present  in  the  cell  become  broken  down  into  smaller  molecules 
and  so  raise  the  osmotic  pressure  of  the  cell  content,  with  the  result  that 
water  is  attracted  from  the  blood  and  is  then  transferred  to  the  lumen. 
When  the  gland  is  excited  so  that  the  zymogen  granules,  as  well  as 
water  and  salts,  are  secreted,  the  primary  change  appears  to  involve  the 
granules  only.  Those  near  the  lumen  swell  up  by  absorbing  water,  and 
become  converted  into  spheres  in  which  salts  are  dissolved  in  smaller 
proportions  than  exist  in  the  lymph  bathing  the  cells.  These  swollen 
structures  are  then  ruptured  at  the  periphery  of  the  cell  and  discharged 
into  the  lumen.  This  discharge  of  a  fluid  containing  fewer  saline  con- 
stituents than  the  cell  or  surrounding  blood  plasma  brings  about  in- 
creased concentration  in  the  remaining  parts  of  the  cell,  a  process  which 
possibly  is  assisted  by  a  breaking  up  of  molecules  in  the  protoplasm  itself, 
and  which  causes  an  increase  in  osmotic  pressure  with  a  consequent 
flow  of  water  from  the  lymph  to  the  cells  and  therefore  from  the  blood 
to  the  lymph. 

OTHER  CHANGES  DURING  ACTIVITY 

Whatever  may  be  the  nature  of  the  physiological  changes  that 
are  responsible  for  the  secretory  activity  of  the  cell,  the  fact  stands  out 
prominently  that  a  considerable  expenditure  of  energy  is  entailed.  This 
is  indicated  by  the  fact  that  considerably  larger  quantities  of  oxygen 
are  taken  up  by  the  gland  when  it  is  in  an  active  state  than  when  at 
rest.  Thus,  the  oxygen  consumption  of  the  resting  submaxillary  gland 
of  the  cat  may  be  increased  five  times  during  active  secretion.  On 
account  of  this  increased  oxygen  consumption  it  is  not  surprising  that 
it  should  be  found  that  the  secretory  activity  of  the  cell  is  greatly  im- 
paired by  a  deficiency  in  oxygen. 


PHYSIOLOGY   OF    THE   DIGESTIVE   GLANDS  457 

These  active  processes  occurring  in  the  gland  when  it  is  excited  to 
secrete  are  associated  with  changes  in  electric  reaction  and  in  the 
volume  of  the  gland.  The  electric  changes  have  been  most  extensively 
studied  in  connection  with  the  salivary  gland.  Cannon  and  Cattel,7  by 
connecting  a  galvanometer  with  nonpolarizable  electrodes,  one  placed 
on  the  gland  and  the  other  on  neighboring  connective  tissue,  were  able 
to  show  that  with  each  period  of  active  secretion  a  current  of  action  was 
set  up.  This  was  first  discovered  by  Hose  Bradford  and  Bayliss,  and 
has  been  carefully  studied  by  Gesell.8  That  the  electric  current  is 
definitely  associated  with  the  secretion  of  saliva  and  is  not  caused  by 
the  vascular  changes  which  usually  accompany  this  act  was  shown  by 
its  occurrence  when  the  blood  supply  was  shut  off  from  the  gland, 
and  by  its  absence  when  there  was  no  secretion  even  though  the  vascular 
changes  were  brought  about;  neither  is  the  electric  change  due  to  the 
movement  of  fluid  along  the  duct,  as  evidenced  by  its  persistence  after 
ligation  of  the  duct. 

With  regard  to  change  in  volume,  it  might  be  expected,  on  account  of 
the  greater  vascularity  of  the  gland  accompanying  activity,  that  this 
would  increase.  On  the  contrary,  however,  it  has  been  shown  to  de- 
crease, because  of  the  large  quantity  of  fluid  secreted  from  the  gland  cells. 

The  action  of  two  drugs  on  the  gland  cells  is  of  considerable  physio- 
logic importance:  that  of  atropine,  which  paralyzes  the  secretion,  and 
that  of  pilocarpine,  which  stimulates  it.  We  shall  see  later  how  this 
information  may  be  used  in  working  out  the  exact  mechanism  of  the 
different  glands. 

Important  observations  concerning  the  relationship  of  glandular  activ- 
ity to  the  blood  supply  have  been  made  by  experiments  in  which  glands 
were  artificially  perfused  outside  the  body.  When  the  submaxillary 
gland  of  the  dog  is  perfused  with  oxygenated  Ringer's  solution,  stimula- 
tion of  its  nerve  supply  does  not  produce  the  usual  secretion,  but  if  the 
"Ringer's  solution  is  mixed  with  blood  plasma,  the  nerve  stimulation  has  its 
usual  effect  for  a  short  time.  Although  no  secretion  occurs  when 
oxygenated  Ringer's  solution  is  perfused  alone,  the  usual  vascular 
changes  still  occur  in  the  gland.  The  results  seem  to  indicate  that  the 
presence  of  some  constituent  of  the  blood  plasma  is  essential  for  the 
change  in  the  permeability  of  the  cell  wall  necessary  for  the  process  of 
secretion.  Similar  results  have  been  obtained  during  artificial  perfusion 
of  the  pancreas  when  secretin  was  used  as  the  stimulus. 

CONTROL  OF  GLANDULAR  ACTIVITY 

Having  outlined  the  general  nature  of  the  changes  occurring  in  gland 
cells  during  their  activity,  we  may  now  proceed  to  study  the  nature  of 


458  DIGESTION 

the  process  by  which  this  glandular  activity  is  controlled.  Two  mechan- 
isms of  control  are  known:  (1)  by  the  nervous  system,  and  (2)  by  means 
of  hormones. 

Nervous  Control. — Control  through  the  nervous  system  is  most  marked 
— indeed  it  may  be  the  only  means  of  control — in  glands  which  have  to 
produce  their  secretion  promptly,  whereas  hormone  control  pre- 
dominates in  those  in  which  prompt  changes  in  secretory  activity  are  not 
required.  Thus,  nervous  control  alone  is  present  in  the  salivary  glands, 
whereas  hormone  control  is  predominant  in  the  pancreas,  intestinal 
glands  and  liver.  The  gastric  glands  are  partly  under  nervous  control, 
and  partly  under  hormone  control.  It  should  be  pointed  out  here  that 
the  glands  of  the  body  other  than  the  digestive  glands  are  also  subject  to 
nervous  or  hormone  control  according  to  the  promptness  with  which  they 
are  required  to  secrete.  The  lachrymal  and  sweat  glands,  and  the  venom 
glands  of  reptiles,  for  example,  are  practically  entirely  under  nervous 
control,  whereas  most  of  the  ductless  glands,  with  the  exception  of  the 
adrenals,  are  mainly  under  the  influence  of  hormones. 

The  exact  nature  of  the  nervous  control  of  glandular  function  has, 
therefore,  been  most  extensively  studied  in  the  salivary  glands,  and  that 
of  the  hormonic  in  the  pancreas.  With  regard  to  the  salivary  glands, 
the  following  points  are  of  importance:  Their  nerve  supply  comes  from 
two  sources:  the  bull5ar__au^nomic,  and  the  sympathetic  autonomic 
(see  page  893).  These  two  nerve  supplies  have  usually  an  opposite  influ- 
ence on  the  secretory  activity  of  the  glands,  and  very  frequently  also  on 
the  vascular  changes  that  accompany  secretory  activity. 

On  account  of  its  ready  accessibility,  the  submaxillary  gland  in  the 
dog  and  cat  has  been  most  thoroughly  investigated.  The  cerebral  auto- 
nomic nerve  in  this  case  is  represented  by  the  chorda  tympani,  and  the 
sympathetic  autonomic  by  postganglionic  fibers  that  run  from  the 
superior  cervical  ganglion  to  the  gland  along  its  blood  vessels  (Fig.  145). 
After  tying  a  cannula  into  the  duct  of  the  gland,  it  will  be  found  in  the 
dog  that  stimulation  of  the  chorda  tympani  produces  an  immediate  and 
abundant  secretion  of  thin  watery  saliva  accompanied  by  a  marked 
dilatation  of  the  blood  vessels  of  the  gland. 

That  this  secretion  is  not  dependent  on  the  vasodilatation  is  easily 
shown  by  repeating  the  experiment  after  administering  a  sufficient  dose 
of  atropine  to  paralyze  the  secreting  cells.  Stimulation  of  the  nerve  then 
produces  a  vasodilatation  but  no  secretion.  The  same  conclusion  is 
arrived  at  by  an  experiment  of  an  entirely  different  nature ;  namely,  by 
observing  the  pressure  produced  in  the  duct  when  the  chorda  tympani  is 
stimulated.  This  pressure  rises  considerably  above  that  in  the  arteries, 
so  that  no  such  physical  process  as  mere  filtration  can  be  held  accountable 


/Tia//  superficial 
petrosal  nerve 
lnf.max.div.N.V 

Jacobson's 
nerve 


Fac/a/  nerve 
Cerebellum, 
Glossopharyrqea 

/_.        .     *  |       J  AVCWC? 


Medulla  oblonga 
Parotid  gland 


Chorda 

tympani 

branch* 


Thoracic 
nerves 


Superor 
cervical  gang. 


}5ubmaxillary 
gland 


Electrodes1 
'(Small  amount  of  thick  saliva 

vaso-constnction  ) 
kVaso  constrictor  fibers 
sympathetic  secretory  fibers 


Parotid  duct 
(5ten  son's) 

ubmaxillary 
duct(VJharton's) 

ublingual 
ducf 

(Bartholin's) 
Lingual  nerve 
Chordo-lingual 

triangle 


Electrodes 
( Large  amount  of  thin 

vaso-dilatation 
Sublingual  gland 


Outgoing  sympathetic 
rami  communicantes 


Post  aanglionic  fibers  are 
dotted  thus  — • 


Fig.  145. — Diagrammatic  representation  of  the  innervation  of  the  salivary  glands  in  the  dog.     (From 

Jackson.) 


PHYSIOLOGY   OF   THE   DIGESTIVE   GLANDS  459 

for  the  secretion,  and  therefore  vasodilatation  alone  can  not  be  respon- 
sible for  it.  If  the  sympathetic  nerve  supply  is  stimulated,  a  very  scanty, 
thick  secretion  takes  place  accompanied  by  vasoconstriction. 

Repetition  of  these  experiments  in  the  cat  yields  different  results, 
particularly  with  regard  to  the  influence  of  the  sympathetic,  a  copious 
secretion  being  produced  by  stimulation  of  this  nerve.  The  histological 
changes  produced  in  the  gland  cells  are  marked  after  sympathetic  stimula- 
tion, but  very  slight,  if  present  at  all,  after  chorda  stimulation. 

The  outstanding  conclusion  which  may  be  drawn  from  these  results 
is  that  two  kinds  of  secretory  activity  are  mediated  through  the  nerves; 
one  causing  a  thin  watery  secretion,  containing  only  a  small  percentage 
of  organic  matter,  and  the  other,  a  thick  viscid  secretion  with  a  large 
amount  of  organic  material.  To  explain  these  differences  the  hypothe- 
sis has  been  advanced  that,  there  are  really  two  kinds  of  secretory 
fibers,  called  secretory  and  trophic,  the  former  having  to  do  with  the 
secretion  of  water  and  inorganic  salts,  and  the  latter  with  the  secretion 
of  organic  matter ;  i.  e.,  with  the  extrusion  of  the  zymogen  granules. 
Certain  authors  (Langley)  believe  that  such  an  hypothesis  is  unneces- 
sary, and  that  the  different  results  are  dependent  upon  the  concomitant 
changes  in  the  blood  supply  produced  by  stimulating  one  or  other  nerve. 

That  there  are  really  different  kinds  of  true  secretory  fibers  is,  however, 
evident  from  the  following  experiment.  If  the  duct  of  the  gland  is 
made  to  open  on  the  surface  of  the  cheek,  secretion  of  saliva  through 
the  fistula  can  be  induced  by  placing  various  substances  in  the  mouth,  such 
as  meat  powder  or  weak  solutions  of  acid.  When  the  experiment  is  per- 
formed in  such  a  way  that  the  bloodflow  through  the  gland  can  be  observed, 
it  has  been  found  that  the  saliva  produced  by  the  stimulation  with  the  meat 
powder  contains  a  very  much  higher  percentage  of  organic  material  than 
that  produced  when  hydrochloric  acid  is  the  stimulant,  whereas  the  vascular 
changes  in  the  gland  and  the  inorganic  constituents  of  the  saliva  are  the 
same  in  both  cases.  Since  stimulation  of  the  chorda  tympani  causes  the 
secretion  of  a  watery  saliva,  while  that  caused  by  stimulation  of  the 
sympathetic  is  thick,  it  might  be  thought  that  the  secretory  fibers  are 
contained  in  the  former  and  the  trophic  fibers  in  the  latter  nerve;  that 
this  is  not  the  case  can  be  shown  by  a  repetition  of  the  above  experiment 
in  animals  from  which  the  superior  cervical  ganglion  has  been  removed. 
The  same  results  are  obtained,  indicating  that  the  chorda  tympani  con- 
tains both  secretory  and  trophic  fibers. 


CHAPTER  LI 

PHYSIOLOGY  OF  THE  DIGESTIVE  GLANDS   (Cont'd) 

THE  HORMONE  CONTROL 

Hormone  control  is  exhibited  best  in  the  case  of  the  pancreas.  The  crucial 
experiment  demonstrating  that  this  gland  is  not  primarily  dependent  upon 
nervous  impulses  for  the  control  of  its  activity  was  performed  by  Bay- 
liss  and  Starling.2  Starting  with  the  well-known  fact  that  the  application 
of  weak  acid  to  the  duodenal  mucous  membrane  excites  secretion  of  pan- 
creatic juice,  "these  workers  carefully  severed  all  the  nerve  connections  of 
a  portion  of  the  duodenum,  and  found  on  again  applying  acid  to  the  mucous 
membrane  that  the  secretion  persisted.  To  explain  this  result  they  postu- 
lated that  the  acid  must  cause  some  substance  to  be  liberated  into  the 
blood  stream,  which  carries  it  to  tfrerpflTJ'fl^fls1  the  q^ngjyf  which  it  then 
excites  to  activity.  To  test  this  hypothesis  they  scraped  off  the  mucous 
membrane~of  the  duodenum  and  ground  it  in  a  mortar  with  weak  hydro- 
chloric acid  (0.6  per  cent),  and,  after  boiling  the  solution  so  as  to  coagulate 
the  protein,  nearly  neutralizing  and  filtering,  they  obtained  a  fluid  which 
immediately  caused  a  copious  secretion  of  pancreatic  juice  when  injected 
intravenously. 

Accompanying  the  secretion,  however,  a  marked  fall  in  arterial  blood 
pressure  was  observed,  making  it  possible  that  the  secretion  might  have 
been  due  to  a  vasodilatation  occurring  in  the  pancreatic  blood  vessels.  To 
eliminate  this  possibility  they  prepared  an  extract  that  was  free  of  the 
depressor  substances  by  extracting  intestinal  epithelium  without  any  of  the 
submucous  tissue.  The  resulting  extract  had  merely  the  secretory  effect 
and  produced  no  fall  in  blood  pressure.  This  secretagoguary  substance 
they  named  secretin. 

Further  evidence  that  the  action  of  secretin  is  independent  of  the 
depressor  substances  has  been  obtained  by  taking  advantage  of  the  fact 
that  the  depressor  substance  is  more  soluble  in  alcohol  than  the  secretin. 
If  an  acid  decoction  of  duodenal  mucous  membrane  is  poured  into  abso- 
lute alcohol,  a  precipitate  is  formed.  If  this  precipitate  is  redissolved 
in  water  and  reprecipitated  several  times  by  absolute  alcohol,  then  after 
drying,  a  white  powder  is  obtained,  which  is  easily  soluble  in  water  The 
resulting  solution  injected  intravenously  has  a  powerful  secretory  action, 
but  produces  no  effect  on  blood  pressure.  The  concentrated  alcoholic 
liquor,  on  the  other  hand,  when  similarly  injected  produces  a  marked  fall  in 

460 


PHYSIOLOGY    OF    THE    DIGESTIVE    GLANDS  461 

blood  pressure.  It  is  believed  that  this  effect  is  due  to  the  action  of  histainme 
(/?-imidazolylethylamine).  A  very  strong  preparation  of  secretin  can  also 
be  prepared  by  the  method  of  Dale  and  Laidlaw,  which  depends  on  pre- 
cipitation by  mercuric  chloride.9 

Secretin  does  not  exist  preformed  in  the  epithelial  cells,  as  is  shown  by 
the  fact  that  an  extract,  made  with  neutral  saline  solution,  does  not  as  a 
rule,  have  any  secretory  action  when  injected  intravenously.  Sometimes 
a  slight  secretion  may  be  produced,  but  this  is  probably  to  be  explained 
by  the  fact  that  some  secretin  remains  behind  in  the  cells  as  a  result  of  a 
preceding  phase  of  activity.  If,  on  the  other  hand,  the  above  neutral  or 
slightly  alkaline  opalescent  solution  of  the  mucous  membrane  is  boiled 
with  acid,  secretin  may  become  developed  in  it.  The  interpretation  put 
upon  these  results  is  that  a  substance,  called  prosecretin,  exists  in  the 
epithelial  cells,  and  that  this  becomes  converted  into 


of  acid  on  the  cells.    The  secretin  thus  produced  is  then  taken  up  by  the 


blood,  none  of  ft  passing  into  the  intestinal  canal,  because  the  free  borders 
of  the  cells  are  impervious  to  secretin.  That  this  is  actually  the  case  has 
been  shown  by  finding  that  the  introduction  of  neutralized  secretin  solu- 
tion into  the  duodenum,  or  other  parts  of  the  small  intestine,  does  not 
cause  a  secretion  of  pancreatic  juice.  Similar  treatment  of  the  gastric 
mucosa,  after  pepsin  has  been  destroyed  by  heat,  also  yields  secretin 
solutions  (Luckhart).  This  fact  indicates  that  the  foregoing  hypothesis 
concerning  the  role  of  secretin  in  bringing  about  secretion  of  pancreatic 
juice  under  normal  conditions  in  the  intact  animal  is  as  yet  uncertain. 

We  know  practically  nothing  concerning  the  chemical  nature  of  secretin. 
Being  soluble  in  about  90  per  cent  alcohol  and  in  fairly  weak  acids,  it  can 
not  belong  to  any  of  the  better  known  groups  of  proteins.  As  it  is 
readily  diffusible  through  parchment  membrane,  it  can  not  be  of  very 
complex  structure,  and  as  it  withstands  heat,  it  can  not  be  an  enzyme. 
It  rapidly  deteriorates  in  strength  in  the  presence  of  alkalies. 

Any  acid  when_applied  to  th£_ mucous  membrane  is  capable  of  producing 
secretin,  and  so  are  certain  other  substances,  such  as  mustard  oil. 
Secretin  is  very  susceptible  to  destruction  by  such  digestive  enzymes 
as  those  present  in  the  pancreatic,  gastric,  and  intestinal  juices. 
That  secretin  is  present  in  the  blood  when  acid  is  in  contact  with  the 
duodenal  mucosa  has  been  shown  by  the  fact  that  injection  into  a  normal 
dog  of  blood  from  one  in  which  secretin  formation  is  going  on  (as  a 
result  of  acid  in  the  duodenum),  excites  pancreatic  secretion. 

The  pancreatic  juice  produced  by  the  injection  of  secretin,  like  that 
which  is  produced  under  normal  conditions,  does 'not  contain  any  active 
trypsin,  but  instead  contains  its  precursor,  trypsinogen.  This  becomes 
converted  into  trypsin  in  the  intestine,  being  activated  by  contact  with 


an  enzyme  present  in  the  intestinal  juice.   By  such  n 
ism  the  muoosa  of  the  pancreatic  duct  is  protected  against  nut  oiliest  ion 

hy  Irypsin. 


NERVOUS  CONTROL  OF  PANCREAS 
Prior  to  the  discovery  of  secretin,  Pavlov1  ami  his  pupils  hud  published 

numerous  experiments  purport  in;;-  lo  show  I  lint   the  secretion  of  pnnerentk' 


Fig.    146".—  Pancreatic  acini  itjuiu-.l    \\iih    hematoxylin,     Tlu-   .u-ini    at    tlu-    top   -uul    to   UK- 

•  figure  are  from  a  resting  gland,  those  10   iiu-   \\*.\\\   1-.  one   tint   h.u!   IHTH   sv.-u-tm^ 

for  over  three  hourt  as  a  result  of  aoul  in  thr  duodenum.     Tlu-  lowermost   figure  is  fi 
the  vagus  nervr  :l,iu-d   oiv   ami    on    toi    several    hi  S    te    th.it 

the  tymogen  granules  are  extruded  only  after  vagus  activity  but  not  aftei   secretin  activi 
r.ai'Kin.  Rubaacbkia  .UK!  Ss.u\tt^-h  > 


nerve.     The   nmonnt    of  s 


ju'u-o   is  controlled    through   the 


produe««d  1\\   nervous  stimulation  VTES,  bO"W6VeP,  never  found  10  l>e  so 

ns  ihnt  produced  by  secretin,  nnd  for  se\  ernl  years  nfler  the  discovery  of 


mivsiouxiY 


TIII' 


UI,ANI>S 


11  u»  la  lie r  hormone,  much  doubt  existed  as  to  the  correctness  of  Pavlov's 
claim.  As  ill  many  oilier  fields  of  physiological  science,  investigators  at- 
tempted to  show  that  one  or  the  other  mechanism  obtained,  and  they  were 
n of  inclined  to  consider  the  possibility  that  both  mechanisms  might  exist 
side  by  side.  That  such  is  the  case,  however,  is  clear  from  the  most  recent 
work,  in  which  it  has  been  found  that  if  proper  precautions  are  taken, 
repeated  stiTrmlntinn -nf  t.hn  irnqnn  nevvfl  flnna  nn.11  fnyfhftafir»rftfiny>  of 

pancreatic  juice  which,  besides  being  less  copious  thantKaT  following 


ii. 


in. 


!•''>:.  147. — Three  preparations  of  pancreatic  acini  stained  by  eosin  orange  tolni.lm  i.iuo.  The 
•I'-ini  of  Fig.  I  were  from  a  gland  after  vagus  stimulation,  and  it  is  noted  that  besides  free  ex- 
trusion of  the  granules,  globules  staining  with  orange  (and  appearing  in  deep  black  in  the  photo- 


iraph)  have  formed  and  may  be  present  in  the  ductules.     Some 

in    Iheir    sl.mnm:    properties,    !>eeonuii>;    li-hl    led     (d.uk    >M.I\     in    photo>;r, 

wen  i loin  danda  excited  by  secretin.     No  globules  appear;  the  gram 
•M'l"  11    in  the  clear  protoplasm.     (Prom  llabkin,   Rubaschktn  and  Ssa 


I  he    globules.    Innvev 
I-1O.      The   .leini    in    I  I 


secret  in  injection,  differs  from  it  in  the  important  fact  that  it  contains 
not  t.rypsinogen  but  activejCTisin.  Since  the  normal  pancreatic  juice 
contains  trypsino^cn,  this  last  mentioned  fact  would  appear  to  indicate 

that  \  a^'iis  cont  rol  of  Ihe  normal  secretion  can  not   he  an  important   affair. 

The  vjiirns  secretion  of  pancreatic  juice  is,  moreover,  paralyzed  by  atro- 
pine,  which  has  no  action  on  the  secretin  mechanism  (cf.  Bayliss). 


464  DIGESTION 

The  copious  secretion  of  pancreatic  juice  produced  by  secretin,  on  the 
one  hand,  and  the  scanty,  thick  secretion  produced  by  vagus  stimula- 
tion, on  the  other,  calls  to  mind  similar  differences  observed  in  the  secre- 
tion of  saliva  as  the  result  of  chorda-tympani  or  sympathetic  stimulation. 
It  will  be  remembered  that  from  these  latter  results  it  was  concluded 
that  there  must  be  secretory  and  trophic  fibers  concerned  in  the  control 
of  the  activities  of  gland  cells.  Interesting  corroboration  of  this  conclusion 
has  recently  been  obtained  by  histological  examination  of  the  pancreas  fol- 
lowing secretin  or  vagus  activity.  After  the  repeated  injection  of  secre- 
tin, it  is  difficult  to  observe  any  signs  of  fatigue  in  the  cells ;  the  zymogen 
granules  remain  practically  as  numerous  as  in  a  resting  gland,  but  in  the 
clear  protoplasm  of  the  outer  third  of  the  cell,  it  is  said  that  fine  channels 
of  fluid  can  be  seen.  Through  these  channels  water  is  believed  to  pass 
from  the  blood  towards  the  lumen  and  in  its  course  to  carry  with  it  some 
of  the  zymogen  granules,  without,  however,  changing  them.  Thus,  when 
the  gland  cells  are  stained  with  eosin  and  orange,  after  secretin  activity 
some  of  the  zymogen  granules  can  occasionally  be  seen  in  the  lumen  of 
the  acini  stained  with  eosin  like  those  in  the  cell  itself.  After  vagus 
stimulation  the  appearances  are  different ;  not  only  are  the  granules  more 
decidedly  removed  from  the  cells,  but  they  undergo  a  preliminary  change ; 
they  lose  the  property  of  staining  with  eosin  and  become  stained  with 
orange,  at  the  same  time  increasing  in  size  so  as  to  form  vacuoles. 
These  vacuoles  may  wander  into  the  ductules,  and  when  they  are  present 
here  they  are  stained  by  orange  (Figs.  146  and  147)  (Babkin,  etc.10). 

Why  there  should  be  both  a  nervous  and  a  hormone  control  of  the  pan- 
creatic secretion  is  not  clear.  This  gland,  unlike  the  gastric  and  salivary 
glands,  is  not  called  upon  to  become  active  all  of  a  sudden,  and  it  is  dif- 
ficult to  see  what  could  serve  as  the  normal  stimulus  operating  through 
the  nervous  pathway.  Taking  it  all  in  all,  it  is  probably  safe  to  con- 
clude that  the  nervous  mechanism  is  relatively  unimportant,  and  that 
under  normal  conditions  it  seldom  if  ever  is  called  into  operation.  Cor- 
roboration for  this  view  is  afforded  by  the  fact,  above  mentioned,  that 
the  pancreatic  juice  produced  by  vagus  stimulation  contains  active  tryp- 
sin,  which  is  not  the  case  with  normal  pancreatic  juice. 


CHAPTER  LII 

PHYSIOLOGY  OF  THE  DIGESTIVE  GLANDS  (Cont'd) 

Up  to  the  present  we  have  been  concerned  with  the  physiological  activi- 
ties of  digestive  glands  in  general,  but  now  we  must  study  each  of  them 
separately  in  order  to  find  out  the  conditions  under  which  they  become 
stimulated  to  activity  in  the  normal  process  of  digestion.  The  secretion 
of  each  gland  has  a  definite  role  assigned  to  it  in  the  complex  and  lengthy 
process  of  digestion.  It  takes  up  its  work  where  the  preceding  secre- 
tion left  off;  e.g.,  the  pepsin  of  gastric  juice  digests  protein  so  far  as 
proteoses  and  peptone;  the  trypsin  of  pancreatic  juice  then  attacks  the 
proteoses  and  peptone,  and  the  resulting  lower  degradation  products 
are  finally  attacked  by  the  erepsin  of  the  intestinal  juice.  The  secre- 
tions of  the  various  glands  are,  therefore,  required  in  a  certain  definite 
order — they  are  correlated;  and  we  must  now  give  some  attention  to  the 
precise  conditions  upon  which  the  activity  and  correlation  depend. 

THE  NORMAL  CONDITIONS  UNDER  WHICH   THE   GLANDS 
BECOME  STIMULATED  TO  INCREASED  ACTIVITY 

To  make  possible  such  observations  on  the  normal  activities  of  the 
glands,  a  preliminary  operation  has  to  be  performed  so  as  to  bring  the 
duct  of  the  gland  to  the  surface  of  the  body  and  permit  of  the  observa- 
tion of  its  secretory  activity  after  the  animal  has  recovered  from  the 
immediate  effects  of  the  operation.  We  owe  to  Pavlov1  the  surgical 
technic  by  which  these  conditions  can  be  fulfilled.  The  general  principle 
of  the  operation,  in  the  case  of  glands  provided  with  ducts,  consists  in 
making  a  circular  cut  through  the  mucous  membrane  surrounding  the 
opening  of  the  duct  and  then,  after  dissecting  the  duct  free,  stitching 
the  edges  of  the  cut  to  the  skin  wound.  Healing  then  takes  place  without 
the  formation  in  the  duct  of  any  stricture  due  to  cicatricial  tissue.  After 
the  wound  has  healed,  the  secretion  can  readily  be  collected  in  a  receiver 
attached  over  the  duct  fistula,  the  animal  being  in  every  other  way  in  a 
perfectly  normal  condition.  In  the  case  of  glands  not  provided  with  a 
duct,  other  methods  must  be  adopted  to  collect  the  secretions.  These 
will  be  described  elsewhere. 

465 


466  DIGESTION 

THE  NORMAL  SECRETION  OF  SALIVA 

The  duct  fistula  can  in  this  case  be  made  either  for  the  submaxillary 
gland,  representing  a  mucous  gland,  or  for  the  parotid,  representing  a 
serous  gland.  Under  ordinary  conditions  there  is  very  little  secretion 
from  either  duct.  When  secretion  occurs,  it  is,  of  course,  caused  by 
influences  acting  on  a  nerve  center  or  centers  in  the  medulla  oblongata, 
the  exact  location  of  which  for  the  different  glands  has  been  worked  out 
in  recent  years  by  Miller.11  The  impulses  acting  on  these  centers  may  be 
transmitted  along  afferent  nerves  coming  from  the  mucous  membrane  of 
the  mouth,  nares,  etc.,  or  by  impulses  which  we  may  call  psychic,  trans- 
mitted from  the  higher  nerve  centers.  The  reflex  secretions  caused  by 
impulses  traveling  by  the  afferent  nerve  from  the  mouth,  etc.,  have  been 
called  unconditioned,  and  those  from  the  higher  nerve  centers,  condi- 
tioned. With  regard  to  the  former,  there  is  considerable  discrimination 
in  the  type  of  stimulus  that  will  be  effective.  Thus,  if  the  dog — for  most 
of  the  experiments  have  been  performed  on  this  animal — is  given  meat, 
a  secretion  of  thick,  mucous  saliva  will  be  observed  to  occur  (submaxil- 
lary gland).  On  the  other  hand,  if  the  meat  is  dried  and  pulverized, 
the  secretion  which  it  calls  forth  will  be  very  copious  and  watery  (par- 
otid gland).  There  is,  then,  an  obvious  association  between  the  nature 
of  the  secretion  and  the  function  it  will  be  called  upon  to  perform  when 
it  becomes  mixed  with  the  food.  The  mucous  secretion  called  forth  by 
meat  will  serve  to  lubricate  the  bolus  of  food  and  thus  facilitate  its 
swallowing,  whereas  the  thin  watery  secretion  produced  by  the  dry 
powder  will  have  the  effect  of  washing  the  powder  from  the  mouth. 

It  is  evident  that  the  mechanical  condition  of  the  food  partly  deter- 
mines its  exciting  quality.  Mechanical  stimulation  of  the  mucosa  in  it- 
self is,  however,  not  an  adequate  stimulus,  for  if  pebbles  are  placed  in 
the  mouth,  little  secretion  occurs,  whereas  with  sand,  secretion  immedi- 
ately becomes  copious.  The  nerve  endings  also  respond  to  chemical  stimuli. 
Thus,  weak  acid  causes  a  copious  secretion,  while  alkali  has  no  effect; 
disagreeable,  nauseous  substances  also  excite  secretion.  The  above  dif- 
ferences in  the  response  of  the  glands  according  to  the  mechanical  condi- 
tion of  the  food  has  been  observed  in  the  case  of  the  parotid  gland, 
increase  in  the  submaxillary  secretion  being  obtained  only  when  actual 
foodstuffs  are  placed  in  the  mouth. 

The  investigations  that  have  been  made  on  the  conditions  of  psychic 
secretion  of  saliva  are  still  more  interesting  and  important.  Their  im- 
portance depends  not  so  much  on  the  information  they  give  us  concern- 
ing the  secretion  of  saliva  as  such,  as  on  the  methods  they  afford  us  for 
investigating  the  various  conditions  that  affect  the  psychic  processes 


PHYSIOLOGY   OF    THE   DIGESTIVE   GLANDS  467 

associated  with,  the  taking  of  food.  It  is  from  the  psychic  rather  than 
from  the  physiologic  standpoint,  therefore,  that  these  observations  are 
of  importance,  for  they  permit  us,  by  objective  methods,  to  study  on 
dumb  animals  problems  that  would  otherwise  be  beyond  our  powers  of 
investigation.  Many  of  the  results,  with  their  bearing  on  the  functions 
of  the  higher  nerve  centers,  have  been  discussed  elsewhere  (Chapt.  Oil). 
Meanwhile,  however,  even  at  the  risk  of  repetition  it  may  not  be  out  of 
place  to  cite  a  few  of  the  most  interesting  experiments. 

If  we  tease  a  hungry  animal  with  food  for  which  he  has  a  great  appe- 
tite, a  copious  secretion  of  saliva  immediately  occurs.  If  we  go  on  teas- 
ing him  without  giving  him  food,  and  repeat  this  procedure  on  several 
succeeding  days,  it  will  be  found  that  gradually  he  no  longer  responds 
to  the  teasing  by  increased  salivation.  Evidently,  therefore,  the  reflex 
is  conditioned  upon  the  animal's  afterward  receiving  the  food. 

The  experiment  may  be  performed  in  another  way.  If,  for  example, 
we  offer  the  animal  some  food  for  which  he  has  no  appetite,  no  secre- 
tion of  saliva  will  occur;  but,  if  at  the  end  of  the  process  we  give  him 
appetizing  food,  it  will  be  found  after  repeating  this  procedure  on 
several  successive  days  that  the  presentation  of  the  unappetizing  food 
calls  forth  a  secretion.  He  has  learned  to  associate  the  presentation  of 
unappetizing  food  with  the  subsequent  gratification  of  his  appetite.  The 
experiment  can  even  be  performed  so  that  a  definite  interval  of  time 
elapses  between  the  application  of  the  stimulus  and  the  salivation:  if 
the  animal  is  teased  on  successive  days  with  food  for  which  he  has  an 
appetite  but  is  not  given  the  food  until  after  ten  or  twenty  minutes, 
presentation  of  this  food  will  come  to  be  followed  by  salivation — not 
immediately,  but  after  the  exact  interval  of  time  that  had  been  allowed 
to  intervene  in  the  training  process.  During  this  interval  there  must  be 
an  inhibition  of  psychic  stimulation  of  the  salivary  centers  by  other  nerve 
centers.  It  is  of  great  interest  that  this  inhibition  may  itself  be  inhib- 
ited by  various  forms  of  stimulation  of  the  nervous  system  (see  page  957). 

THE  SECRETION  OF  GASTRIC  JUICE 

Methods  of  Investigation 

There  being  no  common  duct,  the  secretion  of  the  gastric  glands  is  a  much  more 
difficult  problem  to  investigate  than  is  that  of  glands  which,  like  the  salivary,  are 
supplied  with  ducts.  One  of  the  most  interesting  chapters  in  the  history  of  physiology 
concerns  the  methods  which,  from  time  to  time  have  been  evolved  for  the  collection  of 
this  juice  and  for  studying  the  digestive  processes  in  the  stomach.  Prominent  among 
the  problems  confronting  the  earlier  investigators  was  the  question  whether  the  main 
function  of  the  stomach  is  to  crush  or  triturate  the  food  or  to  act  on  it  chemically. 
The  great  French  scientist  Eeaumur  and  a  little  later  the  Italian  Abbe  Spallanzani 


468 


DIGESTION 


(1729-1799)  attacked  this  problem  by  methods  that  anticipated  those  of  Behfuss  and 
Einhorn.  Spallanzani  ultimately  devised  the  method  of  swallowing  small  perforated 
wooden  tubes  containing  foodstuffs  and  covered  by  small  linen  bags.  After  the  bags 
were  passed  per  rectum,  he  found  that  considerable  erosion  or  digestion  of  the  food 
had  occurred,  but  that  the  wooden  tubes,  however  thin-walled  they  might  be,  were 
not  crushed.  In  order  to  secure  samples  of  the  gastric  juice  free  from  food,  the 
only  method  available  to  the  older  investigators  consisted  in  swallowing  sponges  at- 
tached to  threads,  which  after  being  for  some  time  in  the  stomach  were  withdrawn 
and  squeezed  dry  of  juice. 

The  next  great  contribution  came  from  this  country,  where,  in  1833,  Dr.  Beaumont, 
while  a  surgeon  in  the  service  of  the  American  troops  located  at  Mackinaw,  made  ob- 
servations on  a  Canadian  voyageur  by  the  name  of  Alexis  St.  Martin,  who  by  the 
premature  discharge  of  his  gun  had  wounded  himself  in  the  stomach,  the  wound  never 
healing  but  leaving  a  permanent  gastric  fistula.  Beaumont  arranged  to  keep  Alexis  St. 
Martin  in  his  service  for  several  years,  during  which  time  he  made  numerous  observa- 


Fig.  148. — Diagram  of  stomach  showing  miniature  stomach  (5)  separated  from  the  main  stomach 
(V)  by  a  double  layer  of  mucous  membrane.  A.A.,  is  the  opening  of  the  pouch  on  the  abdominal 
wall.  (Pavlov.) 


tions  on  the  process  of  digestion  in  the  stomach — observations  many  of  which  are  of 
great  value  even  at  the  present  day. 

By  none  of  these  methods,  however,  could  a  sample  of  pure  gastric  juice  be  secured 
while  the  digestive  process  was  actually  in  progress.  To  make  the  collection  of  such  a 
sample  possible,  Heidenhain  devised  a  method  of  isolating  portions  of  the  stomach  wall 
as  pouches  opening  through  iistulse  on  the  abdominal  wall.  The  results  of  Heidenhain 's 
experiments  are,  however,  open  to  the  objection  that  the  secretion  in  the  isolated 
pouches  may  not  really  correspond  to  that  occurring  in  the  main  stomach,  since  the 
connections  of  the  pouches  with  the  central  nervous  system  must  have  been  severed. 
In  order  that  these  connections  might  remain  as  nearly  intact  as  possible,  the  Russian 
physiologist,  Pavlov,  1  devised  an  ingenious  operation  in  which  the  pouch,  or  "  minia- 
ture stomach,"  remains  connected  with  the  main  stomach  through  a  considerable  width 
of  mucous  and  submucous  tissue  and  in  which  the  nervous  connections  are  not  severed. 
The  essential  nature  of  this  operation  will  be  evident  from  the  accompanying  diagram. 
(Fig.  148.) 


PHYSIOLOGY   OF    THE   DIGESTIVE   GLANDS  469 

The  most  recent  investigations  have  been  made  by  Cannons  and  by  Carlson.*  The 
former  fed  animals  food  impregnated  with  bismuth  subnitrate,  and  then  exposed  the 
animal  to  the  x-rays.  A  shadow  is  produced  by  the  food  mass  in  the  stomach,  and 
from  the  changes  in  the  outline  of  this  shadow  facts  have  been  collected,  not  only 
concerning  the  movements  of  the  viscus,  but  also  concerning  the  rate  of  discharge  of 
food  into  the  intestine  and  therefore  the  duration  of  the  gastric  digestive  process. 
Carlson's  contribution  has  been  rendered  possible  by  his  good  fortune  in  having  in 
his  service  a  second  Alexis  St.  Martin,  a  man  with  complete  closure  of  the  esophagus 
and  a  gastric  fistula  large  enough  to  permit  of  direct  inspection  of  the  interior  of 
the  stomach.  Seizing  the  opportunity  thus  presented,  Carlson  during  the  last  four 
or  five  years  has  devoted  his  attention  exclusively  to  a  thorough  investigation,  not 
only  of  the  movements  of  the  stomach,  but  also  of  the  rate  of  secretion  of  the  gastric 
juice  under  different  conditions.  He  has  also,  with  praiseworthy  enthusiasm  and  keen 
scientific  spirit,  extended  his  observations  both  on  laboratory  animals  and  on  himself 
and  his  coworkers,  so  as  not  to  incur  the  error,  which  is  all  too  frequently  made  of 
confining  the  observations  to  one  species  of  animal. 

The  Nervous  Element  in  Gastric  Secretion 

The  first  stimulus  to  the  secretion  of  gastric  juice  is  nervousjn  origin, 
and  is  dependent  on  the  gratification  of  the  appetite  and  the  pleasure  of 
taking  food.  This  fact,  after  having  been  suggested  by  observations 
made  in  the  clinic,  was  first  thoroughly  investigated  by  Pavlov,  who  for 
this  purpose  observed  the  gastric  secretion  flowing  either  from  a  fistula 
of  the  stomach  itself,  or  from  a  "miniature  stomach,"  in  dogs  in  which 
also  an  esophageal  fistula  had  been  established.  When  food  was  given 
by  mouth  to  these  animals,  it  was  chewed  and  swallowed  in  the  usual 
manner,  but  before  reaching  the  stomach,  it  escaped  through  the  esopha- 
geal fistula.  This  experiment  is  known  as  that  of  "sham  feeding." 
Within  a  few  minutes  after  giving  food  the  gastric  juice  was  found  to 
be  secreted  actively,  and  if  the  feeding  process  was  kept  up,  which  could 
be  done  almost  indefinitely  since  the  animal  never  became  satisfied,  the 
secretion  continued  to  flow.  Thus,  in  one  instance  Pavlov  succeeded  in 
collecting  about  700  c.c.  of  gastric  juice  after  sham  feeding  an  animal 
for  five  or  six  hours  in  the  manner  above  described. 

After  the  stomach  has  emptied  itself  of  the  food  taken  with  the  pre- 
vious meal,  it  is  said  by  Pavlov  to  contain  only  a  little  alkaline  mucus. 
The  more  recent  work  of  Carlson,  however,  shows  that  this  is  not  strictly 
the  case,  there  being  more  or  less  of  a  continuous  secretion  of  gastric  juice 
An  the  entire  absence  of  food.    The  amount  varies  from  a  few  c.c.  up  to 
/  60  c.c.  per  hour,  more  secretion  being  produced  when  it  is  collected  every 
|  five  or  ten  minutes  than  if  it  is  collected  every  thirty  or  sixty,  thus 
indicating  that,  ordinarily,  some  escapes  through  the  pylorus  into  the 
duodenum.     The  secretion  contains  both  pepsin  and  hydrochloric  acid. 
As  to  the  cause  of  this  continuous  secretion,  little  is  known.    It  may  be 
an  example  of  the  periodic  activities  of  the  digestive  glands  described  by 


470  DIGESTION 

Boldyreff,  or  it  may  in  part  be  due  to  a  psychic  stimulation  dependent 
upon  the  thought  of  food.  That  the  latter  is  probably  not  the  cause,  is 
indicated  by  the  fact  that,  at  least  in  Carlson's  patient,  the  psychic  juice 
could  not  be  made  to  flow  short  of  giving  food. 

The  sham  feeding  causes  stimulation  of  the  gastric  secretion  through 
impulses  transmitted  to  the  stomach  along  the  vagus  nerves;  for  it  has 
been  found,  in  animals  in  which  the  vagus  nerve  has  been  cut,  that  the 
sham  feeding  no  longer  induces  a  secretion  of  gastric  juice.  The  ques- 
tion therefore  arises  as  to  how  the  nerve  center  is  stimulated.  Three 
possible  causes  may  be  considered:  (1)  mechanical^  stimulation  of  the 
sensory  nerves  of  the  mouth;  (2)  chemical  stimulation  of  these  nerves; 
(3)  the  agreeable  stimulation  of  the  taste  buds  and  olfactory  endings 
concerned  in  the  tasting  of  food.  In  investigating  these  possibilities, 
mechanical  stimulation  was  readily  ruled  out  by  showing  that  mere 
taking  of  solid  matter  in  the  mouth  did  not  excite  any  secretion,  although 
it  might  cause  a  flow  of  saliva.  Mere  chemical  stimulation  could  not  be 
the  cause,  for  no  secretion  was  induced  by  placing  substances  such  as 
acetic  acid  or  mustard  oil  in  the  mouth.  By  exclusion,  then,  it  would 
appear  that  the  adequate  stimulus  must  consist  in  the  agreeable  stimula- 
tion of  the  taste  buds,  etc. — that  is  to  say,  in  the  gratification  of  appetite. 

Further  justification  for  this  conclusion  was  readily  secured  by  noting 
that  foodstuffs  for  which  the  animal  had  no  particular  desire  or  appe- 
tite failed  to  excite  the  secretion.  Most  dogs,  for  example,  although 
they  may  take  it,  are  not  particularly  fond  of  bread,  and  when  fed  with 
it,  these  animals  did  not  produce  any  appetite  juice.  In  one  animal  that 
showed  considerable  liking  for  bread,  active  secretion  occurred  when  he 
was  fed  with  this  foodstuff. 

Pavlov  further  noted  that  usually  it  was  not  necessary  actually  to 
allow  the  animal  to  take  the  food  into  his  mouth,  but  that  mere  teasing 
with  savory  food  was  sufficient  to  cause  the  secretion,  and  that  in 
highly  sensitive  animals  even  the  noises  and  other  events  usually  asso- 
ciated with  feeding  time  were  sufficient  to  excite  the  secretion.  In  the 
case  of  a  hungry  animal,  the  mere  approach  of  the  attendant  with  food, 
or  some  other  noise  or  action  definitely  associated  with  feeding  time, 
was  a  sufficient  excitant.  The  appetite  juice  when  started  was  found 
to  persist  for  some  time  after  the  stimulus  causing  it  had  been  removed. 

Carlson  has  succeeded  in  confirming  in  man  most  of  these  observa- 
tions. He  noted,  however,  that  the  secretion  produced  by  seeing  or 
smelling  or  thinking  of  food  is  much  less  than  would  be  expected  from 
Pavlov's  observations  on  dogs.  Even  when  his  subject  was  hungry, 
Carlson  did  not  observe  that  the  bringing  of  a  tray  of  savory  food  into 
the  room  caused  any  secretion  of  gastric  juice.  It  is,  of  course,  to  be 


PHYSIOLOGY   OF   THE   DIGESTIVE   GLANDS 


471 


expected  that  the  quantity  of  the  psychic  secretion  will  not  be  the  same 
in  different  individuals.  It  has  been  observed  by  Pavlov,  for  example, 
to  vary  considerably  in  the  case  of  dogs,  and  it  is  very  likely  that  it  will 
vary  still  more  in  man,  with  his  more  highly  complicated  nervous  system. 
In  no  case  could  Carlson  observe  any  secretion  of  gastric  juice  to  be  pro- 
duced by  having  his  patient  chew  on  indifferent  substances,  or  by  stim- 
ulating the  nerve  endings  in  the  mouth  by  substances  other  than  those 
directly  related  to  food. 

In  man  the  rate  of  secretion  is  proportional  to  the  palatability  of  the 
food,  the  smallest  amount,  during  twenty  minutes'  mastication  of  pal- 
atable food,  being  30  c.c.  and  the  largest  150  c.c.,  in  a  series  of  156  obser- 
vations. A  typical  curve  showing  the  amount  of  the  secretion  is  given 
in  Fig.  149.  To  construct  this  curve  the  gastric  juice  was  collected  diy- 


\ 


25' 


30' 


50* 


55 


Chewing  food 

Fig.  149. — Typical  curve  of  secretion  of  gastric  juice  collected  at  5-minute  intervals  on  mas- 
tication of  palatable  food  for  20  minutes.  The  rise  in  secretion  during  the  last  5  minutes  of 
mastication  is  due  to  chewing  the  dessert  (fruit)  for  which  the  person  had  great  relish.  (From 
Carlson.) 

ing  five-minute  intervals  while  the  man  was  chewing  a  meal  of  average 
composition  and  of  his  own  choice.  An  interesting  feature  depicted  on 
this  curve  is  that  the  secretion  rate  was  highest  in  the  last  five-minute 
period,  this  being  the  time  during  which  the  dessert  was  being  taken, 
for  which  this  man  had  a  great  relish.  Quite  clearly  there  was  a  direct 
relation  between  the  rate  of  the  secretion  of  the  appetite  juice  and  the 
palatability  of  the  food.  It  will  further  be  observed  that  it  took  only 
from  fifteen  to  twenty  minutes  after  discontinuing  the  chewing  before 
the  juice  returned  to  its  original  level. 

The  practical  application  of  these  facts  in  connection  with  the  hygiene 
of  diet  and  the  feeding  of  patients  during  convalescence,  is  obviously 
very  great.  However  perfect  in  other  regards  a  diet  may  be,  it  will 
probably  fail  to  be  digested  at  the  proper  rate  unless  it  is  taken  with 
relish.  Frequent  feeding  with  favorite  morsels  is  more  likely  to  be  fol- 


472  DIGESTION 

lowed  by  thorough  digestion  and  assimilation  than  occasional  stuffing 
with  larger  amounts.  We  see  too  in  these  experiments  an  explanation 
of  the  well-established  practice  of  starting  a  meal  with  something 
savory.  A  hors  d'oeuvre  is  nothing  more  than  a  physiological  stimulant 
to  appetite.  It  is  also  interesting  from  a  practical  standpoint  to  observe 
that  with  those  who  have  a  keen  relish  for  sweetmeats  the  taking  of  des- 
sert has  a  real  physiological  significance,  for,  as  in  Carlson's  patient,  it 
stimulates  toward  the  end  of  a  meal  a  further  secretion  of  the  gastric 
juice,  and  thus  insures  a  more  rapid  digestion  of  the  food.  Good  cooking, 
it  should  be  remembered,  is  really  the  first  stage  in  digestion,  and  it  is 
the  only  stage  over  which  we  can  exercise  voluntary  control. 

The  Hormone  Element  in  Gastric  Secretion 

Although  gastric  digestion  is  initiated  by  the  appetite  juice,  it  is 
clear  that  this  alone  can  not  account  for  all  the  secretion  that  occurs 
during  the  time  the  food  is  in  the  stomach.  After  an  ordinary  meal  this 
occupies  usually  about  four  hours,  whereas  we  have  seen,  particularly 
from  Carlson's  observations,  that  the  appetite  juice  lasts  only  for  some 
fifteen  or  twenty  minutes  after  the  exciting  stimulus  has  been  removed. 
The  appetite  juice,  in  other  words,  serves  only  to  initiate  the  process  of 
secretion,  and  the  question  arises,  What  keeps  up  the  secretion  during 
the  rest  of  gastric  digestion?  The  answer  was  furnished  by  Pavlov,  who 
observed  animals  in  which  not  only  a  miniature  stomach  had  been  made, 
but  a  fistula  into  the  main  stomach  as  well.  The  behavior  of  the  secre- 
tion of  gastric  juice  as  a  whole  could  be  followed  by  collecting  that 
which  was  secreted  in  the  miniature  stomach,  for  it  was  shown,  in  con- 
trol experiments,  that  this  secretion  runs  strictly  parallel  with  that  in 
the  main  stomach,  being  quantitatively  a  definite  fraction  of  it — accord- 
ing to  the  relative  size  of  the  miniature  stomach — and  qualitatively 
identical.  The  miniature  stomach,  in  other  words,  mirrors  the  events 
of  secretion  in  the  main  stomach. 

It  was  observed  that  when  the  animal  was  allowed  to  take  the  food 
into  the  main  stomach  by  the  mouth  and  esophagus,  the  secretion  from 
the  miniature  stomach  continued  to  flow  until  the  process  of  gastric 
digestion  had  been  completed,  a  result  which  was  quite  different  from 
that  obtained  after  sham  feeding.  The  only  possible  explanation  for  this 
result  is  that  the  food  in  the  stomach  sets  up  secretion  as  a  result  of 
local  stimulation.  To  investigate  the  nature  of  this  local  stimulation, 
whether  mechanical_or_ chemical,  food  and  other  substances  were  placed 
in  the  main  stomach  through  the  gastric  fistula  without  the  animal's 
knowledge  so  as  to  avoid  possible  psychic  stimulation,  and  the  secretion 
observed  from  the  miniature  stomach.  When  the  mucous  membrane  of 


PHYSIOLOGY    OF    THE    DIGESTIVE   GLANDS  473 

the  main  stomach  was  stimulated  mechanically,  as  by  placing  inert 
objects  such  as  a  piece  of  sponge  or  sand  in  the  stomach,  no  secretion 
occurred.  Evidently,  therefore,  the  stimulus_is_dependent  upon  some 
chemical  quality  of  the  food. 

By  introducing  various  foods  it  was  found  that  there  is  considerable 
difference  in  the  degree  to  which  they  can  excite  the  secretion.  Water 
and  egg  white  had  a  slight  effect;  bread  and  starch  in  the  dry  state  had  no 
effect.  On  the  other  hand,  when  protein  that  had  been  partly  digested 
by  means  of  pepsin  and  hydrochloric  acid  was  introduced  into  the 
stomach,  it  immediately  called  forth  a  secretion.  The  conclusion  is  that 
the  partly  digested  products,  even  of  insipid  food,  are  capable  of  directly 
exciting  the  secretion.  These  include  proteoses  and  peptones,  and  it 
was,  therefore,  of  great  interest  to  find  t^at  a.  solution  of  commercial 


peptone  is  also  an  fvffee.t.ivp  ptinmlns.  This  is  a  result  of  deep  significance, 
for  it  indicates  that  the  food  which  has  been  partially  digested  by  the 
appetite  juice  will  serve  as  a  stimulus  to  continued  secretion. 

The  psychic  juice  has  been  aptly  called  the  "ignition  juice,"  because 
by  producing  partial  digestion  it  serves  to  ignite  the  process  of  gastric 
secretion.  Experimental  evidence  of  its  great  importance  in  gastric 
digestion  was  secured  by  Pavlov  in  experiments  in  which  he  placed 
weighed  quantities  of  meat  attached  to  threads  in  the  stomach  through 
a  gastric  fistula,  and  after  some  time  removed  them  and  determined  by 
the  difference  in  weights  the  extent  to  which  they  had  become  digested. 
It  was  found  that  when  the  appetite  juice  was  excited  by  sham  feeding 
at  the  same  time  that  food  was  placed  directly  in  the  stomach,  its  diges- 
tion was  much  more  rapid  than  in  cases  in  which  it  was  placed  in  the 
stomach  without  the  animal's  knowledge,  as  when  he  was  asleep. 

Other  foods  having  a  direct  stimulating  effect  on  the  gastric  secre- 
tion are  meat  extracts  and,  to  a  certain  extent,  milk.  This  effect  of  meat 
extract  is  interesting  in  connection  with  the  practice  of  taking  soup  as 
a  first  or  early  stage  in  dining.  It  not  only  excites  the  appetite  juice, 
but  also  serves  as  a  direct  stimulus  to  the  gastric  secretion. 

As  to  the  nature  of  the  mechanism  J)y  which  this  direct  secretion  takes 
place,  it  was  shown  by  Popielski12  that  the  secretion  still  occurs  after  all 
the  nerves  proceeding  to  the  stomach  are  cut.  Evidently,  therefore,  it 
is  independent  of  the  extrinsic  nerve  supply  of  the  viscus.  As  a  result 
of  his  experiments  Popielski  concluded  that  the  secretion  must  depend 
on  a  local  reflex  mediated  through  the  nerve  structures  present  in  the 
walls  of  the  stomach  itself.  Another  explanation  of  the  result  has, 
however,  in  recent  years  been  given  more  credence  by  the  experiments  of 
Bayliss  and  Starling  on  the  influence  of  hormones  on  the  secretion  of 
pancreatic  juice  (cf.  page  460).  Edkins18  suggested  that  a  similar 


474  DIGESTION 

process  in  the  stomach  might  account  for  the  continued  secretion  of 
gastric  juice.  To  test  such  a  possibility  this  investigator,  after  ligating  the 
cardiac  sphincter  in  anesthetized  animals,  inserted  a  tube  into  the 
pyloric  end  of  the  stomach,  through  which  he  placed  in  the  stomach 
about  50  c.c.  of  physiological  saline.  After  this  had  been  in  the  stomach 
for  an  hour,  he  found  that  no  water  was  absorbed,  and  that  it  contained 
neither  hydrochloric  acid  nor  pepsin.  On  the  other  hand,  if  during  the 
time  the  saline  was  in  the  stomach  a  decoction  of  the  mucous  membrane  of 
the  pyloric  end,  made  either  with  peptone  solution  or  with  a  solution  of 
dextrine,  was  injected  intravenously  in  small  quantities  every  few  min- 
utes, the  saline  contained  distinct  quantities  of  hydrochloric  acid  and  pep- 
sin. Furthermore,  it  was  found  that,  if  the  peptone  solution  or  the  dextrine 
solution  alone  was  injected  intravenously,  there  was  no  such  evidence 
of  gastric  secretion.  The  conclusion  which  Edkins  drew  from  his  experi- 
ments is  to  the  effect  that  the  half-cjigested  products  of  the  earlier  stages 
of  gastric  digestion  act  on  the  mucous  membrane  of  the  stomach  so  as  to 
produce  a  hormone,  which  is  then  carried  by  the  blood  to  the  cells  of 
the  gastric  glands,  upon  which,  like  secretin,  it  directly  develops  an 
exciting  effect.  This  hormone  has  been  called  gastrin.  These  observa- 
tions of  Edkins  have  been  confirmed,  and  they  explain  very  simply  how 
gastric  secretion  is  maintained  after  the  cessation  of  the  secretion  of  the 
appetite  juice.  ,By  such  a  mechanism  gastric  juice  would  continue  to  be 
secreted  so  long  as  any  half -digested  food  remains  in  the  stomach. 

The  action  of  gastrin  is  the  first  instance  of  a  hormone  control  of  the 
digestive  glands.  In  the  earlier  stages  of  digestion,  the  secretion  of  saliva 
and  appetite  juice  is  mediated  through  the  nervous  system,  because  these 
juices  must  be  produced  promptly.  In  the  later  stages  of  gastric  diges- 
tion, such  promptitude  in  response  on  the  part  of  the  gland  is  no  longer 
necessary,  so  that  the  slower,  more  continuous  process  of  hormone  con- 
trol is  sufficient. 

Quantity  of  Gastric  Juice  Secreted 

According  to  Carlson,  the  total  amount  of  gastric  juice  secreted  in 
man  on  an  average  meal  composed  of  meat,  bread,  vegetables,  coffee  or 
milk,  and  dessert,  amounts  to  about  700  c.c.,  being  divided  into  200  c.c. 
in  the  first  hour,  150  in  the  second,  and  350  c.c.  during  the  third,  fourth 
and  fifth  hours.  These  figures  were  estimated  partly  on  the  basis  of 
observations  made  on  the  man  with  the  gastric  fistula,  and  partly  from 
the  data  supplied  by  Pavlov's  observations  on  dogs.  Carlson  believes 
that  Pavlov  overestimated  'the  relative  importance  of  the  appetite  juice 
in  gastric  digestion.  He  found,  for  example,  that  after  division  of  both 
vagus  nerves  in  dogs  normal  gastric  digestion  might  be  regained  a  few 


PHYSIOLOGY   OF   THE   DIGESTIVE   GLANDS 


475 


days  after  the  operation,  although,  of  course,  under  such  circumstances  no 
appetite  juice  could  have  been  secreted.  Moreover,  he  observed  that  cats 
when  forcibly  fed  with  unpalatable  food  may  digest  that  food  as  rapidly 
as  when  they  eat  voluntarily.  In  support  of  his  contention,  Carlson 
states  that  he  has  frequently  removed  all  of  the  appetite  juice  from  his 
patient's  stomach  before  the  masticated  meal  was  put  into  it  without 
any  evident  interference  with  the  digestive  process. 

Fat  has  a  distinct  inhibiting  influence  on  the  direct  secretion  of  gas- 
tric juice;  cream  takes  considerably  longer  to  be  be  digested  than  milk, 


345678123456789    10    123456 


Flesh.  200  gm. 


Bread,  200  gm. 


Milk,  600  c.c. 


Fig.  150. — Cubic  centimeters  of  gastric  juice  secreted  after  diets  of  meat,  bread,  and  milk.     (From 

Pavlov.) 


Hours   1 

10.0 

c         An 

2345678234     5678923456 

Mm  of'Protei 
Column 

<=>  £  §  g  { 

/ 

^ 

/ 

\| 

\ 

x-"' 

—  . 

—  • 

/ 

\ 

t 

\ 

^ 

\ 

/ 

\ 

/ 

\ 

I 

\ 

^ 

Flesh,  200  gm. 


Bread,  200  gm. 


Milk,  600  c.c. 


Fig.   151.— 


. — Digestive  power  of  the  juice,  as  measured  by  the  length  of  the  protein  column  digested 
in   Mett's   tubes,    with    diets    of   flesh,    bread,    and    milk.      (From    Pavlov.) 

and  the  presence  of  oil  in  the  stomach  delays  the  secretion  of  juice  poured 
out  on  a  subsequent  meal  of  otherwise  readily  digestible  food.  By  col- 
lecting all  of  the  gastric  juice  from  the  miniature  stomach  after  feeding 
by  mouth  with  quantities  of  different  protein-rich  foods  containing  the 
same  quantities  of  nitrogen,  interesting  observations  have  been  recorded 
concerning  the  amount  of  juice  secreted  and  its  proteolytic  power.  The 
results  of  some  of  the  experiments  are  shown  in  the  accompanying 
curves  (Figs.  150  and  151). 


476  DIGESTION 

It  will  be  seen  that  the  most  abundant  secretion  occurs  with  meat,  that 
of  milk  being  not  only  smaller  but  also  slower  in  starting.  The  digestive 
power  is  greatest  in  the  case  of  bread. 

THE  INTESTINAL  SECRETIONS 

Pancreatic  Juice 

Regarding  the  natural  secretion  of  pancreatic  juice,  little  need  be  added 
to  what  has  already  been  said  (see  page  460).  The  secretion  begins  when  the 
chyme.,  enters  the  duodenum,  and  attains  its  maximum  when  the  outflow 
of  this  is  greatest.  By  collecting  the  juice  from  a  permanent  fistula  of  the 
pancreatic  duct,  it  has  been  found  that  the  amount  varies  with  different 
foods.  When  quantities  of  food  containing  equivalent  amounts  of  nitro- 
gen are  fed,  the  greatest  secretion  is  said  to  occur  with  bread  and  the  least 
with  milk.  Such  differences  are  probably  dependent  upon  the  amount  of 
acid  secreted  in  the  stomach  and  passed  on  into  the  duodenum.  It  was 
thought  at  one  time  that,  besides  variation  in  quantity,  the  nature  of  the 
enzymes  in  the  pancreatic  juice  might  vary  according  to  the  kind  of 
food.  This,  however,  has  been  shown  not  to  be  the  case. 

Bile 

The  secretion  of  bile  runs  pracJieallyLjsarallel  with  that  of  pancreatic 
juice.  The  liver  is  producing  bile  more  or  less  continuously,  since  besides 
being  a  digestive  fluid  it  is  also  an  excretory  product.  The  bile  produced 
between  the  periods  of  digestion  is  mainly  stored  in  the  gall  bladder. 
When  the  acid  chyme  comes  in  contact  with  the  duodenal  mucous  mem- 
brane, it  excites  afferent  nerve  endings  that  cause  a  reflexjiontraction  of 
the  gall  bladder,  and  this  expresses  some  of  the  bile  into  the  duodenum. 
The  secretin,  which  the  acid  at  the  same  time  produces,  besides  affecting 
the  pancreas,  acts  on  the  liver  cells,  stimulating  them  to  the  increased 
secretion  of  bile.  Thus,  by  a  nervous  reflex  operating  oil  the  gall  bladder 
and  later  by  a  hormone  mechanism  operating  on  the  liver  cell,  the  increased 
secretion  of  bile  is  insured  throughout  digestion.  Of  the  bile  discharged 
into  the  intestine,  a  certain  proportion  of  the  bile  salts  is  reabsorbed  into 
the  portal  blood.  When  these  arrive  at  the  liver  they  also  excite  secre- 
tion of  bile,  thus  assisting  secretin  in  maintaining  the  secretion  through- 
out the  process  of  intestinal  digestion. 

Intestinal  Juice 

The  secretion  of  intestinal  juice,  or  succus  entericus,  can  obviously  be 
studied  only  after  isolating  portions  of  the  intestine  and  connecting  them 


PHYSIOLOGY   OF   THE   DIGESTIVE   GLANDS  477 

with  fistulse  of  the  abdominal  walls.  It  appears  here  again  that  both  a 
nervous  and  a  hormone  mechanism  exist.  Mechanical  stimulation  of  the 
intestinal  mucous  membrane  causes  an  immediate  outflow  of  intestinal 
juice,  the  purpose  of  which  under  normal  conditions  is  evidently  to  assist 
in  moving  forward  the  bowel  contents.  This  mechanically  excited  juice 
does  not  contain  any  enterokinase  and  only  small  amounts  of  the  other 
enzymes.  Further  evidence  for  nervous  control  of  the  secretion  of  intes- 
tinal juice  has  been  obtained  by  isolating  three  pouches  of  intestine  be- 
tween ligatures,  and  then  denervating  the  central  pouch  by  carefully 
cutting  all  the  nerves  without  wounding  the  blood  vessels.  On  returning 
the  pouches  to  the  abdomen  and  leaving  them  several  hours,  it  has  been 


Fig.    152. — Loop  of  intestine  after  tying  off  the  portions,  cutting  the  nerves  running  to  the  middle 
portion,   and   returning  the   loop   to   the   abdomen   for   some  time.      (From   Jackson.) 

found  that  the  middle  pouch  becomes  distended  with  secretion,  whereas 
the  two  end  pouches  remain  empty  (Fig.  152).  If  the  pouches  are  left  for 
several  days  in  the  abdomen,  however,  the  secretion  from  the  denervated 
portion  disappears  again.  The  explanation  of  the  result  is  possibly  that 
the  nerves  under  ordinary  conditions  convey  impulses  to  the  intestinal 
glands,  which  tonically  inhibit  their  activity. 

The  existence  of  hormone  control  is  evidenced  by  the  fact  that  no 
enterokinase  is  present  in  the  intestinal  juice  unless  pancreatic  juice  is 
placed  in  contact  with  the  mucous  membrane.  Injection  of  pancreatic 
juice  into  the  blood,  however,  does  not  cause  any  secretion  of  intestinal 
juice ;  whereas  the  injection  of  secretin  has  such  an  effect. 


CHAPTER  LIII 

THE  MECHANISMS  OF  DIGESTION 
MASTICATION,  DEGLUTITION,  VOMITING 

Mastication 

By  the  movements  of  the  lower  jaw  on  the  upper,  the  two  rows  of 
teeth  come  together  so  as  to  serve  for  biting  or  crushing  the  food.  The 
resulting  comminution  of  the  food  forms  the  first  step  in  digestion.  The 
up  and  down  motion  of  the  lower  jaw  results  in  biting  by  thei  incisors, 
and  after  the  mouthful  has  been  taken,  the  side  to  side  movements  enable 
the  grinding  teeth  to  crush  and  break  it  up  into  fragments  of  the  proper 
size  for  swallowing.  The  most  suitable  size  of  the  mouthful  is  about 
5  c.c.,  but  this  varies  greatly  with  habit.  After  mastication,  the  mass 
weighs  from  3.2  to  6.5  gm.,  about  one-fourth  of  this  weight  being  due  to 
saliva.  The  food  is  now  a  semifluid  mush  containing  particles  which 
are  usually  less  than  2  mm.  in  diameter.  Some,  however,  may  measure 
7  or  even  12  mm. 

Determination  of  the  proper  degree  of  fineness  of  the  food  is  a  func- 
tion of  the  tongue,  gums,  and  cheeks,  for  which  purpose  the  mucous 
membrane  covering  them  is  supplied  with  very  sensitive  touch  nerve 
endings.  The  sensitiveness  of  the  tongue,  etc.,  in  this  regard  explains 
why  an  object  which  can  scarcely  be  felt  by  the  fingers  seems  to  be 
quite  large  in  the  mouth.  If  some  particles  of  food  that  are  too  large 
for  swallowing  happen  to  be  carried  backward  in  the  mouth,  the  tongue 
returns  them  for  further  mastication. 

The  saliva  assists  in  mastication  in  several  ways:  (1)  by  dissolving 
some  of  the  food  constituents;  (2)  by  partly  digesting  some  of  the 
starch;  (3)  by  softening  the  mass  of  food  so  that  it  is  more  readily 
crushed;  (4)  by  covering  the  bolus  with  mucus  so  as  to  make  it  more 
readily  transferable  from  place  to  place.  The  secretion  of  saliva  is 
therefore  stimulated  by  the  chewing  movements,  and  its  composition 
varies  according  to  the  nature  of  the  food  (page  466).  In  some  animals, 
such  as  the  cat  and  dog,  mastication  is  unimportant,  coating  of  the  food  with 
saliva  being  practically  the  only  change  which  it  undergoes  in  the  mouth. 
In  man  the  ability  thus  to  bolt  the  food  can  readily  be  acquired,  not,  how- 
ever, without  some  detriment  to  the  efficiency  of  digestion  as  a  whole.  Soft 

478 


THE   MECHANISMS   OF   DIGESTION  479 

starchy  food  is  little  chewed,  the  length  of  time  required  for  the  mastica- 
tion of  other  foods  depending  mainly  on  their  nature,  but  also  to  a 
certain  degree  on  the  appetite  and  on  the  size  of  the  mouthful. 

It  can  not  be  too  strongly  insisted  upon  that  the  act  of  mastication  is 
of  far  more  importance  than  merely  to  break  up  and  prepare  the  food 
for  swallowing.  It  causes  the  food  to  be  moved  about  in  the  mouth  so  as 
to  develop  its  full  effect  on  the  taste  buds;  the  crushing  also  releases 
odors  which  stimulate  the  olfactory  epithelium.  On,  these  stimuli  depend 
the  satisfaction  and  pleasure  of  eating,  which  in  turn  initiate  the  process 
of  gastric  digestion  (see  page  470). 

The  benefit  to  digestion  as  a  whole  of  a  large  secretion  of  saliva,  brought 
about  by  persistent  chewing,  has  been  assumed  by  some  to  be  much 
greater  than  it  really  is,  and  there  has  existed,  and  indeed  may  still 
exist,  a  school  of  faddists  who,  by  deliberately  chewing  far  beyond 
the  necessary  time,  imagine  themselves  to  thrive  better  on  less  food  than 
those  who  occupy  their  time  with  more  profitable  pursuits. 

Deglutition  or  Swallowing 

After  being  masticated  the  food  is  rolled  up  into  a  bolus  by  the  action 
of  the  tongue  against  the  palate,  and  after  being  lubricated  by  saliva  is 
moved,  by  elevation  of  the  front  of  the  tongue,  towards  the  back  of  the 
mouth.  This  constitutes  the  first  stage  of  swallowing,  and  is,  so  far,  a 
voluntary  act.  Al^put  this  time  a  slight  ^ap^t.QTy  f»*vntT>a/*1™n  of  the 
diaphragm  occurs — the  so-called  respiration)  of  swallowing — and  the 
mylohyoid  quicklv__cpntracts.  wit]LJ;hej?pnsequence  that  the  bolus  passes 
between  the  pillars  of  the  fauces.  This  marks  the  beginning  of  the 
second  stage,  the  first  event  of  which  is  that  the  bolus,  by  stimulating 
sensory  nerve  endings,  acts  on  nerve  centers  situated  in  the  medulla 
oblongata  so  as  to  cause  a  coordinated  series  of  movements  of  the 
muscles  of  the  pharynx  and  larynx  and  an  inhibition  for  a  moment  of 
the  respiratory  center  (page  351). 

The  movements  alter  the  shape  of  the  pharynx  and  of  the  various 
openings  into  it  in  such  a  manner  as  to  compel  the  bolus  of  food  to  pass 
into  the  esophagus  (see  Fig.  153) :  thus,  (1)  the  soft  palate  becomes 
elevated  and  the  posterior  wall  of  the  pharynx  bulges  forward  so  as  to 
shut  off  the  posterior  nares,  (2)  the  posterior  pillars  of  the  fauces  ap- 
proximate so  as  to  shut  off  the  mouth  cavity,  and  (3)  in  about  a  tenth  of 
a  second  after  the  mylohyoid  has  contracted,  the  larynx  is  pulled  up- 
wards and  forwards  under  the  root  of  the  tongue,  which  by  being 
drawn  backwards  becomes  banked  up  over  the  laryngeal  opening.  This 
pulling  up  of  the  larynx  brings  its  upper  opening  near  to  the  lower  half 
of  the  dorsal  side  of  the  epiglottis,  but  the  upper  half  of  this  struc- 


480 


DIGESTION 


ture  projects  beyond  and  serves  as  a  ledge  to  guide  the  bolus  safely  past 
this  critical  part  of  its  course.  (4)  As  a  further  safeguard  against  any 
entry  of  food  into  the  air  passages,  the  laryngeal  opening  is  narrowed  by 
approximation  of  the  true  and  the  false  vocal  cords. 

So  far  the  force  which  propels  the  bolus  is  mainly  the  contraction  of 
the  mylohyoid,  assisted  by  the  movements  of  the  root  of  the  tongue. 
When  it  has  reached  the  lower  end  of  the  pharynx,  however,  the  bolus 
readily  falls  into  the  esophagus,  which  has  become  dilated  on  account 
of  a  reflex  inhibition  of  the  constrictor  muscles  of  its  upper  end.  This  so- 
called  second  stage  of  swallowing  is,  therefore,  a  complex  coordinated 
movement  initiated  by  afferent  stimuli  and  involving  reciprocal  action 


Fig.  153. — The  changes  which  take  place  in  the  position  of  the  root  of  the  tongue,  the  soft 
palate,  the  epiglottis  and  the  larynx  during  the  second  stage  of  swallowing.  The  thick  dotted  line 
indicates  the  position  during  swallowing. 


of  various  groups  of  muscles:  inhibition  of  the  respiratory  muscles  and 
of  those  that  constrict  the  esophagus,  and  stimulation  of  those  that 
elevate  the  palate,  the  root  of  the  tongue,  and  the  larynx.  It  is  purely 
an  involuntary  process. 

The  third  stage  of  deglutition  consists  in  the  passage  of  the  swallowed 
food  along  the  esophagus.  The  mechanism  by  which  this  is  done  de- 
pends very  much  on  the  physical  consistence  of  the  food.  A  solid  bolus 
that  more  or  less  fills  the  esophagus  excites  a  typical  peristaltic  wave, 
which  is  characterized  by  a  dilatation  of  the  esophagus  immediately  in 
front  of  and  a  constriction  over  and  behind  the  bolus.  This  wave  travels 
down  the  esophagus  in  man  at  such  a  rate  that  it  reaches  the  cardiac 
sphincter  in  about  five  or  six  seconds.  On  arriving  here  the  cardiac 


THE    MECHANISMS   OF   DIGESTION  481 

sphincter,  ordinarily  contracted,  relaxes  for  a  moment  so  that  the  bolus 
passes  into  the  stomach.  In  many  animals,  including  man  and  the  cat, 
the  peristaltic  wave  travels  much  more  rapidly  in  the  upper  part  of  the 
esophagus  than  lower  down  because  of  differences  in  the  nature  of  the 
muscular  coat,  this  being  of  the  striated  variety  above,  and  of  the  non- 
striated  below.  The  purpose  of  more  rapid  movement  in  the  upper  part 
is  no  doubt  that  the  bolus  may  be  hurried  past  the  regions  where,  by 
distending  the  esophagus,  it  might  interfere  with  the  function  of  neigh- 
boring structures,  such  as  the  heart.  In  other  animals,  as  the  dog,  the 
muscular  fiber  is  striated  all  along  the  esophagus,  and  the  bolus  of  food 
correspondingly  travels  at  a  uniform,  quick  rate  all  the  way.  It  takes 
only  about  four  seconds  for  the  bolus  to  reach  the  stomach  in  the  dog. 

The  peristaltic  wave  of  the  upper  part  of  the  esophagus  in  the  cat  and 
presumably  in  man,  unlike  that  of  the  intestines  (see  page  501),  is  trans- 
mitted by  the  esophageal  branches  of  the  vagus  nerves.  If  these  are 
severed,  but  the  muscular  coats  left  intact,  the  esophagus  becomes  dilated 
above  the  level  of  the  section  and  contracted  below,  and  no  peristaltic 
wave  can  pass  along  it;  on  the  other  hand,  the  muscular  coat  may  be 
severed  (by  crushing,  etc.)  but  the  peristaltic  wave  will  continue  to 
travel,  provided  no  damage  has  been  done  to  the  nerves. 

In  the  lower  part  of  the  esophagus,  however,  the  wave  of  peristalsis, 
like  that  of  the  intestines,  travels  independently  of  extrinsic  nerves. 
This  has  been  observed  in  animals  in  which  all  of  the  extrinsic  nerves 
have  been  cut  some  time  previously.  This  difference  between  the  upper 
and  the  lower  portions  is  associated  with  the  difference  in  the  nature  of 
the  muscular  fibers  above  noted  (Meltzer).14 

The  propagation  of  the  wave  by  the  nerves  in,  the  upper  part  of  the 
esophagus  indicates  that  the  second  stage  and  the  first  part  of  the  third 
stage  of  deglutition  must  be  rehearsed,  as  it  were,  in  the  medullary 
centers  from  which  arise  the  nerve  fibers  to  the  pharynx  and  the  upper 
levels  of  the  esophagus.  It  is  thought  that  the  discharges  from  these 
local  centers  are  controlled  by  a  higher  swallowing  center  situated  in  the 
medulla  just  above  that  of  respiration,  the  afferent  stimuli  to  which 
proceed  from  the  pharynx  by  the  fifth,  superior  laryngeal,  and  vagus 
nerves.  The  exact  location  of  the  sensory  areas  whose  stimulation  is 
most  effective  in  initiating  the  swallowing  reflex  varies  considerably 
in  different  animals.  In  man  it  is  probably  at  the  entrance  to.,  the 
pharynx;  in  the  dog  it  is  on  the  posterior  wall.  A  foreign  body  placed 
directly  in  the  upper  portion  of  the-  esophagus  of  man  has  been  observed 
to  remain  stationary  until  the  individual  made  a  swallowing  movement. 
The  afferent  fibers  in  the  glossopharyngeal  nerve  exercise  a  powerful 
inhibitory  influence  on  the  deglutition  center  as  well  as  on  that  of  respira- 


482  DIGESTION 

tion.  Thus,  if  swallowing  movements  are  excited  by  stimulating  the  cen- 
tral end  of  the  superior  laryngeal  nerve,  they  can  be  instantly  inhibited 
by  simultaneously  stimulating  the  glossopharyngeal,  and  the  respiratory 
movements  stop  in  whatever  position  they  may  have  been  at  the  time. 
When  the  glossopharyngeal  nerves  are  cut,  the  esophagus  enters  into  a 
condition  of  tonic  contraction,  which  may  last  a  day  or  so.  This  shows 
that  the  inhibiting  impulses  are  acting  continuously. 

This  inhibition  of  the  esophagus  is  indeed  a  most  important  part  of 
the  process  when  liquid  or  semiliquid  food  is  swallowed.  By  contraction 
of  the  mylohyoid  muscle  fluids  are  quickly  shot  down  the  dilated  esopha- 
gus, at  the  lower  end  of  which,  on  account  of  the  closure  of  the  cardiac 
sphincter,  they  accumulate  until  the  arrival  of  the  peristaltic  wave  which 
iias  meanwhile  been  set  up  by  stimulation  of  the  pharynx.  As  the  per- 
istaltic wave  approaches  the  cardia  the  sphincter  becomes  inhibited  al- 
lowing the  fluids  to  be  passed  into  the  stomach.  If  the  swallowing  is 
^immediately  repeated  the  esophagus  remains  dilated  because  peristalsis 
is  inhibited  and  the  fluid  collects  above  the  closed  cardiac  sphincter 
until  the  last  mouthful  is  taken  Avhen  the  peristaltic  wave  passes  over 
the  esophagus  and  sweeps  the  contents  through  the  sphincter  which  is 
at  the  same  time  relaxed.  When  a  series  of  swallows  in  rapid  succes- 
sion, as  in  drinking,  is  made  the  cardiac  sphincter  may  remain  inhibited 
throughout,  so  that  the  fluid  passes  directly  into  the  stomach  unassisted  bv 
\  the  peristaltic  wave. 

The  Cardiac  Sphincter 

The  passage  between  the  esophagus  and  the  stomach  is  guarded  by 
the  cardiac  sphincter  or  cardia.  This  exists  in  a  permanently  con- 
tracted state,  or  tonus,  superimposed  on  which  from  time  to  time  are 
rhythmic  alternations  of  contraction  and  relaxation.  This  tonus  is  never 
very  pronounced.  In  man  it  is  said  that  a  water  pressure  of  from  2  to  7 
cm.  applied  to  the  esophageal  side  of  the  sphincter  will  drive  air  or 
water  into  the  stomach,  this  pressure  being  less  than  that  of  a  column 
of  fluid  filling  the  thoracic  esophagus  in  the  erect  position.  During 
repeated  deglutition  the  tonus  becomes  less  and  less  marked,  and  after 
a  number  of  swallows  the  sphincter  may  become  completely  relaxed. 
When  this  relaxation  disappears,  however,  the  sphincter  becomes  more 
contracted  than  usual  and  remains  so  for  a  longer  time. 

The  tonic  condition  of  the  sphincter  is  controlled  by  the  vagus  nerve, 
stimulation  of  which  causes  relaxation  with  an  after-effect  of  strong 
contraction.  Mechanical  or  chemical  stimulation  of  the  lower  end  of  the 
esophagus  increases  the  tonus  of  the  sphincter.  Forcing  of  the  sphincter 
from  the  stomach  side  requires  a  higher  pressure  than  from  the  esopha- 
geal. Eructation  of  gas,  for  example,  does  not  take  place  until  intra- 


THE    MECHANISMS    OF    DIGESTION  483 

gastric  pressure  has  risen  to  about  %Lc,m.  of  water.  In  deep  anesthesia, 
however,  intragastric  pressure  may  rise  considerably  higher  without 
forcing  the  sphincter. 

In  animals  fed  with  starch  paste  impregnated  with  subnitrate  of  bis- 
muth and  then  examined  by  means  of  the  x-rays,  the  variation  in  degree 
of  tone  of  the  sphincter  has  been  observed  to  be  responsible  for  occasional 
regurgitation  of  some  of  the  gastric  contents  into  the  esophagus  up  to  the 
level  of  the  heart  or  even  to  the  base  of  the  neck.  The  presence  of  the 
gastric  contents  in  the  esophagus  starts  a  peristaltic  wave,  which  pushes 
the  material  back  again  into  the  stomach.  This  peristaltic  wave  starts 
in  the  absence  of  any  other  phases  of  the  deglutition  process,  indicating 
that  it  has  been  excited  by  the  presence  of  the  material  in  the  esophagus 
itself,  and  belongs,  therefore,  to  the  lower  order  of  peristaltic  wave,  as 
seen  in  the  intestines  but  not  in  the  upper  half  of  the  esophagus.  Regur- 
gitation of  food  into  the  esophagus  occurs  only  when  the  intragastric 
pressure  is  fairly  high.  It  may  last  for  a  period  of  from  twenty  to  thirty 
minutes  after  the  meal  is  taken,  and  disappears  when  the  tonus  of  the 
sphincter  becomes  increased  as  a  result  of  the  presence  in  the  gastric 
contents  of  free  hydrochloric  acid. 

Much  information  has  been  secured  by  listening  with  a  stethoscope  to 
the  sounds  caused  by  swallowing  and  by  observing  with  the  x-ray  the 
shadows  produced  along  the  course  of  the  esophagus  when  food  impreg- 
nated with  bismuth  subnitrate  is  taken.  When  a  solid  bolus  is  swal- 
lowed only  one  sound  is  usually  heard,  but  with  liquid  food  there  are 
two,  one  at  the  upper  end,  due  to  the  rush  of  the  fluid  and  air,  and 
the  other  at  the  lower  end  (heard  over  the  epigastrium),  four  or  six 
seconds  later,  due  to  the  arrival  here  of  the  peristaltic  wave  with  the 
accompanying  opening  of  the  cardiac  sphincter  and  the  escape  of  the 
fluid  and  air  into  the  stomach.  Sometimes,  when  the  person  is  in  the 
horizontal  position,  this  second  sound  may  be  broken  up  into  several, 
indicating  that,  unassisted  by  gravity,  the  fluid  does  not  so  readily  pass 
through  the  sphincter.  The  x-ray  shadows  yield  results  in  conformity 
with  the  above.  After  swallowing  milk  and  bismuth,  for  example,  the 
shadow  falls  quickly  to  the  lower  end  of  the  esophagus  and  then  passes 
slowly  into  the  stomach.  When  the  passage  of  a  solid  bolus  is  watched 
by  the  x-ray  method,  its  rate  of  descent  will  be  found  to  depend  on 
whether  or  not  it  is  well  lubricated  with  saliva;  a  well  lubricated  bolus 
takes  from  eight  to  eighteen  seconds. 

Vomiting 

Vomiting  is  usually  preceded  by  a  feeling  of  sickness  or  nausea,  and 
is  initiated  by  a  very  active  secretion  of  saliva.  The  saliva,  mixed  with 


484  DIGESTION 

air,  accumulates  to  a  considerable  extent  at  the  lower  end  of  the  esopha- 
gus, which  it  distends.  A  forced  inspiration  is  now  made,  during  the 
first  stage  of  which  the  glottis  is  open  so  that  the  air  enters  the  lungs, 
but  later  the  glottis  closes  so  that  the  inspired  air  is  sucked  into  the 
esophagus,  which,  already  somewhat  distended  by  saliva,  now  becomes 
markedly  so.  The  abdominal  muscles  then  contract  so  as  to  compress 
the  stomach  against  the  diaphragm  and,  simultaneously,  the  cardiac 
sphincter  relaxes,  the  head  is  held  forward  and  the  contents  of  the 
stomach  are  ejected  through  the  previously  distended  esophagus.  The 
compression  of  the  stomach  by  the  contracting  abdominal  muscles  is 
assisted  by  an  actual  contraction  of  the  stomach  itself,  as  has  been  clearly 
demonstrated  by  the  x-ray  method.  After  the  contents  of  the  stomach 
itself  have  been  evacuated,  the  pyloric  sphincter  may  also  relax  and 
permit  the  contents  (bile,  etc.)  of  the  duodenum  to  be  vomited. 

The  act  of  vomiting  is  controlled  by  a  center  located  in  the  medulla, 
and  the  afferent  fibers  to  this  center  may  come  from  many  different 
regions  of  the  body.  Perhaps  the  most  potent  of  them  come  from  the 
sensory  nerve  endings  of  the  fauces  and  pharynx.  This  explains  the 
tendency  to  vomit  when  the  mucosa  of  this  region  is  mechanically  stimu- 
lated. Other  afferent  impulses  come  from  the  mucosa  of  the  stomach 
itself,  and  these  are  stimulated  by  emetics,  important  among  which  are 
strong  salt  solution,  mustard  water  and  zinc  sulphate.  Certain  other 
emetics,  particularly  tartar  emetic  and  apomorphine,  act  on  the  vomit- 
ing center  itself,  and  can  therefore  operate  when  given  subcutaneously. 
Afferent  vomiting  impulses  also  arise  from  the  abdominal  viscera,  thus 
explaining  the  vomiting  which  occurs  in  strangulated  hernia,  and  in 
other  irritative  lesions  involving  this  region.  X-ray  observations  have 
been  made  on  the  movements  of  the  stomach  of  cats  after  the  admin- 
istration of  apomorphine  (Cannon).  The  first  change  observed  is  an 
inhibition  of  the  cardiac  end  of  the  stomach,  which  becomes  a  perfectly 
flaccid  bag.  About  the  midregion  of  the  organ,  deeper  contractions  then 
start  up,  which  sweep  towards  the  pylorus,  each  contraction  stopping  as  a 
deep  ring  at  the  beginning  of  the  vestibule,  while  a  slighter  wave  con- 
tinues. A  very  strong  contraction  at  the  incisura  angularis  finally 
develops  and  completely  divides  the  gastric  cavity  into  two  parts.  On 
the  left  of  this  constriction  the  stomach  remains  completely  relaxed,  but 
at  the  right  of  it  waves  continue  running  over  the  vestibule.  It  is  while 
the  stomach  is  in  this  condition  that  the  sudden  contraction  of  the  dia- 
phragm and  abdominal  muscles  shoots  the  cardiac  contents  into  the 
relaxed  esophagus.  As  these  jerky  contractions  are  continued,  the  gastric 
walls  seem  to  reacquire  their  tone.  Afferent  impulses  from  the  duodenal 
mucosa  are  even  more  potent  for  the  initiation  of  the  vomiting  reflex  than 
are  impulses  arising  in  the  stomach  itself. 


CHAPTER  LIV 

THE  MECHANISMS  OF  DIGESTION  (Cont'd) 
THE  MOVEMENTS  OF  THE  STOMACH 

The  Character  of  the  Movements 

Even  from  the  earliest  days  it  has  been  recognized  that  the  stomach 
performs  two  important  functions:  (1)  receiving  the  swallowed  food 
and  then  discharging  it  slowly  into  the  intestine,  and  (2)  initiating  the 
chemical  processes  of  digestion.  In  order  to  understand  the  mechanism 
by  which  the  stomach  collects  and  then  discharges  the  food,  it  is  neces- 
sary first  of  all  to  recall  certain  anatomical  facts  concerning  the  organ, 
and  for  this  purpose  it  is  most  convenient  to  accept  the  description 
given  by  Cannon,  which  is  illustrated  in  the  accompanying  figure.  The 
organ  is  divided  into  a  cardiac  and  a  pyloric  portion  by  a  deep  notch  in 
the  lesser  curvature,  called  the  incisura  angularis.  The  cardiac  portion 
is  further  subdivided  into  two  by  the  cardiac  orifice.  The  part  which 
lies,  in  man,  above  a  line  drawn  horizontally  through  the  cardia  is  the 
fundus.  The  part  lying  between  the  fundus  and  the  incisura  angularis 
is  known  as  the  body  of  the  stomach,  which,  when  full,  has  a  tapering 
shape.  The  pyloric  portion  lying  on  the  right  of  the  incisura  angularis 
is  further  divided  into  three  parts:  the  pyloric  vestibule,  the  antrum  and 
the  pyloric  canal,  the  latter  of  which  lies  next  the  pyloric  sphincter  and 
in  man  measures  about  3  cm.  in  length  (see  Fig.  154).  From  a  study  of 
its  development  and  structure  and  from  a  consideration  of  its  behavior 
when  examined  radiographically  Cole30  believes  that  the  ascending  or 
first  part  of  the  duodenum  virtually  belongs  to  the  stomach  and  should 
be  so  considered  when  the  gastric  movements  are  under  investigation. 
Since  this  portion  of  the  duodenum  receives  and  retains  the  chyme  for  a 
short  time  after  its  egress  from  the  stomach  and  in  radiographs  appears 
to  surmount  the  pyloric  sphincter,  he  has  termed  it  the  " reservoir  cap" 
or  pilleus  ventriculi. 

The  filled  stomach  of  a  person  standing  erect  is  so  disposed  that  the 
greatest  curvature  forms  its  lowest  point,  which  may  be  considerably 
below  the  umbilicus.  As  digestion  proceeds  and  the  stomach  empties, 
the  greater  curvature  becomes  gradually  raised,  so  that  ultimately  the 
pylorus  comes  to  be  the  most  dependent  part  of  the  stomach.  From 

485 


486 


DIGESTION 


these  and  many  other  observations  it  is  certain  that  the  emptying  of  the 
stomach  does  not  at  all  depend  on  the  operation  of  the  force  of  gravity. 
Indeed,  that  this  can  not  be  the  case  is  perfectly  clear  when  we  con- 
sider the  disposition  of  the  stomach  in  quadrupeds. 

Exact  observation  on  the  movements  which  the  stomach  performs  from 
the  time  it  is  filled  with  food  till  it  empties,  have  been  made  by  the 
x-ray  method,  first  introduced  by  Cannon.15  The  method  consists  in  feed- 
ing the  animal  with  food  that  has  been  impregnated  with  bismuth  sub- 
nitrate,  then  exposing  him  to  the  x-ray  and  either  taking  instantaneous 
photographs  of  the  shadows  or  observing  them  by  means  of  a  fluorescent 
screen.  In  the  accompanying  figure  (Fig.  155)  the  outline  of  the  shadow 
cast  by  the  stomach  is  shown  at  intervals  of  an  hour  each  during  diges- 
tion. Soon  after  the  stomach  has  become  filled,  peristaltic  waves  are 

seen  to  take  their  origin  about  the  middle 
of  the  body  of  the  viscus,  and  to  course 
toward  the  pylorus.  The  region  above  the 
origin  of  these  waves — that  is,  the  cardiac 
half  of  the  body  of  the  stomach  and  all  the 
fundus,  often  called  the  cardie  pouch — is 
free  from  peristaltic  Avaves  but  is  the  seat 
of  a  tonic  contraction  which  as  digestion 
proceeds  presses  steadily  with  increasing 
force  upon  the  mass  of  food  and  delivers 
it  slowly  to  the  lower  and  more  active  por- 
tion of  the  stomach. 

As  the  food  passes  into  the  lower  part 
of  the  stomach,  the  cardiac  pouch  becomes 
gradually  reduced  in  size  until  finally  when 
the  stomach  is  empty  its  outline,  as  re- 
vealed by  radiographs,  departs  from  the  pyri- 
form  shape  characteristic  of  the  full  organ  to  assume  a  more  or  less 
tubular  form. 

From  this  description  it  is  evident  that  the  function  of  the  cardiac 
portion  of  the  stomach  is  to  serve  as  a  reservoir  for  the  food  which  by 
a  slow  contraction  of  the  gastric  wall  is  gradually  delivered  into  the 
lower  and  more  motile  portion  of  the  stomach.  The  motor  phenomena 
of  this  portion  are  of  a  complex  nature  and  will  now  be  considered. 

Cole,30  by  the  employment  of  serial  x-ray  photographs  taken  at  short 
intervals  has  shown  that  this  portion  of  the  stomach  undergoes  a  succes- 
sion of  rapid  changes  in  shape  (Fig.  156),  due  to  the  peristaltic  waves 
which  course  over  this  region  toward  the  pyloric  sphincter.  The  waves 


Fig.  154. — Schematic  outline  of 
the  stomach.  At  C  is  the  cardia: 
F,  fundus;  I  A,  incisura  angularis; 
B.  body;  PC,  pyloric  canal;  P, 
pylorus.  The  antrum  is  the  portion 
from  IA  to  PC  inclusive.  (From 
Cannon.) 


THE    MECHANISMS    OF    DIGESTION 


487 


in  their  passage  do  not  progress  as  an  unvarying  band  of  constriction  but 
exhibit  alternately  phases  of  increased  and  diminished  tone — phases  of 
contraction  and  relaxation.  The  period  of  gastric  activity  intervening 
between  a  phase  of  complete  relaxation  and  the  reappearance  of  this 
phase  is  termed  a  gastric  cycle.  In  some  types  of  gastric  motility  a 
peristaltic  wave  takes  but  one  gastric  cycle  to  complete  the  journey  from 
its  origin  to  the  pylorus.  Such  a  wave  would  show  in  consequence  one 
phase  each  of  complete  relaxation  and  maximal  contraction.  In  other 
types  two,  three  or  four  gastric  cycles  may  occur  during  the  passage 
of  the  wave.  The  waves  therefore  are  spoken  of  as  one,  two,  three  or 


Fig.   155. — Outlines  of  the  shadows  cast  by  the  stomach  at  intervals   of  an  hour  each  after  feeding 
a    cat    with    food    impregnated    with    bismuth    subnitrate.      (From    Cannon.) 


four  cycle  types  of  peristalsis  respectively.  It  follows  from  this  that  at 
any  moment  the  stomach  will  show  one,  two,  three,  or  four  waves  accord- 
ing to  the  particular  type  of  peristalsis  which  is  present.  The  four  cycle 
is  the  most  common  type ;  the  rapid  one  cycle  type  is  very  rare. 

The  duration  of  a  gastric  cycle  is  from  2-3  seconds.  The  time  required 
for  the  passage  of  a  four  cycle  type  of  peristaltic  wave  from  its  origin 
to  the  pyloric  sphincter  therefore  will  be  from  8-12  seconds.  It  rarely 
exceeds  10  seconds.  Following  the  cardiac  analogy  Cole  divides  the 
gastric  cycle  into  a  systole  and  a  diastole.  In  the  former  which  occupies 
7/10  of  the  cycle  the  constrictions  produced  by  the  peristaltic  waves 
are  most  marked.  Diastole  occupies  3/10  of  the  cycle  and  represents  the 
period  during  which  relaxation  is  taking  place.  (Fig.  156,  VII-X.) 


488 


DIGESTION 


The  adaptation  of  the  capacity  of  the  normal  stomach  to  the  volume  of 
its  contents  is  remarkable.  When  the  stomach  of  a  living  animal  is  dis- 
tended by  fluid  the  intragastric  pressure  shows  very  little  change  even 
up  to  the  point  of  rupture  of  the  viscus  (Grey16).  After  excision,  the 
stomach  loses  in  great  part  this  adaptive  power  which  seems  to  be  con- 
trolled not  through  the  extrinsic  nerves,  but  by  the  nervous  elements 
residing  in  the  gastric  wall  itself. 


The  Effect  of  the  Stomach  Movements  on  the  Food 

This  has  been  studied:   (1)   by  dividing  the  food  into  portions  that 
are  differently  colored  and,  after  some  time,  killing  the  animal,  freezing 


Fig.    156. — Skiagrams    of    human    stomach    at    intervals    after    food    illustrating    a    gastric    cycle. 

(From  Cole.) 

the  stomach  and  making  sections  of  it  (see  Fig.  157) ;  (2)  by  mak- 
ing little  pellets  of  bismuth  subnitrate  with  starch  and  observing  their 
behavior  under  the  x-rays;  or  (3)  by  removing  samples  of  the  stomach 
contents  by  means  of  a  stomach  tube  (Rehfuss  tube)  inserted  so  that 
its  free  end  lies  in  either  the  cardiac  or  the  pyloric  region.  By  the 
first  of  the  above  methods  it  has  been  found  that  the  first  mouthfuls 
of  food  lie  along  the  greater  curvature,  where  they  form  a  layer  over 
which  that  subsequently  swallowed  accumulates,  with  the  last  por- 
tions next  the  cardia.  The  pepsin  and  hydrochloric  acid  of  the  car- 


THE  MECHANISMS   OF   DIGESTION  489 

diac  end,  therefore,  act  soonest  on  the  first  swallowed  portion  of  a 
meal,  and  the  more  recently  swallowed  central  masses  are  not  affected 
by  the  secretions  for  some  time,  so  that  opportunity  is  given  for  the 
saliva  mixed  with  the  food  to  develop  its  digestive  action. 

As  has  been  shown  by  removing  the  stomach  contents  with  a  tube  at 
various  periods  after  feeding  with  starchy  food,  considerable  amylolysis 
may  occur  for  some  time.  When  separate  samples  are  removed  in  this 
way  from  the  cardiac  and  pyloric  parts,  it  has  been  found  that  after 
half  an  hour  the  contents  of  both  have  about  the  same  percentage  of 
sugar,  but  that  for  some  time  after  this  interval  the  cardiac  contents 
contain  considerably  more  sugar  than  the  pyloric.  Later  the  percentages 
of  sugar  again  become  about  equal,  no  doubt  on  account  of  diffusion. 
The  diastatic  action  in  the  fundus  is  finally  brought  to  an  end  when 
the  contents  become  completely  permeated  by  the  hydrochloric  acid. 
In  this  connection  it  is  worthy  of  note  that  the  addition  of  hydrochloric 


Fig.    157. — Section   of  the   frozen  stomach    (rat)    some  time  after   feeding  with   food   given   in   three 
differently   colored   portions.      (From  Howell's   Physiology.") 

acid  up  to  the  point  of  neutrality  greatly  accelerates  the  rate  of  diastatic 
digestion. 

As  the  outer  layers  of  food  in  the  stomach  become  partly  digested  on 
account  of  the  action  of  the  pepsin  and  hydrochloric  acid,  the  food  is 
slowly  pressed  into  the  active  right  half  of  the  stomach,  where  by  the 
action  of  the  peristaltic  waves  it  is  moved  on  to  the  pyloric  vestibule. 
By  observing  the  x-ray  shadows  cast  by  two  pellets  of  bismuth  subni- 
trate  it  has  been  noted  by  Cannon  that,  as  the  peristaltic  wave  approaches 
a  pellet,  it  causes  it  to  move  forward  more  rapidly  for  a  short  distance, 
but  soon  overtakes  it  and  in  doing  so  causes  the  pellet  to  move  back  a 
little  towards  the  fundus.  This  backward  movement  is  less  than  the 
forward  movement,  so  that  after  the  wave  has  passed,  the  position  of 
the  pellet  is  a  little  forward  of  that  which  it  would  have  occupied  had 
there  been  no  wave.  The  behavior  of  the  pellet,  and,  therefore,  of  the 
stomach  contents,  is  very  like  that  of  a  cork  floating  at  the  edge  of  the 
sea;  as  each  wave  approaches,  it  hurries  the  cork  on  a  little,  but  after 


490  DIGESTION 

its  passage  the  cork  recedes  again  until  the  second  wave  carries  it  still 
a  little  farther  forward.  As  the  peristaltic  wave  approaches  the  pyloric 
vestibule  and  becomes  more  powerful  its  effect  on  the  pellets  becomes 
more  marked. 

These  observations  made  on  cats  and  other  laboratory  animals  no 
doubt  also  apply  in  the  case  of  man.  Removal  of  the  contents  of  the 
cardiac  and  pyloric  regions  separately  with  a  stomach  tube  after  feeding 
with  a  test  meal  part  of  which  was  colored  with  carmine  or  charcoal, 
has  shown  that  none  of  the  coloring  material  was  present  in  the  contents 
of  the  pyloric  end  up  to  twenty  minutes  or  so  after  the  food  had  been 
taken.  It  then  appeared  but  at  first  only  in  traces.  Another  important 
distinction  between  the  food  in  the  two  portions  of  the  stomach  relates 
to  its  consistency.  In  the  pyloric  end  it  is  semifluid  and  homogeneous 
in  character;  in  the  cardiac  end,  on  the  other  hand,  it  is  a  lumpy,  rather 
incoherent  mass. 

The  gastric  movements  must  greatly  facilitate  the  digestive  processes 
in  the  stomach.  In  the  cardiac  part  the  undisturbed  condition  of  the 
food  will,  as  we  have  seen,  facilitate  the  digestive  action  of  ptyalin, 
whereas  in  the  body  of  the  stomach  the  peristaltic  waves,  besides  mov- 
ing the  food  onward,  will  tend  to  bring  fresh  portions  of  mucous  mem- 
brane and  food  in  contact,  so  that  the  latter  becomes  more  thoroughly 
mixed  with  the  pepsin  and  hydrochloric  acid.  In  the  pyloric  part,  where 
no  hydrochloric  acid  is  secreted,  the  contents,  already  sufficiently  acid 
in  reaction,  become  more  thoroughly  churned  up  with  the  local  pepsin 
secretion,  so  that  proteolytic  action  progresses  very  rapidly. 

The  peristaltic  waves  also  facilitate  absorption  from  the  stomach  of  such 
substances  as  glucose  in  concentrated  solution  and,  probably,  of  hydro- 
lyzed  protein ;  water,  however,  is  not  absorbed.  The  fact  that  the  mucosa 
of  the  vestibule  has,  relatively  to  the  cardiac  end,  few  secreting  glands 
is  in  harmony  with  the  view  that  absorption  is  an  important  function 
of  this  part  of  the  stomach. 

The  observations  of  Carlson,17  Ginsburg18  and  others  indicate  that  the 
usually  accepted  explanation  of  the  pains  of  gastric  and  duodenal  ulcers, 
namely,  corrosion  and  irritation  of  exposed  nerve  endings  in  the  gastric 
and  duodenal  mucosae  by  highly  acid  stomach  contents,  is  not  correct. 
The  pains  of  ulcer  may  be  present  when  the  contents  of  the  stomach  are 
alkaline  and  they  may  be  absent  when  marked  hyperacidity  exists.  Ac- 
cording to  these  authors  the  pains  are  analogous  in  origin  to  those  of 
hunger,  and  are  the  result  of  contractions  of  the  stomach  and  duodenum, 
the  nerves  of  which  are  in  a  hyperexcitaBIe~stateV^  Hyperacidity  then, 
will  affect  the  pain  of  ulcer  in  so  far  only  as  it  increases  the  motility 
of  the  stomach. 


THE    MECHANISMS    OF    DIGESTION  491 

THE  EMPTYING  OF  THE  STOMACH 

The  Control  of  the  Pyloric  Sphincter 

Recent  experimental  work  demands  that  the  view  originally  advanced 
by  Pavlov  and  elaborated  by  Cannon,  namely  that  the  acidity  of  the 
chyme  constitutes  the  chief  factor  in  the  control  of  the  pyloric  sphincter, 
be  abandoned.  This  conception  of  the  pyloric  mechanism  fails  to  account 
for  the  rapid  passage  of  w^ater  and  egg  white  into  the  duodenum,  and 
leaves  unexplained  the  normal  emptying  time  of  the  stomach  in  certain 
pathological  states  in  which  the  secretion  of  acid  is  suppressed  or  greatly 
reduced. 

From  the  study  of  serial  radiographs  Cole30  showed  that  in  man  a  def- 
inite relationship  existed  between  the  movements  of  the  antrum  and  those 
of  the  pyloric  sphincter.  The  activities  of  the  sphincter  were  found  to 
be  directly  proportional  to  the  magnitude  of  the  antral  contractions; 
Avhen  the  motility  of  the  antrum  was  low  the  sphincter  contractions  were 
feeble,  powerful  antral  waves  on  the  other  hand  were  associated  with 
vigorous  sphincter  movements.  Chyme  passed  into  the  duodenum  during 
gastric  systole  but  not  during  diastole.  Luckhardt,  Phillips  and  Carl- 
son31 combining  fluoroscopic  observations  with  graphic  records,  obtained 
by  means  of  a  balloon  inserted  into  the  stomach,  have  shown  that  the 
passage  of  chyme  into  the  duodenum  coincides  with  peristaltic  waves 
travelling  over  the  stomach.  The  gastric  contents  collected  from  a  duode- 
uostomy  made  immediately  below  the  pyloric  sphincter  rarely  showed  the 
presence  of  free  acidity  as  tested  by  congo-red.  It  has  been  noted  that  water 
placed  in  the  stomach  passed  through  the  sphincter  in  gushes  of  varying 
intervals  apart,  but  the  emissions  on  the  whole  showed  evidence  of 
rhythm  and  it  was  assumed  on  this  account  that  they  were  dependent 
upon  peristaltic  waves  (Ivy).  The  water  as  it  left  the  stomach  was 
neutral  in  reaction. 

These  observations  in  the  main  have  been  confirmed  and  extended 
by  other  investigators.  The  more  precise  study  of  the  interdependence 
of  the  antral  and  sphincter  movements  has  been  made  by  Wheelon  and 
Thomas32  who  combined  the  study  of  radiographs  with  graphic  records 
obtained  by  balloons  placed  respectively  in  the  antrum  and  pyloric 
canal.  In  this  manner  tracings  could  be  taken  of  movements  occurring 
simultaneously  in  the  two  regions.  These  observers  find  that  when 
the  peristaltic  wave — commencing  in  the  body  of  the  stomach  and  trav- 
elling over  the  vestibule — reaches  the  antrum  the  sphincter  becomes 
relaxed  so  that  any  material  swept  forward  by  the  constricting  wave  is 
free  to  pass  through  the  pyloric  opening.  The  wave  is  sufficiently 
broad  to  involve  the  whole  antrum  at  one  time  and  indeed  it  involves 


492  DIGESTION 

the  sphincter  before  it  has  begun  to  disappear  from  the  antrum  with  the 
result  that  for  a  short  period  the  antrum  and  sphincter  together  are  in 
the  contracted  state.  Soon  after  this,  the  antrum  enters  upon  its  neg- 
ative phase  (relaxation)  the  sphincter  being  still  contracted.  These 
facts  are  shown  in  Fig.  158.  Fluoroscopic  examination  of  the  movements 
of  the  human  stomach  showed  that  some  chyme  escaped  through  the 
sphincter  during  the  passage  of  every  peristaltic  wave  over  the  antrum. 
On  the  other  hand  the  reaction  of  the  contents  of  the  stomach  or  duo- 
denum did  not  have  any  influence  on  the  emptying.  When,  for  exam- 
ple, tenth-normal  hydrochloric  acid  was  poured  through  a  tube  into  the 
antrum,  in  sufficient  quantity  to  render  its  contents  distinctly  acid,  no 
effect  upon  the  sphincter  movements  or  their  relation  to  the  antral  waves 
could  be  demonstrated.  One  to  five  per  cent  sodium  bicarbonate  solu- 
tions likewise  were  without  effect  upon  the  opening  of  the  sphincter. 


Fig.  158. — Tracings  showing  the  relationship  between  contractions  of  the  antrum  (lower  tracing) 
and  the  pyloric  sphincter  (upper  tracing).  Note  that  the  antrum  precedes  the  sphincter  but 
that  the  latter  contracts  before  the  antrum  has  relaxed.  (From  Wheelon  and  Thomas.) 

Acids  introduced  through  a  tube  into  the  duodenum  in  quantities  suf- 
ficient to  render  the  chyme  in  this  situation  of  an  H-ion  concentration 
considerably  in  excess  of  that  normally  present  was  unable  to  prevent 
relaxation  of  the  sphincter  in  response  to  an  antral  wave.  Alkaline 
solutions  in  the  same  region  failed  to  produce  sphincter  relaxation.  The 
various  foodstuffs,  carbohydrates,  proteins  and  fats  took  approximately 
the  same  time  to  leave  the  stomach,  and  each  type  of  food  commenced 
to  pass  through  the  pyloric  opening  within  a  few  minutes  (3-12)  after 
its  ingestion.  (McClure,  Reynolds  and  Swartz.34) 

The  foregoing  account  of  the  movements  of  the  antrum  and  pyloric 
sphincter  indicates  that  the  "law  of  the  intestine"  (page  501)  with  some 
minor  modifications,  directs  the  activities  of  these  portions  of  the  stom- 
ach. The  experiments  also  appear  to  establish  definitely  the  paramount 
importance  of  the  movements  of  these  regions  as  a  factor  in  gastric 


THE   MECHANISMS   OF   DIGESTION 


493 


evacuation.  The  sphincter  opens  in  response  to  every  peristaltic  wave 
arriving  at  the  antrum  and  apparently  does  so  blindly  without  regard  to 
the  reaction  of  the  gastric  or  duodenal  contents.  That  some  factor  other 
than  gastric  peristalsis,  however,  may  influence  the  emptying  time  is 
probable.  It  is  difficult,  otherwise,  to  account  for  the  rapid  passage  from 
the  stomach  of  water  and  egg-white  and  the  retention  of  other  substances 
until  they  reach  a  more  or  less  fluid  consistency. 

The  later  work  of  Wheelon  and  Thomas33  points  to  the  existence  of 
an  intimate  relationship  between  the  activities  of  the  duodenum  below 


Fig.  159. — Diagram  of  the  relationships  of  the  contractions  of  antrum,  sphincter  and  duo- 
denum and  of  the  passage  of  chyme  from  the  antrum  into  the  duodenum  €3,  Ci,  Cz.  The  seg- 
mental  waves  of  the  duodenum  are  marked  A,  B,  Ct  D,  and  E  and  it  will  be  noted  that  A  oc- 
curs when  the  antrum  is  completely  relaxed  and  the  sphincter  contracted.  It  will  therefore 
assist  to  empty  the  "reservoir  cap"  of  the  duodenum.  The  duodenum  is  seen  to  be  relaxed  to 
its  greatest  extent  after  the  antrum  has  ceased  contracting  and  when  the  sphincter  is  contracted. 
(After  Wheelon  and  Thomas.) 

the  " reservoir  cap"  and  the  movements  of  the  antrum  and  pyloric  sphinc- 
ter. When  simultaneous  tracings  were  taken  of  the  antrum  and  sphinc- 
ter and  of  the  duodenum  below  the  "cap"  definite  relationships  were 
found  to  exist  between  the  activities  of  these  portions  of  the  digestive 
tube.  These  relationships  are  shown  diagrammatic  ally  in  Fig.  159.  The 
duodenum  enters  upon  its  positive  phase  2%  seconds  after  the  commence- 
ment of  the  sphinster  contraction  and  at  this  moment  the  antrum  is  relax- 
ing and  remains  relaxed  throughout  the  sphincter  and  duodenal  contrac- 
tions. The  sphincter  enters  upon  its  negative  phase  a  short  time  prior 
to  the  maximal  contraction  of  the  duodenum  and  the  greatest  relaxation 


494  DIGESTION 

of  the  duodenum  occurs  a  short  time  after  the  commencement  of  the 
sphincter  contraction.  Superimposed  upon  the  duodenal  peristaltic 
waves  are  rhythmical  segmentary  movements  (A,  B,  C,  D,  E)  .  The  first 
of  these  occurs  at  the  commencement  of  the  peristaltic  wave  and  coin- 
cidently  with  the  maximal  height  of  the  sphincter  contraction.  The  sec- 
ond segmentary  wave  surmounts  the  crest  of  the  peristaltic  wave  in  the 
duodenum  and  occurs  during  relaxation  of  the  sphincter. 

The  peristaltic  waves  in  the  duodenum  by  the  withdrawal  of  material 
from  the  " reservoir  cap"  will  aid  in  the  evacuation  of  the  latter.  This 
receives  the  chyme  during  the  contraction  of  the  antrum  but  none  can 
return  to  the  antrum  when  this  relaxes  since  now  the  sphincter  is  closed. 
The  motility  of  the  stomach  appears  to  influence  duodenal  peristalsis 
and  in  this  way  indirectly  aids  in  the  withdrawal  of  material  from  the 
''cap"  which  it  is  the  purpose  of  the  antral  and  sphincter  activities  to 
fill.  On  the  other  hand  duodenal  motility  influences  the  activity  of  the 
sphincter  for  stimulation  of  the  duodenum  below  the  "cap"  in  addi- 
tion to  a  contraction  at  the  stimulated  point  and  relaxation  below,  pro- 
duces a  sharp  contraction  of  the  sphincter  followed  by  a  prolonged  nega- 
tive phase.  Sphincter  motility  unassociated  with  antral  activity  may  in 
this  way  be  induced.  From  these  considerations  it  may  be  seen  that  the 
peristaltic  waves  in  the  duodenum  which  hasten  the  emptying  of  the 
cap  by  the  withdrawal  of  its  contents  are  probably,  through  their  influ- 
ence upon  the  sphincter,  a  factor  also  in  the  filling  of  the  "cap"  from 
the  stomach  side.  That  the  degree  of  receptivity  of  the  duodenum  is  an 
important  factor  in  emptying  the  cap  is  indicated  by  the  observation  that 
a  dog  starved  for  18  hours  emptied  its  stomach  of  an  8  oz.  barium  meal 
in  80  minutes  while  a  second  meal  of  the  same  amount  was  not  entirely 
removed  after  2%  hours. 

Influence  of  Pathological  Conditions  on  the  Emptying 

An  important  surgical  application  of  these  facts  concerns  the  behavior 
of  food  after  gastroenterostomy.  It  has  been  thought  that  this  operation 
would  cause  the  food  to  be  drained  from  the  stomach  into  the  intestine 
and  thus  leave  the  region  of  the  stomach  between  the  fistula  and  the 
pylorus  inactive.  This  assumption  is  based  on  the  idea,  which  we  have 
seen  to  be  erroneous,  that  gravity  assists  in  the  emptying  of  the  stomach. 
As  a  matter  of  fact,  it  has  been  found  that,  if  the  gastroenterostomy  is 
fnade  when  there  is  no  obstruction  at  the  pylorus,  the  chyme  takes  its 
Aiormal  passage  through  the  sphincter  and,  almost  without  exception, 
'/none  leaves  by  the  fistula.  When  the  pylorus  is  partly  occluded,  the 
food  sometimes  passes  in  the  usual  way,  and  sometimes  by  the  fistula. 
The  cause  for  this  predilection  for  the  pyloric  pathway  depends  on  the 


THE    MECHANISMS   OP    DIGESTION  495 

pressure  conditions  in  the  gastric  contents.  Gastroenterostomy,  there- 
fore, is  efficient  only  when  gross  mechanical  obstruction  exists  at  the 
pylorus.  The  operation  should  never  be  performed  in  the  absence  of 
demonstrable  organic  pyloric  disease. 

Another  objection  to  gastroenterostomy  in  the  presence  of  a  patulous 
pyloric  sphincter  rests  on  the  fact  that  the  food,  after  passing  the  sphinc- 
ter and  moving  along  the  intestine,  mav__again  enter  the  stomach  through 
the  fistula.  This  is  most  likely  to  occur  when  the  stomach  is  full  of 
food,  for  under  these  conditions  the  stretching  of  its  walls  separates  the 
edges  of  the  opening,  the  intestine  being  drawn  taut  between  the  edges, 
so  that  the  opening  between  the  stomach  and  the  intestine  assumes  the 
form  of  two  narrow  slits,  which  act  like  valves  permitting  the  food  to 
enter  but  preventing  its  escape  from  the  stomach.  Only  seldom  under 
these  circumstances  can  any  food  pass  into  the  intestine  beyond  the 
stomach  opening.  Repeated  vomiting  after  gastroenterostomy  has  been 
observed  in  experimental  animals  only  when  obstructive  kinks  or  other 
demonstrable  obstacles  were  present  in  the  gut,  the  obstruction  being  lo- 
cated in  that  part  of  the  intestine  beyond  its  attachment  to  the  stomach. 

When  the  pyloric  obstruction  is  complete,  food  must,  of  course,  leave 
by  the  fistula,  digestion  by  the  pancreatic  juice  and  bile  being  still  car- 
ried on  because  of  the  fact  that  for  a  considerable  distance  down  the 
intestine,  secretin,  which  we  have  seen  is  essential  for  the  secretion 
of  these  fluids,  is  still  produced  by  the  contact  of  the  acid  chyme  with 
the  intestinal  mucosa.  Further  provision  for  adequate  digestion  of 
food  in  such  cases  is  secured,  as  some  of  the  food  after  leaving  the 
fistula  passes  back  for  a  certain  distance  into  the  duodenum,  where,  however, 
it  soon  excites  peristaltic  waves,  which  again  carry  it  forward.  This 
insures  thorough  mixing  with  the  digestive  juices.  From  their  experi- 
mental experience  Cannon  and  Blake19  recommend  that,  when  the 
fistula  has  to  be  made,  it  should  be  as  large  as  possible  and  near  the 
pylorus,  and  that  the  stomach  afterwards  should  not  be  allowed  to 
become  filled  with  food.  To  avoid  kinking  of  the  gut,  they  also  recom- 
mend that  several  centimeters  of  the  intestine  should  be  attached  to  the 
stomach  distal  to  the  anastomosis. 

The  consistency  of  the  food  appears  to  have  little  influence  on  its  rate  of 
discharge  from  the  stomach — at  least  in  the  case  of  potatoes.  Distinctly 
hard  particles  in  the  food  retard  the  stomach  evacuation. 

There  is  usually  a  considerable  amount  of  gas  in  the  part  of  the  stomach 
above  the  entrance  of  the  cardia,  on  account  of  which  this  part  of  the 
stomach  has  sometimes  been  called  the  stomach  bladder.  In  the  upright 
position  this  gas  forms  a  bright  area  in  the  x-ray  plate  (Fig.  155),  but 
when  the  person  reclines  it  spreads  to  a  new  location.  Its  presence  may 


496  DIGESTION 

influence  gastric  digestion  by  preventing  the  contact  of  the  food  with 
the  mucous  membrane,  and  by  interfering  with  the  efficiency  of  the  peri- 
staltic waves  in  moving  the  food.  Considerable  gas  therefore  retards  the 
emptying  of  the  stomach,  as  has  been  shown  experimentally  by  x-ray 
observations  on  animals  fed  with  the  standard  amount  of  food  followed 
by  the  introduction  of  air.  It  was  noted  that  the  air  did  not  diminish 
the  frequency  or  strength  of  the  peristaltic  waves,  but  that  these  could 
not  efficiently  act  on  the  food.  When  along  with  gas  there  is  also  atony 
of  the  stomach  wralls,  the  retardation  in  the  discharge  will,  of  course,  be 
still  more  pronounced.  The  temperature  of  the  swallowed  food  does 
not  appear  to  have  much  influence  on  the  stomach  movements  or  on  the 
the  rate  of  discharge  from  the  organ. 


CHAPTER  LV 
THE  MECHANISMS  OF  DIGESTION  (Cont'd) 

THE  MOVEMENTS  OF  THE  INTESTINES 

The  length  of  the  small  intestine  and  the  size  of  the  cecum  of  the 
large  intestine  vary  considerably  in  different  animals.  In  the  carnivora, 
such  as  the  cat,  the  small  intestine  is  relatively  short;  in  the  herbivora, 
relatively  long.  Thus,  it  is  three  times  the  length  of  the  body  in  the  cat, 
and  four  to  six  times  in  the  dog;  whereas  in  the  goat  and  sheep,  it  may 
be  nearly  thirty  times  the  length  of  the  body.  In  the  carnivora  the 
cecum  is  either  absent  or  rudimentary,  whereas  in  those  herbivora  which 
do  not  have  a  divided  stomach  the  cecum  is  very  large  and  sacculated, 
as  is  also  the  colon.  The  reason  for  the  great  size  in  herbivora  is  that 
practically  the  whole  of  the  digestion  of  cellulose  takes  place  in  this 
part  of  the  gut.  This  digestion,  as  we  shall  see  later,  does  not  depend 
on  any  secretion  poured  forth  by  the  animal  itself,  but  upon  the  action 
of  bacteria  and  of  certain  enzymes  (cytases)  that  are  taken  with  the 
vegetable  food. 


Movements  of  the  Small  Intestine 


The  movements  of  the  small  intestine  have  been  studied  (1)  by  the 
bismuth  subnitrate  and  x-ray  method,  (2)  by  observing  them  after  open- 
ing the  abdomen  of  an  animal  submerged  in  a  bath  of  physiologic  saline 
at  body  temperature,  (3)  by  observing  the  changes  in  pressure  produced 
in  a  thin-walled  rubber  balloon  inserted  in  the  lumen  of  the  gut  and 
connected  with  a  recording  tambour  (Fig.  160),  and  (4)  by  excising 
portions  of  the  intestine  and  keeping  them  alive  in  a  bath  of  saline  solu- 
tion at  body  temperature,  through  which  oxygen  is  made  to  pass. 

THE  SEGMENTING  MOVEMENTS 

When  a  suitably  fed  animal  is  placed  on  the  holder  for  examination 
)y  the  x-ray  method,  no  movement  in  the  intestinal  shadows  is  generally 
)bserved  for  some  time.  The  first  movement  to  appear  is  the  breaking  of 
me  of  the  columns  of  food  into  small  segments  of  nearly  equal  size. 

ich  of  these  segments  again  quickly  divides,  and  the  neighboring 
lalves  suddenly  unite  to  form  new  segments,  and  so  on,  in  a  manner 

497 


DIGESTION 

which  will  be  made  clear  by  consulting  Fig.  161.  This  rhythmic  seg- 
mentation, as  Cannon  has  called  it,  continues  without  cessation  for  more 
than  half  an  hour,  and  the  food  shadow  does  not  meanwhile  seem  to  change 
its  position  in  the  abdomen  to  any  extent.  The  splitting  up  of  the  seg- 
ment and  the  rushing  together  of  the  neighboring  halves  proceed  as  a 
rule  with  great  rapidity;  thus,  if  we  count  the  number  of  different  seg- 


Fig.    160. — Apparatus    for    recording    contractions    of    the    intestine.       (From    Jackson.) 

inents  during  a  definite  period,  we  may  find  the  rate  of  division  in  the 
cat  to  be  as  high  as  28  or  30  a  minute.  In  man  the  divisions  occur  at  a 
frequency  of  approximately  10  per  minute,  which  corresponds  to  the  fre- 
quency with  which  sounds  can  be  heard  when  the  abdomen  is  auscultated. 
Although  half  an  hour  is  the  period  which  this  process  usually  oc- 
cupies, it  may  last  considerably  longer.  In  certain  animals,  such  as  the 
rabbit,  segmenting  movements  have  not  been  observed,  but  instead 


THE    MECHANISMS   OF   DIGESTION 


499 


of  them  a  rhythmic  to-aiid-fro  shifting  of  the  masses  of  food  along  the 
lumen  of  the  gut,  rapidly  repeated  for  many  minutes. 

When  the  intestines  are  floated  out  in  a  warm  bath  of  saline  solution, 
it  is  seen  that  the  rhythmic  segmentation  is  caused  by  narrow  rings  of 
contraction.  Under  such  conditions  also  it  is  often  noted  that  the 
loops  of  intestine  sway  from  side  to  side.  The  balloon  method  also  re- 
veals the  presence  of  slight  waves  of  contraction  that  pass  rapidly  along 
the  gut,  and  follow  each  other  at  the  rate  of  twelve  to  thirteen  per  minute. 
Both  of  the  muscular  coats  of  the  intestine  are  involved,  and  it  is  believed 
that  the  contractions  are  responsible  not  only  for  the  pendular  move- 
ments but  for  the  rhythmic  segmentation  observed  by  the  x-ray  method. 
According  to  this  view  these  movements  are  constantly  passing  along 
the  intestine,  and  become  exaggerated  by  the  mechanical  stimulus  -which 
is  offered  by  the  masses  of  food  to  such  an  extent  that  they  divide  the 
masses  into  portions.  The  evidence  for  this  belief  rests  on  the  fact  that 


[/    *v-r<  >T^\  f~r\  >-^sti>Z 
*s*~\.  C  : J  vA^  vj_J  (  fS  /^~K  v 


Fig.  161. — Diagrammatic  representation  of  the  process  of  segmentation  in  the  intestine.  An 
unbroken  shadow  is  shown  in  I  and  its  segmentation  in  2.  The  dotted  lines  across  each  mass 
show  the  position  of  division  and  in  3  is  shown  how  new  masses  are  formed  by  the  split  portions 
coming  together.  (.From  Cannon.) 

when  the  contraction  is  studied  by  the  balloon  method,  it  becomes  marked 
over  the  middle  of  the  balloon,  where  the  greatest  tension  exists. 

Several  functions  can  be  assigned  to  these  movements.  They  cause 
intimate  mixture  of  the  food  with  the  digestive  juices,  and  by  bringing 
ever  new  portions  of  food  in  contact  with  the  mucosa,  they  encourage 
absorption.  They  also  have  an  important  massaging  influence  on  the 
blood  and  lymph  in  the  vessels  of  the  intestinal  walls.  Indeed,  the  pas- 
sage of  lymph  from  the  lacteals  into  the  mesenteric  lymphatics  seems  to 
depend  very  largely  upon  these  movements. 

The  investigations  of  Alvarez20  and  his  coworkers  show  that  the  rhyth- 
mic intestinal  contractions  are  not  of  uniform  rate  throughout  the  entire 
length  of  the  small  bowel,  but  vary  in  frequency  inversely  with  the  dis- 
tance from  the  pylorus.  For  example,  the  contractions  of  a  segment 
>f  the  duodenum  proceed  at  a  more  rapid  rate  (17-21  per  minute)  than 
do  the  contractions  of  an  ileal  segment  (10-12  per  minute)  under  the 


500  DIGESTION 

same  experimental  conditions.  Associated  with  the  variations  in  fre- 
quency are  also  differences  in  the  amplitude  of  the  contractions  of  the  in- 
testinal muscle.  As  the  contractions  become  less  frequent  their  ampli- 
tude increases  to  the  extent  that  the  ratio  between  the  amplitude  of  the 
contractions  of  duodenal  and  ileal  segments  is  as  3  to  20.  Tone  and  irrita- 
bility diminish  progressively  from  duodenum  to  ileum.  According  to 
Alvarez  the  underlying  cause  of  the  decline  in  contraction  rate  is  to  be 
found  in  a  study  of  the  metabolism  of  the  intestinal  muscle  in  the  differ- 
ent regions.  The  determination  of  the  metabolic  changes  in  different 
parts  of  the  intestinal  muscle  from  pylorus  to  the  lower  end  of  the  ileum 
showed  a  gradual  descent  in  the  curve  of  energy  output  (metabolic  gra- 
dient) which  ran  a  course  parallel  to  that  of  the  intestinal  contractions, 
a  slow  or  a  rapid  metabolism  being  associated  with  a  slow  or  a  rapid 
contraction  rate,  respectively.  This  direct  relationship  between  the  fre- 
quency of  rhythm  and  the  metabolism  rate  of  intestinal  muscle  is  in  favor 
of  the  view  that  the  intestinal  contractions  are  myogenic,  moreover, 
the  graded  activity  of  the  muscle  with  regard  to  rhythm,  tonus  and  ir- 
ritability is  probably  an  important  factor  in  the  production  of  peristalsis 
and  in  the  determination  of  the  direction  which  this  movement  shall  take. 

THE  PERISTALTIC  MOVEMENTS 

The  other  movement  observed  in  the  small  intestine  is  that  known  as  the 
peristaltic  wave.    It  occurs  in  two  forms:  (1)  as  a  slowly  advancing  con- 


Fig.  162. — Intestinal  contractions  (balloon  method)  after  excision  of  the  abdominal  ganglia  and 
section  of  both  vagi.  Mechanical  stimulation  above  (/)  and  below  (2)  the  balloon  causes  relaxa- 
tion and  contraction  respectively.  (From  Starling.) 

traction  (1  to  2  cm.  per  minute),  preceded  by  an  inhibition  of  the  walls, 
and  proceeding  only  through  a  short  distance  in  a  coil  (4  to  5  cm.);  and 
(2)  as  a  swift  movement  called  the  peristaltic  rush,  which  sweeps  with- 
out pause  for  much  longer  distances  along  the  canal. 
Further  analysis  of  the  peristaltic  wave  can  readily  be  made  by  the 


THE   MECHANISMS   OF   DIGESTION  501 

balloon  method  (Fig.  162).  If  the  gut  is  pinched  above  the  balloon,  a 
marked  relaxation  occurs  over  the  latter,  and  this  relaxation  extends  for 
about  two  feet  down  the  intestine.  If,  on  the  other  hand,  the  gut  is  pinched 
a  little  below  the  situation  of  the  balloon,  a  long-continued  contraction 
occurs  over  the  latter.  The  conclusion  that  we  may  draw  from  this  result 
is  that  the  stimulation  of  the  gut  causes  contraction  above  the  point  of 
the  stimulus  and  relaxation  below,  this  being  known  as  "the  law  of  the 
intestine"— (Bayliss  and  Starling).  We  have  seen  that  it  applies  also  in 
the  case  of  the  cardiac  and  pyloric  sphincters. 

THE  PHYSIOLOGICAL  NATURE  OF  THE  EHYTHMIC  AND  PERISTALTIC  MOVE- 
MENTS 

Interesting  information  in  this  connection  has  been  gained  by  obser- 
vation of  the  behavior  of  the  movements  after  the  application'  of  drugs 
to  the  gut  or  after  cutting  the  nerve  supply.  The  rhythmic  movements 
are  not  affected  by  the  application  of  nicotine  or  cocaine.  Since  these 
drugs  paralyze  nervous  structures  it  has  been  concluded_tha,tJJae^ rhythmic 
movements,  are  jnvjagsftie  in  origin.  The  question  is  not  a  settled  one, 
however,  for  it  has  been  found  by  Magnus  that,  although  strips  of  the 
longitudinal  muscle,  isolated  in  oxygenated  saline  solution,  will  continue 
to  beat,  they  do  not  do  so  if  the  adherent  Auerbach's  plexus  of  nerves 
is  stripped  off  from  them.  The  nature  of  the  peristaltic  contractions  is 
more  definite;  they  must  clearly  depend  upon  a  local  nervous  struc- 
ture, since  they  are  paralyzed  by  the  application  to  the  gut  of  cocaine  or 
nicotine.  This  local  nervous  system  no  doubt  also  resides  in  Auerbach's 
plexus,  which  must  therefore  be  considered  as  complex  enough  to  be  (see 
page  830)  endowed  with  the  power  of  directing  nervous  impulses  so  as  to 
bring  about  relaxation  of  the  gut  in  front  of  the  stimulus  and  contrac- 
tion over  it. 

NERVOUS  CONTROL  OF  MOVEMENTS 

The  influence  of  the  central  nervous  system  on  the  intestinal  movements 
has  been  studied  by  the  usual  methods  of  cutting  and  stimulating  the 
extrinsic  nerve  supply.  Through  the  splanchnic  nerves  tonic  inhibitory 
impulses  are  conveyed  to  the  intestine  (except  the  ileocolic  sphincter), 
for  after  these  nerves  are  severed  the  movements  become  more  distinct. 
Indeed,  in  many  animals  after  opening  the  abdomen  no  intestinal  move- 
ment can  be  observed  until  these  nerves  have  been  cut.  Stimulation  of  the 
peripheral  end  of  the  nerve  also  inhibits  any  movement  which  may  mean- 
while be  in  progress.  The  impulses  through  the  vagus  nerve  are  of  an 
opposite  character.  Section  of  these  nerves  has  little  effect,  but  stimula- 
tion causes  contraction.  (Figs.  163  and  164.)  ^ 

» 


502 


DIGESTION 


By  observing  the  rhythmic  contractions  of  an  isolated  strip  of  the  small 
intestine  suspended  in  a  bath  of  oxygenated  saline  solution  at  body  tem- 
perature, it  can  readily  be  shown  that  the  presence  of  even  a  minute  trace 
of  epinephrine  is  sufficient  to  produce  complete  inhibition  of  the  movement. 
The  parallelism  between  the  effects  of  splanchnic  stimulation  and  those  of 


Kig.  163. — The  effect  of  excitation  of  both  splanchnic  nerves  on  the  intestinal  contractions. 

Starling.) 


(From 


Fig.    164. — The   effect   of  stimulation    of   right   vagus    nerve   on   the   intestinal    contractions.      (From 

Starling.) 

epinephrine  injection  is  very  significant,  for  in  this  way  the  marked  inhi- 
bition of  intestinal  movement  which  occurs  during  fright  may  possibly 
be  explained  (see  page  787). 

The  circular  muscular  coat  of  the  last  two  or  three  centimeters  of 
the  ileum  before  it  joins  the  cecum  is  definitely  thicker  than  the  rest  of 
this  coat,  indicating  that  it  has  a  sphincter-like  action.  This  ileocolic 


THE    MECHANISMS    OF   DIGESTION  503 

sphincter,  as  it  is  called,  opens  when  food  is  pressed  against  it  from  the 
ileum,  but  remains  closed  when  food  is  pressed  against  it  from  the  cecum. 
It  therefore  obeys  the  law  of  the  intestine.  That  it  is  physiologically 
distinct  from  the  musculature  of  the  rest  of  the  ileum  is  indicated  by  the 
fact  that  the  splanchnic  and  vagus  nerves  do  not  affect  it  in  the  same 
way;  thus,  stimulation  of  the  splanchnic  causes  a  strong  contraction  of 
the  sphincter,  whereas  this  is  unaffected  by  stimulation  of  the  vagus. 

Peristalsis  is  much  more  rapid  in  the  duodenum  than  in  other  parts  of 
the  small  intestine.  During  the  first  stages  of  digestion,  the  food  ordi- 
narily lies  mainly  in  the  right  half  of  the  abdomen,  and  later  in  the  left 
half.  There  is  considerable  variation  in  the  time  that  elapses  before  it 
enters  the  colon.  In  the  cat,  carbohydrates  reach  this  part  of  the  gut  in 
about  four  hours. 

Movements  of  the  Large  Intestine 

On  account  of  the  great  differences  which  we  have  already  seen  to 
exist  in  the  size  and  relative  importance  of  the  colon  as  a  digestive  organ 
in  different  classes  of  animals,  it  is  not  surprising  that  the  movements 
observed  are  very  different  according  to  the  dietetic  habits  of  the  animal. 
Apparently  the  movements  are  much  the  same  in  the  cat  as  in  man.  As 
the  food  passes  through  the  ileocolic  sphincter  into  the  cecum  and 
accumulates  there,  it  gradually  sets  up,  by  its  pressure,  a  contraction  of 
the  muscular  walls  of  the  gut  somewhere  about  the  junction  between 
the  ascending  and  transverse  colon.  This  wave  of  contraction  then 
begins  to  travel  slowly  toward  the  cecum,  without,  however,  being  pre- 
ceded by  any  relaxation  of  the  wall  of  the  gut,  as  is  the  case  with  a  true 
peristaltic  wave.  This  first  wave  is  soon  followed  by  others,  with  the 
result  that  the  food  is  forced  up  into  the  cecum,  against  the  blind  end 
of  which  it  is  crowded,  being  meanwhile  prevented  from  passing  into 
the  ileum  by  the  operation  of  the  ileocolic  sphincter  and  by  the  oblique 
manner  in  which  the  ileum  opens  into  the  cecum. 

As  the  result  of  the  distention  of  the  cecnm  set  up  by  tjlfinr  iff  finllH 
antiperistaltic  waves,  a  true  coordinated  peristaltic  wave  is  occasionally 
initiated,  and  passes  along  the  ascending  colon  preceded  by  the  usual 
wave  of  inhibition.  These  waves,  however,  disappear  before  they  reach 
the  end  of  the  colon,  so  that  the  food  is  again  driven  back  by  the  so- 
called  antiperistaltic  waves.  The  effect  of  the  movements  is  to  knead 
and  mix  the  intestinal  contents,  and  thus  encourage  the  absorption  of 
water  from  them.  The  resulting  more  solid  portions  then  collect  toward 
the  splenic  flexure,  and  become  separated  from  the  remaining  more  fluid 
portion  by  transverse  waves  of  constriction,  which  develop  into  peri- 
staltic waves  carrying  the  harder  masses  into  the  distal  portions  of  the 


504 


DIGESTION 


colon,  where  they  collect  chiefly  in  the  sigmoid  flexure.  The  descending 
colon  itself  is  never  distended  with  contents  and  merely  serves  as  a  tube 
for  transferring  the  masses  from  the  transverse  colon  to  the  sigmoid 
flexure.  The  time  taken  for  a  capsule  of  bismuth  to  reach  the  various 
parts  of  the  large  intestine  is  shown  in  Fig.  165. 

After  a  certain  mass  has  collected  in  the  sigmoid  flexure  and  rectum, 
the  increasing  distention  causes  a  reflex  evacuation  of  this  portion  of  the 
gut  through  centers  located  in  the  spinal  cord.  The  impulses  from  these 
centers,  besides  contracting  the  rectum,  etc.,  also  coordinate  the  contrac- 
tion of  the  abdominal  muscles  and  the  relaxation  of  the  sphincter  ani 
so  as  to  bring  about  the  act  of  defecation.  By  the  skiagraphic  method  it 


Fig.    165. — Diagram   of   time   it  takes   for    a   capsule   containing   bismuth   to    reach   the   various    parts 

of   the    large    intestine. 

has  been  found  that  the  pelvic  colon  gradually  becomes  filled  with  feces 
from  below  upward,  and  that  the  rectum  remains  empty  until  just  before 
defecation.  The  bulbosacral  autonomic  fibers  to  the  large  intestine  are 
transmitted  by  the  pelvic  nerve  (nervi  erigentes)  and  their  stimulation 
causes  increased  contractions.  The  thoracic  autonomies,  on  the  other 
hand,  diminish  the  contractions. 

EFFECT  OF  CLINICAL  CONDITIONS  ON  THE  MOVEMENTS 

Observations  of  practical  value  have  been  made  on  the  behavior  of  the 
peristaltic  wave  after  various  intestinal  operations.  After  an  end-to-end 
anastomosis  of  the  gut,  no  evidence  can  be  obtained  by  the  x-ray  method 
that  any  hesitation  occurs  in  the  movement  of  the  shadows  at  the  anas- 


THE   MECHANISMS   OF   DIGESTION  505 

tomosis.  On  the  other  hand,  when  a  lateral  anastomosis  is  established, 
stagnation  of  the  food  in  the  region  of  the  junction  may  occur,  this 
having  been  found,  on  opening  the  gut,  to  be  caused  by  the  accumu- 
lation of  hair  and  undigested  detritus  at  the  opening  between  the  op- 
posed loops.  Another  objection  to  lateral  anastomosis  is  the  fact  that 
in  performing  the  operation  a  considerable  amount  of  the  circular  muscle 
is  cut,  which  interferes  with  peristaltic  activity.  Moreover,  the  end  of 
the  proximal  loop  beyond  the  opening  is  in  danger  of  becoming  filled  up 
with  hardened  material,  and  the  end  of  the  distal  loop  may  become 
invaginated  and  induce  obstruction  in  the  region  of  the  anastomosis. 

Observations  have  also  been  made  by  the  x-ray  method  on  the  be- 
havior of  the  intestinal  contents  following  intestinal  obstruction.  It  has 
been  observed  that,  as  the  material  collects  in  the  gut  just  above  the 
obstruction,  strong  peristaltic  waves  are  set  up,  which  move  the  food 
toward  the  obstruction  so  powerfully  as  to  cause  the  walls  of  the  canal 
in  front  to  become  bulged,  until  at  last  the  pressure  causes  the  con- 
tents to  be  squirted  back  through  the  advancing  ring  of  peristaltic  con- 
traction. These  waves  were  observed  to  succeed  one  another  rapidly. 
When  a  portion  of  gut  is  reversed  in  position,  the  peristaltic  waves  con- 
tinue to  travel  in  their  old  direction  toward  the  duodenum.  The  effect  of 
this  is  to  produce  a  partial  obstruction  at  the  upper  end  of  the  re- 
versed gut. 

The  type  of  peristalsis  known  as  the  peristaltic  rush  can  be  induced 
experimentally  in  animals  by  intravenous  injection  of  ergot.  It  prob- 
ably also  occurs  in  conditions  of  abnormal  irritation  of  the  gut  in  man, 
and  is  believed  to  be  the  characteristic  acuity  of  the  gut  after  a 
strong  purge. 


CHAPTER  LVI 

HUNGER,  APPETITE  AND  THIRST 

The  sensations  of  hunger  and  appetite  are  due  to  different  causes,  the 
former  being  definitely  correlated  with  contraction  of  the  empty  stomach, 
and  the  latter  being  a  complex  of  sensations  operating  in  the  nervous 
system  along  with  memory  impressions  of  the  sight,  taste,  and  smell  of 
palatable  food.  Appetite  is  therefore  a  highly  complex  nervous  integra- 
tion, whereas  hunger  is  a  much  simpler  process.  It  is  particularly  with 
hunger  that  we  shall  concern  ourselves  at  present. 

Hunger 

When  a  thin- walled  rubber  balloon  of  proper  size  is  placed  in  the 
stomach  and  connected  by  a  rubber  tube  with  a  water,  bromoform  or 
chloroform  manometer  (made  of  wide  glass  tubing  1.5  cm.  in  diameter 
and  provided  with  a  suitable  float  on  the  free  limb)  a  tracing  may  be 
taken  of  the  movements  of  the  stomach  (Fig.  166).  For  use  on  man  the 
capacity  of  the  balloon  should  be  from  75  to  150  cubic  centimeters.  The 
record  thus  obtained  when  the  balloon  is  placed  in  the  empty  stomach  of  a 
normal  person  shows  four  types  of  wave.  Two  of  these  may  be  discounted, 
being  due  to  the  arterial  pulse  and  the  respiratory  movements.  The 
third  is  known  as  the  tonus  rhythm,  and  is  caused  by  tonic  contractions 
of  the  fundus  of  the  stomach  of  varying  amplitude.  The  periods  of  tonus  in- 
crease during  the  powerful  rhythmic  contractions  to  be  immediately 
described.  While  these  changes  in  tone  are  occurring,  no  subjective  sen- 
sation of  hunger  is  experienced.  (See  Fig.  167.) 

The  fourth  and  most  significant  type  consists  of  powerful_r%#/imic 
contractions,  alternating  with  periods  of  quiescence.  These  contrac- 
tions occupy  a  period  of  about  twenty  seconds,  and  are  superimposed 
upon  the  tonus  rhythm.  They  gradually  increase  in  amplitude  and  fre- 
quency; and,  in  the  case  of  young  and  vigorous  persons,  may  pass  into 
a  condition  of  incomplete  tetanus,  after  which  they  suddenly  subside, 
leaving  only  a  faint  tonus  rhythm.  The  rhythmic  contractions  are  defi- 
nitely associated  with  the  sensation  of  hunger,  and  are '~ more  marked 
the  more  intense  the  sensation  is.  When  tetanus  occurs  the  hunger  sen- 
sation is  continuous,  but  it  instantly  disappears  when  the  tetanus  gives 
place  to  relaxation. 

500 


HUNGER    AND    APPETITE 


507 


When  the  contractions  are  comparatively  feeble,  the  length  of  the  period  during 
which  they  occur  is  about  twelve  minutes.  When  the  contractions  are  powerful,  the 
periods  are  always  initiated  by  weaker  contractions  with  long  intervening  pauses; 
finally  the  pauses  disappear  and  the  contractions  become  more  and  more  pronounced 
until,  as  above  mentioned,  a  virtual  tetanus  lasting  from  two  to  five  minutes,  may 
supervene.  The  duration  of  the  entire  hunger  period  varies  from  one-half  to  one 
and  a  half  hours,  with  an  average  of  from  thirty  to  forty-five  minutes,  and  the  num- 
ber of  individual  contractions  in  a  period  varies  from  twenty  to  seventy.  Between  the 
hunger  periods,  intervals  of  from  one-half  to  two  and  one-half  hours  of  quiescence 
may  supervene.  (See  Fig.  168.) 

Similar  contractions,  often  passing  into  incomplete  tetanus,  have  been 
observed  in  the  stomach  of  healthy  infants,  some  of  the  observations  hav- 
ing been  made  before  the  first  nursing.  The  intervals  of  motor  quies- 
cence between  the  hunger  periods  are  shorter  than  in  adults.  In  obser- 


Fig.  166. — Diagram  of  method  for  recording  stomach  movements.  B,  rubber  balloon  in  stomach. 
1),  kymograph.  F,  cork  float  with  recording  flag.  M,  manometer.  L,  manometer  fluid  (bromo- 
form,  chloroform,  or  water).  R,  rubber  tube  connecting  balloon  with  manometer.  S,  stomach. 
7',  side  tube  for  inflation  of  stomach  balloon.  (From  Carlson.) 


vations  made  during  sleep,  it  was  observed  that,  when  the  contractions 
were  very  vigorous,  the  infant  would  show  signs  of  restlessness  and 
might  awake  and  cry.  As  in  the  adult,  the  contractions  are  evidently 
associated  with  subjective  sensations  of  hunger.  Contractions  of  the 
empty  stomach  have  also  been  recorded  on  a  large  variety  of  animals, 
including  the  dog,  rabbit,  cat,  guinea  pig,  bird,  frog  and  turtle.  They 
vary  somewhat  in  type  in  different  animals. 

With  regard  to  the  time  of  onset  of  the  tonus  and  hunger  contractions, 
it  has  been  observed  that  the  only  period  during  which  the  fundus  is 
free  of  them  is  immediately  after  a  large  meal.  After  a  moderate  meal 
the  tonus  rhythm  begins  to  appear  in  about  thirty  minutes.  It  gradually 
increases  in  intensity,  until  by  the  time  the  stomach  has  nearly  emptied 


508  DIGESTION 

itself  the  tonus  has  become  conspicuous,  and  the  stronger  hunger  con- 
tractions usually  begin  to  appear.  Superimposed  upon  those  of  the 
tonus  rhythm,  hunger  pangs  may  appear  in  man  when  the  stomach  still 
contains  traces  of  food. 

By  studying  the  shadow  of  the  outline  of  the  stomach  produced  by 


Fig.    167. — Tracing  of  the  tonus  rhythm  of  the  stomach    (man)    three   hours  after  a  meal.      (From 

Carlson.) 

having  a  person  or  animal  swallow  two  balloons,  one  inside  the  other 
and  with  a  paste  of  bismuth  subnitrate  between  them,  it  has  been  ob- 
served that  the  weaker  type  of  hunger  contraction  begins  as  a  con- 
striction involving  the  cardiac  end  of  the  stomach,  and  moving  toward 
the  pyloric  end  as  a  rapid  peristaltic  wave.  When  the  contractions  are 


Fig.  168. — Tracings  from  the  stomach  during  the  culmination  of  a  period  of  vigorous  gastric  hunger 
contractions.      One-half   original    size.      (From    Carlson.) 

very  vigorous,  this  wave  spreads  so  rapidly  over  the  stomach  that  it  is 
difficult  to  determine  whether  it  really  occurs  as  a  very  rapid  peristalsis 
or  as  a  contraction  involving  the  fundus  as  a  whole.  These  contractions 
resemble  very  closely  the  movements  that  have  sometimes  been  observed 


HUNGER   AND   APPETITE 


509 


after  a  bismuth,  meal,  and  which,  have  been  thought  by  clinical  observers 
to  indicate  a  hyperperistalsis  of  the  stomach.  The  fundus  is  therefore 
not  entirely  passive  during  digestion;  for,  although  early  in  this  act 
there  may  be  no  evidence  of  contraction,  yet  the  contractions  of  the  tonus 
rhythm  may  appear  and  become  pronounced  before  the  stomach,  is  en- 
tirely empty.  In  other  words,  the  digestion  contractions  of  the  filled 
stomach  (see  page  485)  pass  gradually  over  into  the  hunger  contractions 
of  the  empty  organ. 

Remote  Effects  of  Hunger  Contractions. — It  is  well  known  that  during 
hunger  certain  general  subjective  symptoms  are  likely  to  be  experienced, 
such  as  a  feeling  of  weakness  and  a  sense  of  emptiness,  with  a  tendency  to 
headache  and  sometimes  even  nausea  in  persons  who  are  prone  to  headache 
as  a  result  of  toxemic  conditions.  Headache  is  likely  to  be  more  pronounced 
or  perhaps  present  only  in  the  morning  before  there  is  any  food  in  the  stom- 
ach. These  symptoms  indicate  that  hunger  contractions  are  associated  with 


ititttttttfttfttttttttniitftttt' 

Fig.    169. — Showing  augmentation  of  the  knee-jerk    (upper  tracing)    during  the  marked  hunger   con- 
tractions   (lower  tracing).      (From   Carlson.) 

hyperexcitability  of  the  central  nervous  system,  and  it  is  of  considerable 
interest  that  objective  signs  of  this  association  can  be  elicited.  If  the 
knee-jerk  be  recorded  along  with  a  record  of  the  gastric  contractions,  it 
will  be  found  that  it  is  markedly  exaggerated  simultaneously  with  the 
strong  hunger  contractions  of  the  empty  stomach,  this  augmentation 
being  greatest  at  the  height  of  the  stomach  contractions,  when  the  hun- 
ger pangs  are  most  intense,  and  falling  off  again  to  normal  when  these 
disappear  (Fig.  169).  Further  changes  occurring  during  the  hunger 
period  include  an  increase  in  the  pulse  rate  and  vasodilatation.  By 
comparing  plethysmo graphic  tracings  of  the  arm  volume  (see  page  209) 
and  stomach  contractions,  it  has  been  found  that  the  increase  in  volume 
occurs  pari  passu  with  the  increasing  tonus  of  the  stomach,  but  that  it 
begins  to  shrink  before  the  stomach  contraction  has  reached  its  maximum. 
Occasionally,  however,  as  in  acute  hunger,  a  somewhat  different  rela- 


510  DIGESTION 

tionship  obtains,  vaso constriction  being  more  prominent.  During  each 
hunger  contraction  there  is  also  increased  salivationA_ll}e  degree  of 
which  varies  with  different  individuals.  This  salivation  is  independent 
of  the  more  copious  "watering  of  the  mouth"  that  accompanies  the 
thought  or  sight  of  appetizing  food. 

Hunger  During  Starvation. — During  enforced  starvation  for  long  periods 
of  time,  it  is  known  that  healthy  individuals  at  first  experience  intense  sen- 
sations of  hunger  and  appetite,  which  last  however  only  for  a  few  days,  then 
become  less  pronounced  and  finally  almost  disappear.  It  is  of  interest  to 
know  the  relationship  between  these  sensations  and  the  hunger  contractions 
in  the  stomach.  This  has  been  investigated  by  Carlson  and  Luckhardt,  who 
voluntarily  subjected  themselves  to  complete  starvation,  except  for  the 
taking  of  water,  for  four  days.  During  a  great  part  of  this  time  records 
of  the  stomach  contractions  wrere  taken  by  the  balloon  method,  and  it 
was  found  that  the  tonus  of  the  stomach  and  also  the  frequency  and 
intensity  of  the  hunger  contractions  became  progressively  more  pronounced 
as  starvation  proceeded.  Towards  the  end  of  the  period  it  was  also  noted 
that  incomplete  hunger  tetanus  made  its  appearance  where  ordinarily, 
as  in  Carlson's  case,  this  type  of  hunger  contraction  was  infrequent. 
Sensations  of  hunger  were  present  more  or  less  throughout  the  period, 
being  therefore  probably  due  to  the  persistently  increased  tonus.  The 
onset  of  a  period  of  hunger  contraction  could  usually  be  foretold  by  an 
increase  in  the  hunger  sensation,  and  as  these  contractions  became  more 
marked,  the  hunger  sensations  became  more  intense.  On  the  last  day  of 
starvation  a  burning  sensation  referred  to  the  epigastrium  was  added  to 
that  of  hunger.  The  appetite  ran  practically  parallel  with  the  sensa- 
tion of  hunger,  and  both  of  these  sensations  became  perceptibly  dimin- 
ished on  the  fourth  or  last  day  of  starvation,  this  diminution  being, 
however,  most  marked  in  the  sensation  of  appetite.  Indeed,  instead  of  an 
eagerness  for  food,  there  developed  on  the  last  day  a  distinct  repugnance 
or  indifference  towards  it.  Accompanying  these  sensations  of  hunger 
and  appetite  a  distinct  mental  depression  and  a  feeling  of  weakness  were 
experienced  during  the  latter  part  of  the  starvation  period. 

On  partaking  of  food  again  the  hunger  and  appetite  sensations  very 
rapidly  disappeared,  and  also  practically  all  of  the  mental  depression 
and  a  great  part  of  the  feeling  of  weakness.  Complete  recovery  from 
the  latter,  however,  did  not  take  place  until  the  second  or  third  day 
Wfter  breaking  the  fast.  From  this  time  on  both  men  felt  unusually 
well;  indeed  they  state  that  their  sense  of  well-being  and  clearness  of 
mind  and  their  sense  of  good  health  and  vigor  were  as  greatly  improved 
as  they  would  have  been  by  a  month's  vacation  in  the  mountains.  They 
further  point  out  that,  since  others  who  have  starved  for  longer  periods 


HUNGER   AND   APPETITE  511 

of  time  unanimously  attest  to  the  fact  that,  after  the  first  few  days,  the 
sensations  of  hunger  become  less  pronounced  and  finally  almost  dis- 
appear, they  must  have  experienced  the  most  distressing  period  during 
their  four  days  of  starvation.  Although  the  hunger  sensation  was 
strong  enough  to  cause  some  discomfort,  it  could  by  no  means  be  called 
marked  pain  or  suffering,  and  was  at  no  time  of  sufficient  intensity  to 
interfere  seriously  with  work.  Mere  starvation  cannot  therefore  be 
designated  as  acute  suffering.  It  is  of  further  interest  to  note  that  dur- 
ing the  starvation  period  a  continuous  flow  of  .secretion  of  acid  gastric 
juice  was  found  to  be  occurring  in  the  stomach,  to  the  presence  of  which 
acid  or  burning  sensation  experienced  in  the  epigastrium  on  the  last  days 
is  probably  to  be  attributed. 

Control  of  the  Hunger  Mechanism. — The  control  of  the  hunger  mecha- 
nism, like  that  of  any  other  mechanism  in  the  animal  body,  may  be  ef- 
fected through  the  nervous  system  or  it  may  depend  on  the  presence  of 
chemical  substances  or  hormones  in  the  blood.  As  a  matter  of  fact,  it 
can  readily  be  shown  that  both  those  methods  of  control  are  employed, 
and  we  will  now  consider  briefly  some  of  the  facts  upon  which  this  con- 
clusion depends. 

Although  many  facts  are  now  known  with  regard  to  the  nervous  control  of  the 
hunger  mechanism,  it  is  difficult  to  piece  these  together  in  such  a  way  as  to  formulate 
a  simple  theory  which  fits  in  with  all  the  observed  facts.  We  know  that  the  stomach 
possesses  in  itself  a  local  nervous  mechanism  by  which,  like  the  heart  or  intestine,  it 
can  automatically  perform  many  of  the  movements  which  are  exhibited  in  the  intact 
animal.  These  local  movements  may,  however,  be  considerably  influenced  by  impulses 
transmitted  to  the  stomach  along  the  vagus  and  splanchnic  nerves.  We  have  therefore 
to  seek  for  evidence  indicating  the  relative  importance  of  the  local  nervous  mechanism 
in  the  stomach  itself  and  of  the  impulses  transmitted  to  this  organ  by  the  extrinsic 
nerves.  We  must  then  seek  the  position  of  the  center  which  perceives  the  sensation 
of  hunger. 

It  will  be  simplest  to  consider  first  the  effect  of  section  of  the  extrinsic  nerves  in 
observations  made  on  lower  animals.  Section  of  the  splanchnic  nerves  increases  gas- 
trie  tonus  and  augments  the  gastric  hunger  contractions.  Section  of  both  vagus  nerves, 
performed  of  course  below  the  level  of  the  heart,  leaves  the  stomach  in  a  more  or  less 
hypotonic  condition.  The  tonus  is  not  entirely  abolished;  it  varies  somewhat  from 
day  to  day,  and  may  become  quite  pronounced  even  though  the  vagi  are  cut.  In  this 
hypotonic  state  the  hunger  contractions  are  diminished  in  rate  and  regularity.  Sec- 
tion of  both  the  splanchnic  and  vagus  nerves  throws  the  stomach  into  a  permanent 
hypotonus,  except  in  prolonged  starvation,  when  hunger  contractions  develop  that  are 
usually  of  great  amplitude  and  with  particularly  long  intervals  between  the  contrac- 
tions. The  general  conclusion  to  be  drawn  from  these  experiments  is  that,  although 
completely  isolated  from  the  central  nervous  system,  the  stomach  still  exhibits  typical 
hunp-er  contractions,  which  must  therefore  be  essentially  dependent  upon  an  automatic 
mechanism  in  the  stomach  wall  itself.  Over  this  mechanism,  extrinsic  nerve  impulses 
have  merely  a  regulatory  control. 

Variations  and  Inhibitions  of  the  Hunger  Contractions. — The  afferent 


512  DIGESTION 

stimuli  that  may  set  up  impulses  traveling  by  the  extrinsic  nerves 
to  the  stomach  are  conveyed  by  the  nerves  of  sense  or  are  of  psy- 
chic origin.  Stimulation  of  the  gustatory  end  organs  in  the  mouth,  as 
by  chewing  palatable  food,  always  causes  an  inhibition  of  the  tonus 
and  a  diminution  or  disappearance  of  the  hunger  contractions.  Even  the 
chewing  of  indifferent  substances,  such  as  paraffin,  suffices  to  produce 
distinct  inhibition,  unless  in  a  case  in  which  the  contraction  has  passed 
into  a  tetanus.  It  is  of  interest  that  swallowing  movements,  in  the  ab- 
sence of  any  food  substance  in  the  mouth,  are  sufficient  to  produce  a 
transitory  inhibition  of  the  gastric  tonus — a  receptive  relaxation  of  the 
stomach,  as  it  has  been  aptly  called.  The  diminution  in  tonus  and 
hunger  contractions  in  these  various  ways  is  accompanied  by  a  diminu- 
tion in  the  hunger  pains. 

Afferent  nerve  stimulation  affecting  the  hunger  contractions  may  also  originate  in 
the  stomach  mucosa  itself,  as  has  been  shown  by  Carlson  on  his  patient  by  introducing 
the  various  substances  to  be  tested  through  a  tube  into  the  stomach.  A  glassful  of 
cold  water  introduced  in  this  way  inhibits  the  tonus  and  the  hunger  contractions  for 
from  three  to  five  minutes  unless  these  are  severe,  this  inhibition  being  followed  by  no 
augmentation  either  of  the  tonus  or  of  contractions.  Ice-cold  water  has  a  greater 
effect  than  water  at  body  temperature.  This  result  is  somewhat  different  from  that 
which  most  men  experience  as  the  result  of  drinking  a  glass  of  cold  water. 

Weak  acids  of  strengths  varying  up  to  that  found  present  in  the  gastric  juice  itself 
— 0.5  per  cent — cause  a  marked  inhibition  of  the  hunger  movements,  but  this  inhibition 
does  not  persist  until  all  the  acid  has  escaped  from  the  stomach  or  been  neutralized, 
which  explains  why  hunger  contractions  should  still  occur  when  an  acid  secretion  is 
present  in  the  stomach,  as  in  starvation.  Normal  gastric  juice  itself  produces  an  in- 
hibition, which  is  no  doubt  dependent  upon  the  acid  which  it  contains,  and  it  is  prob- 
able that,  at  the  same  time  that  it  leads  to  inhibition  of  the  hunger  contractions,  the 
acid  initiates  peristalsis  of  the  pyloric  region  (see  page  487).  Weak  alkaline  solu- 
tions have  no  greater  effect  on  the  hunger  contractions  than  an  equal  volume  of  water. 
Weak  solutions  of  local  anesthetics,  such  as  phenol  or  chloretone,  are  without  effect. 

With  regard  to  alcoholic  leverages  interesting  results  were  obtained.  Wine,  beer, 
brandy,  and  diluted  pure  alcohol  inhibit  both  the  tonus  and  the  contractions.  The 
duration  of  this  inhibition  varies  directly  with  the  quantity  of  the  beverage  intro- 
duced into  the  stomach  and  with  its  alcohol  percentage.  These  observations  are  ap- 
parently not  in  harmony  with  the  experience  of  most  men  that  the  taking  of  alcoholic 
beverages  serves  to  awaken  or  increase  the  appetite,  the  difference  being  no  doubt  due 
to  the  fact  that  appetite  and  hunger  contractions  of  the  stomach  are  not  dependent  on 
each  other,  appetite  being,  as  we  have  seen,  a  complex  psychic  affair,  whereas  the 
hunger  contractions  depend  upon  a  local  mechanism  in  the  stomach  wall  itself. 

As  the  inhibition  produced  in  one  or  other  of  these  ways  passes  off, 
the  hunger  contractions  are  resumed  at  their  previous  intensity  and  not 
in  an  augmented  form.  From  the  promptness  of  the  inhibition,  it  would 
appear  that  the  stomach  contractions  are  affected,  not  reflexly  through 
the  central  nervous  system  or  by  changes  in  the  chemical  composition 
of  the  blood,  but  by  a  direct  action  on  the  neuromuscular  mechanism 


HUNGER   AND    APPETITE  513 

in  the  stomach  walls,  and  it  is  important  to  bear  in  mind  that  the 
inhibitory  effects  011  the  stomach  contractions  of  the  fundus  may  proceed 
quite  independently  of  the  changes  in  the  pyloric  region  that  are  con- 
cerned with  the  mechanical  processes  of  digestion.  After  one  or  both 
of  the  extrinsic  nerves  of  the  stomach  were  severed  in  dogs,  a  certain 
degree  of  inhibition  could  still  be  induced  by  the  above  methods,  indicat- 
ing that,  although  section  of  the  extrinsic  nerves  depresses  the  inhibitory 
reflex,  it  does  not  abolish  it. 

Various  mitigations  of  the  hunger  contractions  have  been  discovered. 
Smoking:  has  this  effect,  and  compression  of  the  abdomen  by  tightening 
the  belt  also  inhibits  the  contractions  provided  they  are  not  of  marked 
intensity.  Considerable  muscular  exercise,  such  as  brisk  walking  or 
running,  causes  inhibition,  which  usually  persists  until  after  the  exer- 
cise is  discontinued.  When  the  tonus  and  contractions  return,  in  this 
case,  they  seem  to  be  somewhat  more  pronounced.  Application  of  cold 
to  the  surface  of  the  body — as  by  placing  an  ice  pack  on  the  abdomen 
or  taking  a  cold  douche,  procedures  which  are  well  known  to  induce 
increased  neuromuscular  tonus,  in  general — causes  an  inhibition  of  the 
gastric  tonus  and  hunger  contractions,  the  degree  of  which  is  roughly 
proportional  to  the  intensity  of  the  stimulation.  There  is  certainly  never 
an  increase  in  the  gastric  tonus  or  hunger  contractions.  If  such  stimula- 
tion is  maintained,  the  inhibitory  effects  on  the  stomach  gradually 
diminish,  even  though  the  individual  be  shivering  intensely. 

With  regard  to  the  nerve  centers  concerned  in  these  phenomena,  little  that  is  definite 
is  known.  The  sensory  nuclei  of  the  vagus  nerve  in  the  medulla  must  be  considered 
as  the  primary  hunger  center,  and  through  this  center,  not  only  influences  affecting  the 
stomach  contractions,  but  also  those  associated  with  the  hunger  sensations,  must  be 
mediated.  It  Avould  appear  from  observations  on  the  hunger  behavior  of  decerebrate 
animals  that  there  can  be  no  hunger  center  located  on  the  cerebral  cortex  itself,  for 
such  animals  exhibit  practically  the  same  hunger  effects  as  normal  animals.  It  is  in- 
teresting to  note  that,  at  least  in  the  case  of  decerebrate  pigeons,  this  hunger  behavior 
entirely  disappears  on  removal  of  the  optic  thalami,  where  important  nerve  centers  hav- 
ing to  do  with  the  bodily  responses  of  the  animal  to  hunger  impulses  would  therefore 
appear  to  be  located.  These  observations  support  the  suggestion  that  has  been  made 
by  several  neurologists  that  the  sense  of  pain  is  located  somewhere  in  the  thalamic 
region. 

Concerning  the  influence  of  psychic  states,  Carlson  says  that  in  his 
own  case  the  hunger  contractions  became  weaker  and  the  intervals 
between  them  greater  when  he  was  suddenly  awakened  during  his 
fast  and  saw  two  of  his  friends  partaking  at  his  bedside  of  a  "feast  of 
porterhouse  steak  with  onions,  potatoes,  and  a  tomato  salad."  These 
results  are  no  doubt  due  to  local  inhibition  dependent  upon  the  psychic 
secretion  of  appetite  gastric  juice.  When  no  such  juice  is  produced, 
the  sight  and  smell  of  good  food  does  not  appear  to  affect  materially 


514  DIGESTION 

the  hunger  contractions  of  the  stomach.     No  doubt  it  stimulates  the 
appetite,  but  that,  as  we  have  seen,  is  a  psychic  affair. 

In  the  diagnosis  of  gastric  and  duodenal  ulcer  stress  has  been  laid 
upon  the  occurrence  of  pains  2-3  hours  following  a  meal  and  relieved 
by  the  ingestion  of  food.  The  possibility  of  the  pains  complained  of 
being  due  to  hunger  contractions  and  consequently  physiological  must 
not  be  lost  sight  of.  Surgical  measures  have  unquestionably  been  need- 
lessly resorted  to  in  cases  where  this  possibility  has  not  been  borne  in 
mind. 

Thirst 

The  Sensation  of  Thirst  has  been  believed  by  some  observers  to  be  a 
general  one  either  dependent  primarily  upon  dehydration  of  the  tissues 
of  the  body,  including  those  of  the  central  nervous  system,  or  resulting 
secondarily  from  a  rise  in  the  osmotic  pressure  of  the  blood  the  hyper- 
tonicity  producing  disturbances  in  the  nerve  cells.  It  is  probable,  how- 
ever, that  the  thirst  sensation  is  a  pureJyjQoaLima^ajnjeJy,  drying  of  the 
mucous  membranes  of  the  mouth  and  pharynx.  This  view  is  supported 
by  the  fact,  that  if  the  pharynx  of  a  person  suffering  from  thirst  be 
painted  with  a  solution  of  cocaine  all  craving  is  relieved  and  it  does  not 
return  until  the  effect  of  the  anesthetic  has  passed  off.  That  thirst 
may  be  produced  through  the  drying  of  the  interior  of  the  mouth  as  by 
prolonged  speaking,  or  mouth  breathing,  is  common  experience.  Admin- 
istration of  atropine  acts  similarly  by  inhibiting  the  oral  secretions. 
According  to  Cannon21  the  salivary  glands  play  the  chief  role  in  the 
mechanism  for  the  production  of  the  thirst  sensations.  He  finds  that  the 
secretion  of  these  glands,  which  normally  moistens  the  interior  of  the 
mouth  and  pharynx,  is  reduced  markedly  (60  to  75  per  cent)  after  a 
few  hours  abstinence  from  fluids.  Since  the  composition  of  the  sali- 
vary secretion  is  from  97  to  99  per  cent  water  it  is  readily  seen  how 
a  fall  in  the  general  water  content  of  the  body  would  bring  about  a  re- 
duction of  salivary  flow  with  consequent  drying  of  the  oral  and  pharyn- 
geal  mucous  membranes,  f  This  view  ascribes  to  the  salivary  glands  the 
important  duty  of  keeping  sentinel  over  the  water  content  of  the  body, 
the  sensation  of  thirst  being  the  signal  which  warns  the  organism  that 
the  tissue  fluids  require  to  be  replenished.  | 


CHAPTER  LVII 

THE  BIOCHEMICAL  PROCESSES  OF  DIGESTION 

In  a  book  designed  primarily  for  clinical  workers,  it  would  be  out  of 
place  to  enter  into  details  concerning  the  biochemical  processes  taking 
place  during  the  digestive  process.  There  is,  however,  a  certain  amount 
of  fundamental  knowledge  which  it  is  essential  that  we  should  consider. 
In  the  first  place  it  should  be  borne  in  mind  that  in  the  digestion  of 
carbohydrates  and  proteins,  various  intermediate  stages  are  passed 
through  before  the  final  absorption  products  are  formed.  The  highly 
complex  molecule  of  which  protein,  for  example,  is  composed,  is  first 
of  all  broken  down  into  several  smaller  but  still  highly  complex  mole- 
cules, each  of  which  then  undergoes  further  disruption,  until  ultimately 
the  amino  acids  are  set  free.  Certain  enzymes,  such  as  trypsin,  can 
carry  this  process  from  the  beginning  through  the  greater  part  of  its 
course  without  the  assistance  of  other  enzymes,  but  in  the  natural  proc- 
ess of  digestion,  as  it  occurs  in  the  gastrointestinal  tract,  the  different 
stages  of  the  disruption  are  controlled  by  different  enzymes.  One  enzyme 
prepares  the  food  for  action  by  the  next.  This  interdependence  of  their 
actions  demands  that  some  provision  should  be  made  whereby  each  en- 
zyme is  secreted  at  the  proper  time;  that  is,  when  the  foodstuff  has  al- 
ready been  prepared  for  its  action  by  that  of  its  predecessor.  Thus,  it 
would  be  useless  after  food  is  taken  for  the  gastric  and  pancreatic 
juices  to  be  secreted  at  the  same  time.  Instead,  the  gastric  juice  is 
secreted  first,  and  the  pancreatic  only  after  the  food  has  been  prepared 
for  its.  action.  •  This  correlation  in  function  we  have  already  seen  to  be 
dependent  largely  on  the  action  of  hormones. 

DIGESTION  IN  THE  STOMACH 

The  gastric  juice  contains  two  important  digestive  agencies:  (1)  the 
enzyme,  pepsin,  and  (2)  hydrochloric  acid.  It  is  particularly  in  juices 
secreted  in  the  cardiac  end  of  the  stomach  that  these  two  substances  are 
found  present;  towards  the  pyloric  end  the  hydrochloric  acid  entirely 
disappears,  and  the  pepsin  content  becomes  distinctly  less. 

515 


DIGESTION 

The  Functions  of  Hydrochloric  Acid 

The  functions  of  hydrochloric  acid  may  be  conveniently  divided  into 
physiological  and  biochemical.  The  former  functions  have  to  do  with 
the  control  of  the  movements  of  the  stomach,  including  the  opening 
of  the  pyloric  sphincter,  and,  after  the  chyme  has  entered  the  duodenum, 
with  the  secretion  of  pancreatic  juice  and  bile.  The  biochemical  functions 
are  concerned:  (1)  in  assisting  the  pepsin  in  the  digestion  of  proteins, 
(2)  in  bringing  about  a  certain  amount  of  inversion  of  disaccharides, 
and  (3)  in  having  an  antiseptic  action  on  the  stomach  contents.  Re- 
garding the  last  mentioned  of  these  functions,  it  may  be  said  that  the 
chyme,  as  it  is  ejected  from  the  stomach,  is  usually  sterile,  although  it 
may  contain  spores  and  certain  bacteria  that  are  protected  against  the 
digestive  agencies  of  the  stomach.  This  protection  is  afforded  by  an 
outer  covering  of  a  chitinous  nature  (spores),  or,  as  in  the  case  of  the 
tubercle  bacillus,  by  a  covering  of  waxlike  material.  It  is  believed  that 
persons  with  strictly  normal  digestion  are  much  less  liable  to  infection 
by  such  bacteria,  as  those  of  typhoid  and  cholera,  than  persons  with  less 
active  gastric  secretion.  When  the  acid  of  the  gastric  juice  falls  below 
the  level  at  which  it  develops  an  antiseptic  action,  various  bacteria  and 
yeasts  grow  in  the  stomach  contents,  producing  by  the  resulting  fermen- 
tation irritating  organic  acids  and  gases.  It  is  under  these  conditions 
that  yeasts,  sarcinse,  and  lactic  and  butyric  acid  bacilli  find  in  the  gastric 
contents  a  suitable  nidus  on  which  to  grow. 

THE  AMOUNT  OF  ACID 

It  has  long  been  known  that  considerable  variations  in  the  amount  of 
hydrochloric  acid  in  the  gastric  juice  are  associated  with  symptoms  of 
indigestion.  On  this  account  a  more  or  less  elaborate  technic  has  been 
developed  for  the  purpose  of  determining  the  amount  of  hydrochloric 
acid  in  the  gastric  contents.* 

There  are  three  things  in  connection  with  this  activity  that  we  may  measure:  (1) 
the  total  titrable  hydrochloric  acid;  (2)  the  free  hydrochloric  acid;  and  (3)  the  actual 
hydrogen-ion  concentration.  The  determination  of  the  total  available  acids  is  made  by 
titrating  a  measured  quantity  of  gastric  juice  against  a  standard  alkali,  using  phenol- 
phthalein  as  an  indicator.  By  this  method  about  75  c.c.  of  decinormal  alkali  solution 
are  required  to  neutralize  100  c.c.  of  normal  gastric  juice.  The  determination  of  the 
free  hydrochloric  acid  is  made  by  using  special  indicators,  such  as  those  of  Giinzbcrg 
and  Topfer,  which  change  color  at  a  hydrogen-ion  concentration  of  about  10-"'  (see 
page  27).  To  produce  this  hydrogen-ion  concentration,  a  considerable  quantity — 
0.05  per  cent  or  more — of  an  organic  acid  is  necessary,  whereas  it  requires  only  a 
trace  of  hydrochloric  acid.  Normal  human  gastric  juice,  when  titrated  with  one  of 


*The  methods  can  be  found  in  any  volume  on  clinical  diagnosis. 


THE   BIOCHEMICAL   PROCESSES   OF   DIGESTION  517 

these  indicators,  gives  a  figure  which  corresponds  to  about  0.03  N.  hydrochloric  acid 
(see  page  22).  For  the  accurate  determination  of  the  hydrogen-ion  concentration,  it 
is  necessary  to  use  the  gas-chain  method  (see  page  29). 

When  gastric  juice  is  collected  through  a  fistula  from  an  empty 
stomach,  very  little  difference  Avill  be  found  between  the  free  hydro- 
chloric acid  and  the  total  acid;  that  is,  between  the  results  obtained  by 
the  second  and  the  first  of  the  methods  described  above.  This  is  because 
in  such  juice  there  is  no  organic  matter  capable  of  combining  with  the 
hydrochloric  acid,  and  there  are  no  other  acids,  such  as  lactic  or  butyric, 
which  might  be  produced  by  fermentative  processes.  The  difference 
between  the  two  titrations,  however,  becomes  marked  when  protein 
food  is  undergoing  digestion  in  the  stomach,  because  at  its  different 
stages  of  digestion  protein  combines  with  increasing  quantities  of  the 
hydrochloric  acid.  The  pathological  condition  in  which  there  is  most 
definitely  a  diminution  of  the  hydrochloric  acid  is  cancer,  either  of  the 
stomach  itself  or  occasionally  of  some  other  part  of  the  body.  An  in- 
crease is  particularly  marked  in  ulcer  of  the  stomach.  A  considerable 
variation  in  hydrochloric  acid  may  however  be  the  result  merely  of  func- 
tional (neurotic)  conditions. 

THE  SOURCE  OF  THE  ACID 

A  question  that  has  puzzled  physiologists  for  many  years  concerns  the 
mechanism  by  which  hydrochloric  acid  is  secreted.  The  percentage  of 
hydrochloric  acid  in  the  gastric  juice  is  considerably  above  that  at  which 
any  animal  cells  can  live,  and  yet  this  acid  is  secreted  by  the  lining 
membrane  of  the  stomach,  its  source  being,  of  course,  the  sodium 
f»TiWirlp  nf  f.Tip  blnnd .  plffW"*1  How  then  do  the  cells  of  the  gastric 
glands  bring  about  the  separation  of  this  powerful  acid  from  the  per- 
fectly neutral  blood  plasma?  In  the  first  place,  it  is  significant  that  the 
mucous  membrane  of  the  stomach  contains  a  higher  percentage  of 
chlorine  than  the  average  of  other  organs  and  tissues,  indicating  that  it 
has  the  power  of  abstracting  chlorine  from  the  blood.  The  excess  of 
chlorine  in  the  mucosa  must,  moreover,  be  but  a  very  small  fraction  of 
that  actually  secreted  into  the  gastric  juice.  The  chlorine  content 
of  the  mucosa  of  the  cardiac  end  is  considerably  greater  than  that  of  the 
pyloric.  These  facts  indicate  that  chlorine  is  attracted  by  the  gastric 
cells,  but  they  throw  no  light  on  the  question  as  to  where  the  hydro- 
chloric acid  is  really  formed.  Is  ifjmjibpi  p^Hg,  HT»  n-nly  in  t,h.ejj1'mp'n  of 
the  gland  tubes?  That  is  to  say,  is  it  formed  before  or  after  the  gastric 
juice  has  been  secreted  from  the  cells?  After  intravenous  injection  of 
solutions  of  potassium  ferrocyanide  and  some  inert  salt  of  iron,  such  as 
one  of  the  scale  preparations,  examination  of  the  gastric  glands  has 


518  DIGESTION 

shown  that  the  prussian  blue  reaction,  which  requires  the  presence  of 
free  mineral  acid,  is  most  pronounced  in  certain  of  the  parietal  cells.  A 
considerable  amount  of  the  precipitate  is,  however,  also  visible  in  the 
lumen  of  the  glands  and  in  the  stomach  itself.  Certain  observers  affirm 
that,  although  some  of  the  parietal  cells  may  take  the  stain,  the  vast 
majority  of  them  do  not  do  so;  and,  moreover,  that  cells  incapable  of 
forming  hydrochloric  acid  (e.  g.,  of  the  liver)  may  also  become  stained, 
and  that  the  precipitation  may  occur  in  the  blood  and  lymph. 

The  confusion  in  the  results  by  these  methods  prompted  A.  B.  Macal- 
lum22  and  Miss  M.  P.  Fitzgerald  to  investigate  the  distribution  of  the 
chlorine  in  the  cells  by  a  rnicrochemical  method,  in  which  the  chlorides 
were  precipitated  with  silver  nitrate  and  the  silver  chloride  then  reduced 
by  exposing  the  section  to  light.  It  was  found  that  both  kinds  of  gas- 
tric-gland cell,  chief  and  parietal,  but  particularly  the  parietal,  gave  the 
chloride  reaction.  Using  as  a  stain  a  substance  (cyaninine)  which  reacts 
blue  with  acid  and  red  with  alkali,  Harvey  and  Bensley,23  however,  aver 
that  the  secretion  of  the  glands  is  practically  neutral  until  the  foveola  is 
reached,  where  the  stain  becomes  blue,  indicating  an  acid  reaction. 
This  seems  to  show  that  the  acid  is  not  really  secreted  by  the  cells  of 
the  gastric  gland,  but  is  formed  after  secretion. 

According  to  the  latter  investigators,  the  chlorine  is  secreted  by  the 
cells  into  the  fovea  as  some  weak  chloride,  such  as  ammonium  chloride, 
or  it  may  be  as  an  ester.  Shortly  after  its  secretion,  this  weak  chloride 
undergoes  a  hydrolytic  or  other  dissociation,  during  which  free  hydro- 
chloric acid  is  liberated  and  ammonia  or  some  other  weak  base  set  free. 
Of  these  two  products  of  the  reaction  the  weak  base  is  reabsorbed  by 
the  gland  cells,  but  the  hydrochloric  acid  is  left  behind  because  the 
cells  are  impervious  to  it.  Indirect  evidence  in  support  of  this  view  is 
afforded  by  certain  other  instances  in  which  hydrochloric  acid  is  pro- 
duced by  the  action  of  cells ;  thus,  the  mould  Penicillium  glaucum  when  it 
is  grown  in  a  medium  containing  ammonium  chloride  absorbs  the  am- 
monia but  leaves  the  hydrochloric  acid.  The  high  penetrating  power 
of  the  ammonia  ion  in  practically  all  cells,  and  the  fact  that  the  mucosa 
of  the  stomach  contains  a  higher  percentage  of  ammonia  than  any  other 
tissue  in  the  body,  must  also  be  considered  as  circumstantial  evidence 
in  favor  of  this  view. 

Whatever  be  the  mechanism  by  which  hydrochloric  acid  is  produced, 
there  is  no  doubt  that  the  epithelium  is  impenetrable  by  it.  When  the 
vitality  of  the  epithelium  becomes  lowered,  as  in  anemia  or  after  partial 
occlusion  of  the  arteries,  the  acid  may  penetrate  the  cells  and  cause 
digestion  of  the  stomach  walls.  Hyperacidity  may  on  this  account 
become  dangerous,  as  it  lowers  the  resistance  of  the  cell. 


THE   BIOCHEMICAL   PROCESSES   OF   DIGESTION  519 

The  digestive  action  of  hydrochloric  acid  is  closely  linked  with  that  of 
pepsin,  with  which  it  will,  therefore,  be  considered. 

The  Action  of  Pepsin 

It  is  commonly  believed  that  before  its  secretion  pepsin  exists  in  the 
cells  of  the  gastric  glands  as  zymogen  granules.  The  chief  evidence  for 
this  belief  appears  to  be  that  after  considerable  activity  the  amount  of 
zymogen  granules  in  the  gland  cells  is  found  to  be  decidedly  dimin- 
ished. By  such  an  hypothesis  it  is  easy  to  explain  certain  interesting 
results  concerning  the  effect  of  weak  alkali  on  the  activities  of  extracts 
of  the  mucous  membrane  of  the  stomach.  When  the  mucous  membrane 
is  extracted  with  weak  acids,  the  extract  is  very  active  proteolytically. 
If  this  so-called  pepsin  solution  be  made  faintly  alkaline,  or  even  only 
neutralized,  and  again  made  acid,  it  will  be  found  to  have  lost  much, 
if  not  all,  of  its  activity.  On  the  other  hand,  an  aqueous  extract  may  be 
rendered  slightly  alkaline  for  a  short  time  and  still  display  its  digestive 
activity  on  subsequent  acidification.  The  extract  made  with  water  is 
therefore  much  more  resistant  toward  alkali  than  that  made  with  weak 
acid,  and  the  difference  is  explained  on  the  supposition  that  the  watery 
extract  contains  pepsinogen,  whereas  the  acid  extract  contains  pepsin. 

It  is  believed  that  there  are  several  varieties  of  pepsin,  because  the  optimum  con- 
centration of  acid  in  which  pepsin,  derived  from  the  stomachs  of  different  animals,  acts 
is  not  always  the  same.  Pepsin  of  the  dog,  for  example,  acts  best  in  a  hydrogen-ion 
concentration  corresponding  to  that  of  a  0.05  N.  hydrochloric  acid  solution,  whereas 
that  of  the  human  stomach  works  best  at  a  concentration  of  0.03  N.  Different  pepsin 
solutions  also  show  a  difference  with  regard  to  the  optimum  temperature  at  which  they 
act,  and  with  regard  to  the  nature  of  the  protein  which  they  most  readily  attack.  Thus, 
the  pepsin  of  a  calf's  stomach  digests  casein  very  rapidly,  but  coagulated  egg  white 
only  slowly,  whereas  the  pepsin  of  the  pig's  stomach  acts  on  both  these  proteins  at 
about  the  same  rate. 

It  is  well  known  that  the  activity  of  pepsin  can  proceed  only  in  the  presence  of 
acids,  but  this  action  of  acids  does  not  appear  to  depend  on  the  hydrogen-ion  concen- 
tration alone,  for  when  equal  quantities  of  the  same  pepsin  are  mixed  with  quantities 
of  different  acids  so  that  the  hydrogen-ion  concentration  of  the  mixtures  is  uniform, 
it  is  found  that  digestion  proceeds  most  rapidly  with  hydrochloric  acid  and  least 
rapidly  with  sulphuric  acid.  The  SO4  ion  seems,  therefore,  to  be  unfavorable  for 
peptic  activities.  The  acid  seems  to  combine  with  the  protein  before  the  pepsin  attacks 
the  latter;  for,  if  we  first  combine  the  protein  with  acid  and  then  wash  away  all 
traces  of  free  acid,  the  protein  can  be  digested  in  a  neutral  pepsin  solution  without  the 
liberation  of  any  free  acid. 

There  is  evidence  to  show  that  pepsin  itself  also  becomes  combined  with  the  pro- 
tein during  the  digestive  process.  If  a  piece  of  protein  such  as  fibrin  be  immersed 
in  a  solution  of  pepsin  and  then  taken  out  and  washed  thoroughly  to  get  rid  of  all 
adherent  pepsin,  it  will  be  found,  on  placing  it  in  a  hydrochloric  acid  solution  of  the 
proper  strength,  that  peptic  digestion  proceeds.  Advantage  may  be  taken  of  this  fact 
to  separate  pepsin  from  a  solution,  but  the  best  protein  to  use  for  this  purpose  is 


520  DIGESTION 

not  fibrin  but  elastin.  By  such  a  method  it  has,  for  example,  been  shown  that  there 
is  some  pepsin  in  the  intestinal  contents,  which  indicates  that  when  the  chyme  passes 
into  the  intestine,  the  pepsin  is  not,  as  used  to  be  thought,  immediately  killed  by  tin- 
proteolytic  enzyme. 

PRODUCTS  OF  PEPTIC  DIGESTION 

With  regard  to  the  products  of  peptic  digestion,  little  can  be  said 
here.  The  first  product  is  a  metaprotein  known  as  acid  albumin  or 
syntonin.  It  is  precipitated  from  the  digestion  mixture  by  neutraliza- 
tion. The  next  product  is  known  as  primary  proteose,  being  precipi- 
tated by  half  saturation  with  ammonium  sulphate.  The  third  product 
is  secondary  proteose,  produced  by  complete  saturation  with  the  above 
reagent;  and  after  all  these  bodies  have  been  separated  out,  there  re- 
mains in  solution  the  fourth  product — peptone — which  among  other 
things  is  characterized  by  the  fact  that  with  the  biuret  test  it  gives  not 
a  violet  but  a  rose-pink  color. 

It  has  often  been  claimed  that  along  with  these  products  a  certain 
amount  of  free  amino  acids  may  also  appear  in  a  peptic  digestive  mix- 
ture. This,  however,  may  be  due  to  the  action  of  erepsin,  which  is 
usually  present  in  pepsin  preparations.  It  is  important  to  note  that  the 
term  proteose  is  a  general  one,  and  that  there  are  probably  many  varieties 
of  this  substance,  differing  from  one  another  according  to  the  protein 
from  which  they  are  derived. 

The  change  produced  by  pepsin  and  hydrochloric  acid  is  of  the  nature 
of  an  hydrolysis,  for  it  has  been  found  that  the  amount  of  hydrogen  and 
oxygen  in  the  digestive  products  is  greater  than  that  in  the  original 
protein.  It  is  by  a  similar  process  of  hydrolysis  that  the  other  proteolytic 
enzymes,  such  as  pancreatin  and  erepsin,  operate,  but  this  does  not 
imply  that  the  exact  grouping  that  is  split  apart  by  the  hydrolytic  proc- 
ess is  the  same  for  each  of  these  enzymes.  Indeed,  there  is  considerable 
evidence  that  pepsin  does  not,  like  the  other  enzymes,  break  up  the  long 
chain  of  amino  acids  that  are  linked  together  to  compose  the  polypep- 
tides,  but  that  it  only  splits  the  big  molecule  of  albumin  or  globulin 
into  several  large  groups,  each  of  which  is  composed  of  long  ammo-acid 
chains.  Its  action  appears  to  be  analogous  with  that  of  amylase  on 
starch,  by  which,  it  will  be  remembered,  the  big  polysaccharide  mole- 
cule is  split  into  smaller  polysaccharide  molecules,  which  then  become 
attacked  by  the  dextrinase  and  split  into  disaccharide xmtfTeeules  (see 
page  689).  The  evidence  in  support  of  this  view  is:  (1)  that  pepsin  is 
unable  to  digest  polypeptides,  and  (2)  that  it  is  able  to  digest  certain 
proteins  upon  which  erepsin  (see  page  52-4)  has  no  action. 

The  hydrolytic  splitting  of  large  into  smaller  protein  molecules,  like 
that  bv  which  the  chains  of  amino  acids  in  the  polypeptides  are  subsc- 


THE    BIOCHEMICAL    PROCESSES    OF    DIGESTION  521 

quently  broken  up,  consists  in  a  breaking  of  amino-carboxyl  linkings 
(XHCO)  (see  page  634),  with  the  consequent  liberation  of  a  large  num- 
ber of  unattached  amino  groups.  The  number  of  these  free  amino  groups 
can  be  determined  quantitatively  by  the  formaldehyde  titration  method 
of  Sorensen.*  By  this  method  it  can  be  shown  that  from  the  very  start 
of  peptic  digestion  the  number  of  free  amino  groups  increases,  and  pari 
passu  the  power  of  the  digestive  products  to  combine  with  free  hydro- 
chloric acid.  Indeed,  when,  the  experiments  are  done  quantitatively  and 
the  digestion  allowed  to  proceed  for  a  considerable  time,  the  increase  in 
the  formol  titration  is  practically  equal  to  the  decrease  in  the  free  acids 
as  determined  by  the  Giinsberg  reagent. 

The  rate  of  peptic  digestion  is  usually  estimated  by  the  law  of  Schiitz 
and  Borissow^,  according  to  which  the  amount  of  coagulated  albumin 
that  is  digested  in  a  Mett's  tube  is  proportional  to  the  square  root  of  the 
amount  of  pepsin,  f 

The  pepsin  which  leaves  the  stomach  in  the  chyme  is  not  all  destroyed 
in  the  intestine,  as  was  at  one  time  believed  to  be  the  case,  for,  as  we 
have  seen  above,  some  pepsin  can  be  detected  in  the  gastrointestinal  con- 
tents. A  part  of  the  pepsin  may  be  absorbed  into  the  blood  and  carried 
back  to  the  gastric  glands  to  be  used  again.  This  would  account  for  the 
presence  of  antipepsin  in  the  blood,  and  also  for  the  presence  of  pepsin 
in  the  urine.  It  is  probable,  however,  that  most  of  the  pepsin  is  de- 
stroyed after  it  enters  the  intestine. 

Clotting  of  Milk  in  the  Stomach 

Besides  its  pOAver  of  digesting  protein,  the  gastric  juice  is  also  endowed 
with  the  property  of  clotting  milk.  This  action  is  commonly  attributed 
to  the  presence  of  another  enzyme  besides  pepsin,  namely,  rennin;  but 
in  recent  years  considerable  controversy  has  raged  around  the  question 
as  to  whether  pepsin  and  rennin  are  not  the  same  thing.  One  strong 
argument  in  favor  of  this  view  is  that  all  digestive  juices  that  are  capable 
of  digesting  protein  can  also  clot  milk.  In  any  case,  when  gastric  juice 
acts  on  milk,  it  splits  *VIP  fflfifT1!  n^  *^A  milk  into  two  portions,  one  of 
which,  called  parjicasoin,  immediately  combines  with  calcium  to  form  an 
insoluble  f.nllmdpl  compound,  which  is  precipitated  and,  by  entangling 
the  fat  of  the  milk,  forms  the  clot;  the  other  protein  remains  in  solution 

*In  this  method  the  basic  character  of  the  amino  acids  is  destroyed  by  the  formaldehyde,  so 
that  a  higher  decree  of  acidity  develops  in  the  mixture.  Bv  determining  the  increased  aciditv  bv 
titration  with  alkali,  an  estimate  is  obtained  of  the  number  of  amino  groups.  (See  page  635.) 

tThe  amount  of  coagulated  egg  albumin  digested  is  ascertained  by  measuring  the  length  digested 
away  from  the  end  of  a  column  of  coagulated  egg  white  contained  in  a  glass  tube  (Mett's  method). 
(See  Cobb,  P.  W. :  Am.  Jour.  Physiol.,  1905,  xiii,  448.) 

Jin  the  above  nomenclature  casein  is  the  same  as  rasc-inogcn,  and  paracasein  the  same  as  casein, 
of  the  Knglish  physiologists. 


522  DIGESTION 

and  is  known  as  whey  ajbumose.  From  studies  on  molecular  weight  it 
is  believed  that  the  paracasein  is  produced  from  casein  by  the  splitting 
of  the  molecule  of  the  latter  into  two,  from  which  it  would  appear  that 
the  action  of  this  enzyme  is  nothing  more  than  the  first  stage  in  the 
hydrolysis  of  the  casein  molecule.  The  whey  albumose,  according  to  this 
view,  is  a  by-product. 

There  are  many  investigators,  however,  who  believe  that  rennin  and  pepsin  are  not 
identical,  since  an  infusion  of  the  stomach  of  a  calf  has  a  powerful  clotting  action 
on  milk  but  a  very  weak  digestive  one  on  egg  white,  whereas  a  similar  infusion  from 
the  stomach  of  a  pig  shows  exactly  the  reverse  properties.  This  question  is  one  of  so 
controversial  a  nature  that  it  would  be  out  of  place  to  go  into  it  further  here.  It 
should  be  pointed  out,  however,  that,  when  the  gastric  contents  are  acid  in  reaction, 
milk  will  become  clotted  by  the  action  of  the  acid  itself  quite  independently  of  any 
pepsin  or  rennin  the  juice  may  contain.  This  acid  clotting  of  milk  is  probably  of  a 
different  chemical  nature  from  that  produced  by  the  enzymes. 

On  other  foodstuffs  than  proteins  the  action  of  the  gastric  juice  is 
relatively  unimportant,  although  polysaccharides  may  be  considerably 
broken  down  in  the  cardiac  end  of  the  stomach  on  account  of  the  action 
of  swallowed  saliva  (see  page  489),  and  disaccharides,  as  we  have  seen, 
may  become  split  by  the  hydrolyzing  effect  of  the  hydrogen  ion.  Fat 
digestion  also  takes  place  in  the  stomach  when  the  fat  is  taken  in  an 
emulsified  condition,  as  in  milk  and  egg  yolk,  but  not  when  in  masses, 
as  in  meat  or  butter.  This  action  is  due  to  the  presence  of  a  fat-splitting 
enzyme,  or  lipase,  in  the  gastric  juice. 


CHAPTER  LVIII 
THE  BIOCHEMICAL  PROCESSES  OF  DIGESTION   (Cont'd) 

DIGESTION  IN  THE  INTESTINES 

The  further  changes  which  the  half-digested  foodstuffs  in  the  chyme 
undergo  in  the  intestinal  canal  depend  on  the  enzymes  present  in  the 
secretion  of  the  various  glands  and  on  the  presence  of  bacteria.  The 
most  important  of  the  digestive  juices  are  the  pancreatic  juice  and  bile. 
The  latter,  however,  does  not  contain  any  enzyme,  its  influence  on  diges- 
tion being  entirely  adjuvant. 

Pancreatic  Digestion 

When  we  were  considering  the  mechanism  of  secretion  of  the  pan- 
creatic juice,  we  saw  that  the  juice  produced  by  the  action  of  secretin  on 
the  gland  cells  does  not  contain  any  active  proteolytic  enzyme,  although 
it  contains  one  capable  of  acting  on  polysaccharides  and  another,  on  fat. 

THE  ACTION  OF  TRYPSIN 

When  pancreatic  juice  is  mixed  with  the  secretion  of  the  duodenum  or  of 
the  upper  part  of  the  small  intestine,  it  immediately  develops  powerful 
proteolytic  power.  The  same  result  may  also  be  obtained  by  mixing  it 
with  an  extract  of  the  mucous  membrane  of  the  duodenum  made  with 
dilute  bicarbonate  solution.  A  very  small  amount  of  the  extract  is 
capable  of  increasing  the  digestive  activity  of-  a  very  considerable  quan- 
tity of  pancreatic  juice,  showing  that  the  action  depends  on  the  presence 
of  an  enzyme  which  has  been  called  grrfg&lkWtP'Se.  This  influence  of  the 
intestinal  secretion  is  readily  destroyed  by  heating. 

Large  quantities  of  alkali  are  contained  in  the  pancreatic  juice  and 
bile,  so  that  in  the  upper  reaches  of  the  intestine  the  acidity  of  the 
chyme  is  practically  neutralized.  A  little  lower  down,  however,  an  acid 
reaction  may  again  develop  (see  page  539).  On  account  of  these  facts  it 
has  been  concluded  that  the  activity  of  trypsin  is  most  rapid  in  the  pres- 
ence of  a  slight  excess  of  hydroxyl  ions;  i.  e.,  in  a  weakly  alkaline  solu- 
tion. It  is  interesting  to  note  that,  as  a  result  of  the  great  secretion  of 
alkali  by  the  pancreas,  extracts  of  this  organ  after  death  show  a  very 
high  degree  of  acidity  in  comparison  with  extracts  from  other  organs 

523 


524  DIGESTION 

and  tissues.  It  has  also  recently  been  shoAvn  that  the  activity  of  trypsin 
does  not  depend  on  the  presence  of  free  hydroxyl  ions,  but  that  it  may 
proceed  in  the  presence  of  a  decided  amount  of  free  acid.  If  pepsin 
is  present  together  with  trypsin  in  a  distinctly  acid  solution,  the  pep- 
sin seems  to  destroy  the  trypsin,  unless  the  mixture  contains  a  con- 
siderable quantity  of  protein,  when  the  tryptic  activity  may  persist 
even  for  several  hours.  A  practical  conclusion  that  we  may  draw  from 
these  results  is  to  the  effect  that  preparations  of  trypsin — the  so-called 
pancreatin,  for  example — if  given  with  the  food,  may  pass  in  an  active 
condition  into  the  duodenum,  where,  in  the  more  favorable  environment 
i  created  by  the  neutralization  of  the  excess  of  acid,  it  will  develop  its 
Iproteolytic  power.  The  therapeutic  administration  of  pancreatin  is, 
therefore,  justified  (Long24). 

The  activated  trypsin  acts  on  proteins  in  very  much  the  same  way  as 
pepsin,  except  that  the  decomposition  of  the  peptone  and  proteoses  into 
polypeptides  is  the  chief  feature  of  the  process.  Thus,  after  tryptic 
digestion  has  proceeded  for  some  time,  only  a  trace  of  primary  proteoses 
but  considerable  quantities  of  leucine,  tyrosine  and  other  amino  acids 
will  be  found  present.  Some  investigators  believe  that  the  thorough 
nature  of  the  digestive  action  of  activated  pancreatic  juice  may  depend 
on  its  also  containing  erepsin,  an  enzyme  which  we  shall  see  to  be  pres- 
ent in  considerable  amount  in  the  mucous  membrane  of  the  intestine  and 
other  tissues,  and  whose  particular  function  is  to  split  polypeptides  into 
the  amino  acids.  From  the  autolytic  digestion  which  takes  place  in 
organs  kept  in  a  sterile  condition  after  death,  tryptic  digestion  differs 
in  that  it  produces  only  small  quantities  of  ammonia.  The  large  quanti- 
ties of  ammonia  produced  in  autolytic  digestion  no  doubt  have  a  rela- 
tionship to  the  acids  simultaneously  set  free  during  this  process. 

In  the  products  of  tryptic  digestion  it  is  usually  found  that,  although 
there  has  been  considerable  splitting  of  the  protein  into,  amino  acids, 
there  are  still  a  good  many  amino-carboxyl  (NHCO)  linkages  left  un- 
broken, indicating  that  certain  polypeptides  are  still  intact  in  the  mix- 
ture. To  split  the  polypeptides  requires  the  aid  of  ._tlie  wepsin,  which  is 
present  in  the  mucous  membrane  of  the  intestine.  Interesting  inves- 
tigations have  been  made  on  the  exact  degree  to  which  trypsin-entero- 
kinase  can  split  up  the  various  known  polypeptides.  This  seems  to 
depend  on  the  structure  of  the  polypeptide  molecule  and  on  the  number 
of  amino  acids  present  in  the  chain.  For  example,  alanylglycine,  but 
not  glycylalanine  is  hydrolyzed,  although  both  contain  the  same  amino 
acids  but  linked  together  in  a  different  way;  and  tetraglycylglycine, 
which  contains  five  glycine  radicles,  is  hydrolyzed,  whereas  diglycylgly- 
cine,  which  contains  only  three,  is  not. 


THE    BIOCHEMICAL    PROCESSES    OF    DIGESTION  525 

The  importance  of  the  presence  of  erepsin  in  the  mucous  membrane 
of  the  intestine  is  that  it  serves  asjjjjarrifir  t.n  the  passage  of  a.nv  unsplit 
amino  acids  from  the  int.ftst.ina,]  p.nr\t_pTTt^  into_  the  blood.  It  insures  the 
breaking  up  of  the  protein  molecule  into  its  ultimate  units  before  absorp- 
tion. The  further  fate  of  the  absorbed  amino  acids  will  be  considered 
under  the  subject  of  protein  metabolism. 

THE  ACTION  OF  LIPASE 

Neutral  fat  is  decomposed  into  fatty  acids  and  glycerine  by  the  lipase 
present  in  the  pancreatic  juice.  This  enzyme  may  also  be  extracted  from 
the  glands  by  means  of  60  per  cent  alcohol.  Its  action  is  remarkably 
accelerated  by  the  presence  of  bile,  and  considerably  depressed  by  inor- 
ganic salts.  It  is  also  very  dependent  on  the  degree  of  alkalinity,  the 
optimum  being  a  hydrogen-ion  concentration  of  H  x  10'8.  The  •  favoring 
action  of  bile  is  undoubtedly  owing  to  the  bile  salts  (see  page  528),  and 
it  is  probable  that  this  action  is  dependent  upon  the  influence  which 
these  have  in  lowering  surface  tension  and  therefore  bringing  about  a 
more  intimate  contact  between  fat  and  water. 

THE  ACTION  OF  AMYLOPSIN 

The  action  of  pancreatic  juice  on  carbohydrates  depends  on  the 
amylolytic  enzyme  called  amylopsin.  In  animals  having  no  active  ptyalin 
in  the  saliva,  amylopsin  serves  as  the  only  diastatlc  enzyme  concerned 
in  the  digestive  process.  In  any  case,  at  least  for  the  first  stages  of  the 
disruption  of  the  starch  molecule — that  is,  its  conversion  into  dextrines — 
amylopsin  is  a  more  powerful  enzyme  than  ptyalin.  It  does  not  appear 
to  be  so  efficient  as  ptyalin  in  the  final  stages  of  the  hydrolysis,  for  it 
does  not  produce  so  much  reducing  sugar  as  ptyalin  does.  Indeed  ex- 
tracts of  pancreas  will  sometimes  convert  starch  into  soluble  starch  and 
dextrine  with  great  speed,  but  produce  scarcely  any  reducing  sugar. 
On  this  account  it  is  believed  by  many  investigators  that  there  are  at  least 
two  distinct  and  separate  enzymes  in  amylopsin  and  also  perhaps  in 
ptyalin,  one  a  true  amylase,  which  converts  starch  into  dextrine,  and 
the  other  a  dextrinase,  which  converts  dextrine  into  maltose.  In  the 
case  of  both  ptyalin  and  amylopsin  digestion  proceeds  best  in  a  very 
weak  acid  reaction.  Amylopsin,  as  it  is  secreted  in  the  pancreatic  juice, 
is  fully  activated;  bile,  apart  from  the  alkali  which  it  contains,  having 
no  influence  on  its  digestive  power. 

Besides  amylopsin  the  pancreatic  juice  also  contains  ..maltose,  and  in 
the  case  of  young  animals  or  of  those  that  take  milk  with  their  food 
throughout  their  lives,  lactase  also.  After  the  suckling  animal  has  dis- 


526  DIGESTION 

continued  taking  milk,  the  lactase  disappears  from  the  pancreatic  juice. 
Attempts  have  been  made  to  bring  it  back  by  feeding  the  adult  upon 
milk,  but  without  success.  Occasionally  the  pancreatic  juice  also  con- 
tains invertase. 

The  Bile 

Associated  with  the  pancreatic  juice  in  all  its  functions  is  the  bile. 
When  this  fluid  is  prevented  from  entering  the  intestine,  the  digestive 
process  becomes  very  imperfect,  the  absorption  of  fat  being  particularly 
interfered  with  (see  page  722).  Bile  is  also  an  excretory  product,  and 
its  composition  therefore  is  much  more  complex  than  that  of  the  other 
digestive  fluids.  This  varies  very  much,  however,  according  to  the 
method  of  collection.  Bile  from  the  gall  bladder  after  death  contains 
much  more  solid  material,  particularly  bile  salts  and  mucin,  than  that 
collected  from  a  fistula  of  the  bile  duct  or  gall  bladder  during  life. 
These  differences  will  be  evident  from  the  accompanying  table. 

Bile  from 

Gall  bladder  Fistula 

100  parts  contain — 

Water    86       .  97 

Solids    14  3 

Organic  salts   (bile  salts) 9  0.9-1-8 

Mucin  and  bile  pigment 3  0.5 

Cholesterol    0.2  0.06-0.16 

Lecithin  and  fat.. 0.5-1.0  0.02-0.09 

Inorganic   salts    0.8  0.7-0.8 

In  general  it  may  be  said  that  bile  obtained  from  a  fistula  in  man 
contains  only  about  3  per  cent  of  total  solids,  of  which  from  one-fourth 
to  one-half  are  inorganic,  whereas  bile  from  the  gall  bladder  contains 
10  to  20  per  cent  of  total  solids,  of  which  only  about  one-twentieth  are 
inorganic.  The  chief  cause  for  this  difference  appears  to  be  that  when 
the  bile  goes  to  the  intestine,  a  considerable  proportion  of  its  bile  salts 
is  reabsorbed  into  the  portal  blood  and  reexcreted  by  the  liver.  Some 
of  the  difference  may  also  be  caused  by  the  fact  that  absorption  of 
water  takes  place  from  the  gall  bladder,  and  that  mucin  and  possibly 
cholesterol  are  secreted  by  this  organ.  These  striking  differences  be- 
tween fistula  and  gall-bladder  bile  are  observed  only  when  the  com- 
mon bile  duct  is  occluded.  If  the  bladder  fistula  is  made  with  the  com- 
mon duct  left  open,  some  of  the  bile  gains  entry  to  the  duodenum  and 
therefore  becomes  reexcreted.  It  is  well  known  that  a  fistula  of  the  gall 
bladder  in  man  after  a  time  closes  up  and  the  bile  again  takes  its  usual 
course  along  the  bile  duct  into  the  duodenum. 


THE   BIOCHEMICAL   PROCESSES    OF   DIGESTION  527 

Interesting  observations  have  been  collected  on  the  amount  of  the  secre- 
tion from  a  fistula,  both  in  man  and  in  the  lower  animals.  In  man  it  is 
commonly  stated  that  about  500  c.c.  of  bile  are  secreted  daily,  the 
amount  varying  considerably  during  the  different  hours  of  the  day.  The 
secretion  of  bile  is  greatly  reduced  by  hemorrhage.  It  is  greater  on  a 
meat  diet  than  on  one  of  carbohydrates.  It  is  reduced  during  starva- 
tion, but  continues  to  be  secreted  up  to  the  moment  of  death. 

FUNCTIONS  OF  BILE 

One  of  the  main  functions  of  the  bile  salts  is  that  they  greatly  assist, 
not  only  in  the  digestion,  but  also  in  the  absorption  of  fats.  When  bile 
is  excluded  from  the  intestine,  the  feces  are  loaded  with  fatty  acids 
which  have  been  split  off  partly  by  the  now  less  effective  lipase  and 
partly  by  the  action  of  bacteria.  The  fatty  acid  thus  liberated  in  the 
absence  of  bile  salts  is  not  absorbed,  because  the  bile  salts  serve  as  the 
carriers  of  fatty  acids  into  the  epithelial  cells  and  lacteals.  They  com- 
bine with  the  fatty  acids,  probably  by  forming  some  chemical  compounds 
in  which  they  carry  them  into  the  endothelial  cells  where  the  compounds 
become  disrupted,  the  fatty  acid  combining  with  glycerine  to  again  form 
neutral  fat  and  the  bile  salts  being  carried  to  the  liver  and  reexcreted. 
The  influence  of  bile  salts  in  assisting  the  action  of  lipase  is  probably 
due  to  a  lowering  of  the  surface  tension,  thus  bringing  water  and  fat 
into  closer  union.  This  accelerating  influence  has  also  been  demonstrated 
when  synthetic  bile  salts  have  been  used,  showing  clearly  that  it  is  really 
these  and  not  any  other  constituent  of  the  bile  that  are  responsible  for 
its  accelerating  influence. 

Bile  also  functionates  as  a  regulator  of  intestinal  putrefaction.  This 
it  does  apparently  because  of  its  slight  laxative  properties,  by  which 
the  intestinal  contents  are  expelled  before  the  bacteria  have  grown  to 
any  great  extent  in  them.  Bile  itself  is  a  favorable  culture  medium  for 
certain  bacteria,  so  that  it  can  have  no  antiseptic  action.  Its  assistance 
in  the  action  of  trypsin  and  amylopsin  depends  very  largely  upon  the 
alkali  which  it  contains. 

As  an  excretory  vehicle,  hilp  is  important,  because  it  possesses  the 
power  of  dissolving  cholesterol.  Toxins  and  metallic  poisons  of  various 
kinds  are  also  excreted  in  it. 

Although  not  directly  concerned  with  the  digestive  function,  it  will  be 
convenient  to  say  something  here  concerning  the  chemical  nature  and 
derivation  of  the  various  biliary  constituents. 


528  DIGESTION 

THE  CHEMISTRY  OF  BILE 

The  Bile  Salts 

In  mostjuiimals  the  bile  salts  consist  of  the  sodium  salts  of  glycocholic 
and  taurocholie  acids.  Each  of  these  acids  is  composed  of  a"part  called 
cholic  acftt"Tvhich  is  more  or  less  related  to  cholesterol,  and  of  glycine 
(CHoNHoCOOH  ammo-acetic  acid)  or  taurine  (C2H7NS03),  a  derivative 
of  cvjstejfts,,  which  is  a-amino-/?-thiopropionic  acid  (CH2HS.CHNH2. 
COOH).  The  exact  form  of  cholic  acid  varies  in  different  animals,  that 
of  the  pig,  for  example,  being  different  from  that  of  man.  Bile  salts  are 
an  exclusive  product  of  liver  metabolism;  i.e.,  they  are  not  formed  in 
any  other  part  of  the  animal  body.  They  give  a  very  sensitive  color 
reaction  known  as  Pettenkof er  's,  which  however  is  not  specific  of  bile  acids, 
since  it  is  also  given  by  oleic  acid  and  by  many  aromatic  substances  and 
alcohols.  It  must  be  remembered  that  the  part  of  the  bile  salts  that  is 
characteristic  of  the  liver  is  the  cholic  acid,  the  taurine  and  glycine 
being  present  in  other  tissues  and  organs. 

When  cholic  acid  is  given  to  animals  mixed  with  the  food,  the  amount 
of  taurocholiB  acid  excreted  with  the  bile  is  increased,  indicating  that 
there  must  be  a  store  of  taurine  available  in  the  organism.  This  store 
can  not,  however,  be  large,  for  if  the  feeding  with  cholic  acid  is  repeated 
several  times,  it  will  be  found  that  the  taurocholie  acid  diminishes  and 
glycocholic  acid  takes  its  place;  and  this  increased  excretion  of  glyco- 
cholic  acid  goes  on  just  as  long  as  cholic  acid  is  fed.  The  reserve  of 
taurine  in  the  animal  body  appears  therefore  to  be  limited,  although  it  is 
used  in  preference  to  glycine  when  there  is  an  excess  of  cholic  acid  to  be 
neutralized.  On  the  other  hand,  the  store  of  glycine  seems  to  be  inexhaust- 
ible. That  there  is  no  reserve  of  cholic  acid  itself  in  the  body  is  indicated  by 
the  fact  that  no  increase  in  taurocholie  acid  excretion  by  the  bile  results 
when  cystine,  the  mother  substance  of  taurine,  is  given  with  the  food. 
If  both  taurine  and  cholic  acid  be  fed,  however,  the  excretion  of  tauro- 
cholie acid  increases. 

The  relative  amounts  of  taurocholie  and  glycocholic  acids  in  the  bile  of 
different  animals  differ  considerably.  Human  bile  contains  relatively 
a  small  amount  of  taurocholie  acid;  on  the  other  hand,  the  bile  of  the  dog 
contains  a  large  excess  of  it. 

Cholesterol 

In  human  bile  the  percentage  of  this  important  substance  is  not  high 
(1.6  parts  per  1000),  but  it  is  of  great  clinical  importance  because  of  the 
fact  that  it  may  separate  out  as  a  precipitate  forming  gallstones.  The 


THE   BIOCHEMICAL,   PROCESSES   OF   DIGESTION  529 

percentage  of  cholesterol  in  these  varies  from  20  to  90;  the  remainder 
being  organic  material  such  as  epithelial  cells,  inorganic  salts,  pigment, 
etc.  The  origin  of  cholesterol  is  partly  endogenous  and  partly  exoge- 
nous. In  the  former  case  it  comes  from  the  envelope  of  red  blood  cor- 
puscles and  from  tl)ft  rmrvnns  tissues,  where  it  is  present  in  considerable 
amount.  The  latter  source  is,  of  course,  the  food.  The  increase  in 
cholesterol  esters  in  the  blood  after  feeding  with  food  rich  in  this  sub- 
stance has  been  shown,  particularly  in  rabbits. 

That  the  bile  should  be  the  pathway  through  which  cholesterol  is 
excreted  depends  no  doubt  on  the  fact  that  it  contains  bile  salts,  which 
along  Avith  their  other  properties  hava..^- remarkable  solvent  action  on 
cholesterol.  This  solvent  property  depends  on  the  cholic  acid  part  of 
the  bile  salts,  which,  as  already  remarked,  is  chemically  very  closely 
related  to  cholesterol;  indeed,  the  relationship  is  so  close  that  some  have 
suggested  that  cholic  acid  is  derived  from  cholesterol.  This  would  mean 
that  the  cholesterol  of  blood  is  excreted  in  two  ways,  as  cholesterol  and 
as  cholic  acid.  Other  observers,  however  maintain  that  the  cholesterol 
is  excreted  mainly  by  the  lining  membrane  of  the  gall  bladder,  and 
that  this  explains  why  gall-bladder  bile  contains  more  of  it  than  fis- 
tula bile.  This  evidence  is,  however,  not  very  strong,  for  the  greater 
excretion  of  cholesterol  under  conditions  where  the  circulation  of  bile 
is  proing  on  may  be  explained  as  due  to  the  presence  of  bile  salts,  which 
serve  to  carry  the  cholesterol  out  of  the  blood. 

Many  problems  remain  to  be  elucidated  in  connection  with  the  metabolic 
history  of  cholesterol.  That  some  of  it  is  absorbed  when  cholesterol  is 
contained  in  the  food  might  seem  to  indicate  that  its  source  is  entirely 
exogenous.  Against  this  view,  however,  stand  two  facts:  (1)  that  the 
cholesterol  in  the  feces  of  herbivorous  animals  is  of  the  same  variety  as 
that  present  in  those  of  carnivorous  animals  and  not  the  phytosterol 
which  is  present  in  plants;  and  (2)  that  the  universal  presence  of 
cholesterol  in  cells  indicates  that  it  must  be  manufactured  there. 

The  Bile  Pigments 

The  pigments  of  bile  are  bilirubin  and  biliverdin.  The  latter  is  pro- 
duced from  the  former  by  oxidation.  If  the  oxidation  be  carried  a 
stage  further,  a  blue  pigment  called  bilicyanin  is  formed.  This  process 
of  oxidation  can  be  observed  in  the  ring  test  for  bile  pigment  with 
fuming  nitric  acid.  When  bilirubin  is  reduced,  urobilin,  one  of  the 
pigments  in  urine,  is  formed.  Bilirubin  must  therefore  be  considered 
as  the  mother  substance  of  all  these  pigments,  and  it  is  of  interest  in 
connection  with  its  derivation  to  know  that  it  has  the  same  formula 


530  DIGESTION 

as  iron-free  hematin  or  hematoporphyrin,  which  is  produced  by  treating 
hemoglobin  with  concentrated  sulphuric  acid. 

Chemical  investigation  has  shown  that  bilirubin  is  built  up  from  sub- 
stituted pyrrols,  probably  four  such  being  contained  in  the  molecule. 
The  pyrrol  group  is  also  present  in  indole  and  tryptophane,  and  con- 
sists of  four  carbon  atoms  and  an  NH  group  linked  together  as  a  ring 
(see  page  639).  Similar  pyrrol  derivatives  can  be  produced  by  decom- 
posing chlorophyl,  the  green  coloring  matter  of  plants.  It  is  important 
to  remember  that  bilirubin  is  acid  in  nature,  and,  therefore,  can  com- 
bine with  alkalies  to  form  salts.  The  relative  amounts  of  bilirubin  and 
biliverdin  vary  in  the  bile  of  different  animals. 

When  these  pigments  enter  the  intestine  they  are  reduced  to  urobilin, 
part  of  which  passes  out  with  the  feces,  another  part  being  absorbed  into 
the  blood  and  excreted  in  the  urine.  Part  of  that  excreted  in  the  urine 
exists,  however,  as  a  so-called  chromogen  named  urobilinogen.  The 
urobilinogen  is  converted  into  urobilin  by  the  action  of  oxygen. 

The  method  by  which  bile  pigments  are  produced  from  blood  pigment  has 
been  studied  by  histological  examination  of  the  liver  particularly  of  birds 
and  amphibia,  in  which  destruction  of  blood  pigment  goes  on  rapidly. 
Increased  destruction  of  blood  pigment  can  be  induced  by  poisoning 
with  certain  substances  such  as  arseniureted  hydrogen.  After  extra- 
vasation of  blood  in  the  subcutaneous  tissues,  as  in  a  bruise,  for  example, 
a  decomposition  of  hemoglobin  proceeds  quite  like  that  occurring  in 
the  liver,  and  leads  to  the  production  of  blue  and  brown  and  green 
pigments  like  those  of  the  bile.  When  hemolysis  is  produced,  as  by 
inhalation  of  arseniureted  hydrogen  or  the  injection  of  inorganic 
or  biological  hemolysins,  there  is  an  immediate  increase  in  the  amount 
of  bile  pigment  in  the  bile.  Even  the  injection  of  hemoglobin  solutions 
has  this  effect.  Under  these  conditions  of  hemolysis,  besides  an  increase 
in  urobilin,  there  may  be  considerable  quantities  of  hemoglobin  secreted 
in  the  urine.  From  such  studies  it  is  usually  believed  that  the  bile  pig- 
ments are  a  peculiar  product  of  hepatic  activity,  being  produced  from 
blood  pigments  that  are  derived  from  erythrocytes  which  have  been 
broken  down  either  in  the  liver  itself  or  in  some  other  viscus  (e.g.,  the 
spleen).  Whipple  and  Hooper25  have  shown  that  bile  pigments  may  also 
be  formed  in  other  tissues  than  the  liver.  They  have  found,  for  example, 
that  the  bile  pigments  are  formed  just  as  readily  in  animals  in  which  the 
circulation  of  the  liver  was  greatly  curtailed,  by  anastomosing  the  portal 
vein  with  the  vena  cava  (Eck  fistula),  as  in  normal  animals.  Even  when 
the  circulation  was  limited  to  the  anterior  end  of  the  animal  (head  and 
thorax)  bile  pigment  appeared  in  the  blood  when  hemolyzed  erythrocytes 
were  injected,  and  it  was  also  formed  when  hemoglobin  was  placed  in  the 


THE   BIOCHEMICAL   PROCESSES   OF   DIGESTION  531 

pleural  and  peritoneal  cavities.  The  endothelial  cells  of  the  blood  vessels 
and  elsewhere  can  evidently  form  the  pigments,  at  least  when  the  liver  is 
absent.  When  such  a  process  occurs  under  normal  conditions,  it  is  quite 
probable  that  the  liver  acts  merely  as  an  excretory  organ  for  the  pig- 
ments in  the  same  way  as  the  kidney  does  for  urea.  Possessed  of  endo- 
thelial cells,  the  liver  might  itself  also  produce  some  of  the  pigments, 
but  no  more  than  other  organs  with  a  similar  number  of  those  cells. 

The  derivation  of  bile  pigments  directly  from  hemoglobin  is  not  their 
only  source,  for  the  same  workers  have  observed  that,  whereas  the  excre- 
tion of  pigment  from  a  biliary  fistula  is  remarkably  constant  in  a  dog 
fed  on  a  fixed  mixed  diet,  it  became  increased,  sometimes  by  100  per 
cent,  when  the  diet  was  changed  to  one  of  carbohydrates,  and  depressed 
on  a  diet  of  meat.  The  question  arises  as  to  whether  all  of  the  bile 
pigments  are  really  derived  from  broken-down  hemoglobin.  May  they 
not  also  be  manufactured  de  novo  out  of  other  materials'? 

Whipple  and  Hooper  have  also  shown  that  bile  is  a  most  important 
secretion,  for  dogs  rarely  survive  on  an  ordinary  diet  if  bile  is  perma- 
nently prevented  from  entering  the  intestine.  Intestinal  symptoms 
soon  supervene,  and  become  progressively  more  severe  until  the  death 
of  the  animal.  Feeding  with  bile  does  not  relieve  the  condition,  but 
feeding  with  cookedjiver  seems  to  have  a  beneficial  effect. 

Bile  salts  and  pigments  usually  accompany  each  other  when  any- 
thing occurs  to  interfere  with  the  free  secretion  of  bile.  For  example, 
after  ligation  of  the  bile  duct  both  bile  pigments  and  bile  salts  accumu- 
late in  the  blood,  in  the  serum  of  which  they  may  be  recognized  by  the 
ordinary  chemical  tests  in  from  four  to  six  hours  after  the  operation. 
If  the  accumulation  be  allowed  to  proceed  further,  the  bile  pigments 
become  deposited  in  the  tissues,  giving  them  the  peculiar  yellowish  ap- 
pearance known  as  jaundice.  Under  these  conditions  the  bile  salts  and 
pigments  also  appear  in  the  urine.  The  accumulation  of  bile  salts  in 
the  body  affects  certain  physiological  processes;  for  one  thing,  it  causes 
a  great  lengthening  in  the  clotting  time  of  the  blood. 

If  the  blood  supply  to  the  liver  is  interrupted  by  ligation  of  the  portal 
vein  and  hepatic  artery  at  the  same  time  that  the  bile  ducts  are  occluded, 
not  a  trace  either  of  bile  salts  or  of  bile  pigment  appears  in  the  blood 
during  the  six  to  eighteen  hours  that  the  animals  survive  the  operation. 

The  amount  of  obstruction  of  the  bile  duct  necessary  to  produce  these 
symptoms  is  very  slight,  since  bile  is  secreted  at  a  very  low  pressure. 
Even  a  clot  of  mucus  or  a  swollen  condition  of  the  mucous  membrane 
of  the  duct  is  sufficient  to  produce  obstruction.  In  the  discharge  of  bile 
from  the  gall  bladder  into  the  duodenum  it  is  claimed  by  Meltzer26  that  a 
reciprocal  relationship  exists  between  the  contraction  of  the  bladder 


532  DIGESTION 

musculature  and  the  relaxation  of  the  muscular  fibers  surrounding  the 
duct  in  the  duodenum.  If  this  reciprocal  innervation  fails  to  operate 
properly,  discharge  of  bile  into  the  duodenum  may  become  obstructed 
so  that  a  certain  amount  passes  back  into  the  blood,  as  in  cases  of  bile- 
duct  obstruction. 

Bile  also  contains  a  certain  amount  of  l&oithiii  and  other  phospholipins. 
The  amount  varies  considerably  in  the  bile  of  different  animals,  even  in 
animals  of  the  same  species.  It  is  probably  derived,  as  already  men- 
tioned, like  the  cholesterol,  from  the  breaking-down  of  red  blood  cor- 
puscles that  goes  on  in  the  liver.  It  is  no  doubt  digested  by  the  ferments 
of  the  intestinal  tract,  the  liberated  cholin,  since  it  is  toxic  if  absorbed, 
being  further  attacked  by  bacteria  so  as  to  become  converted  into  cer- 
tain substances  of  a  nontoxic  nature. 


CHAPTER  LIX 

BACTERIAL  DIGESTION  IN  THE  INTESTINE 

On  an  average  diet,  in  twenty-four  hours  the  feces  of  man  weigh 
about  100  grams,  or  after  drying,  about  20  grams.  About  one-fourth  of 
the  dry  matter  consists  of  the  bodies  of  bacteria.  If  plated  out  by  the 
ordinary  bacteriologic  methods,  however,  it  will  be  found  that  only  a 
small  proportion  of  these  bacteria  are  living.  The  greater  number  have 
been  destroyed,  probably  by  the  action  of  the  mucin  in  the  large  intes- 
tine. The  nitrogen  content  of  the  feces  amounts  to  about  1.5  grams  a 
day,  of  which  about  one-half  is  bacterial  nitrogen.  If  the  diet  contains 
large  quantities  of  cellulose  material,  as  in  green  vegetable  food  and 
fruit,  the  mass  of  feces  as  well  as  the  bacterial  content  may  be  consid- 
erably greater. 

The  foregoing  facts  indicate  that  very  extensive  bacteriologic  proc- 
esses must  be  going  on  all  the  time  in  the  intestinal  contents,  and  the 
question  arises  as  to  whether  such  action  is  beneficial  or  otherwise  to  the 
animal  economy.  To  answer  this  question  interesting  observations  have 
been  made  on  the  growth  and  well-being  of  animals  excised  from  the 
uterus  under  strictly  sterile  conditions  and  maintained  thereafter  on 
sterile  food.  Such  observations  made  on  guinea  pigs  have  shown  that 
the  animals  thrive  and  grow  perfectly  for  a  considerable  time.  Experi- 
ments carried  out  on  chicks  have  not,  however,  yielded  similar  results. 
Chicks  hatched  out  from  the  egg  under  strictly  sterile  conditions  and 
then  fed  on  sterile  grain,  do  not  thrive,  but  do  so  if  the  grain  is 
mixed  with  a  certain  amount  of  fowl  excrement.  These  experiments,  appar- 
ently contradictory  in  their  results,  show  that  for  certain  groups  of 
animals  bacteria  are  required,  but  not  for  others. 

The  difference  is  probably  dependent  on  the  nature  of  the  foods.  It 
will  be  remembered  that  the  size  of  the  large  intestine  varies  consider- 
ably according  to  the  nature  of  the  diet  (see  page  497).  Animals  taking 
great  quantities  of  cellulose  foodstuffs  have  very  large  ceca  and  very 
long  large  intestines;  whereas  those  which,  like  the  cat,  live  practically 
entirely  on  cellulose-free  food,  have  a  rudimentary  large  intestine.  The 
size  of  the  lower  intestine  is  obviously  dependent  on  the  presence  or 
absence  of  cellulose  in  the  food.  It  will  be  remembered  also  that  the 
forward  movement  of  the  contents  of  the  large  intestine  is  very  slow; 
indeed,  special  provision  is  made,  by  the  presence  of  the  so-called  anti- 
peristaltic  wave,  to  delay  its  movement.  This  suggests  that  an  important 

533 


534  DIGESTION 

digestive  process  must  be  proceeding  in  this  part  of  the  gut.  In  these 
ways  conditions  become  established  in  the  cecum  for  the  active  opera- 
tion of  bacteria.  They  attack  the  cellulose,  and  liberate  the  more  diges- 
tible foodstuffs  contained  in  the  vegetable  cells,  also  producing  out  of 
the  cellulose  itself  materials  of  nutritive  value.  The  acids  that  are  also 
produced  by  this  process  are  neutralized  by  the  carbonates  secreted 
by  the  mucosa. 

In  certain  herbivorous  animals — the  ruminants — this  process  in  the 
cecum  is  not  relatively  of  such  importance,  because  it  takes  place  mainly  in 
the  paunch.  The  animals  swallow  the  food  and  it  mixes  in  this  part  of  the 
stomach  with  the  saliva,  so  that  bacteria  and  ferments  called  cytases,  con- 
tained in  it,  attack  the  cellulose,  liberating  the  more  easily  digested  food- 
stuffs inclosed  within  the  cell  walls.  As  this  process  goes  on  acids  accumu- 
late in  the  digestive  mixture.  The  food  is  then  returned  to  the  mouth  and 
chewed  over  again,  after  which  it  is  swallowed  into  the  main  stomach, 
where  it  is  digested.  The  aid  which  bacteria  render  to  digestion  depends 
therefore  on  the  nature  of  the  diet.  Man,  being  omnivorous,  stands  mid- 
way between  the  two  groups  of  animals  discussed  above.  Although  the 
cellulose  contained  in  his  food  is  not  itself  sufficiently  digested  to  furnish 
nutriment,  yet  it  is  so  far  acted  upon  as  to  permit  the  rupture  of  the 
cell,  the  contents  of  which  are  then  digested.  The  cellulose  is,  however, 
of  value  in  furnishing  bulk  to  the  intestinal  contents — "intestinal  bal- 
last," it  is  sometimes  called. 

In  the  small  intestine  in  man  there  are  bacteria  capable  of  acting  on 
carbohydrates  and  producing  from  them  organic  acids,  such  as  lactic, 
acetic,  etc.  So  long  as  a  sufficiency  of  carbohydrate  exists  to  encourage 
the  action  of  these  bacteria,  others  having  an  action  on  protein  do  not 
seem  to  thrive.  It  may  be  that  this  is  to  be  accounted  for  partly  by  the 
production  of  acid  substances  by  the  carbohydrate  fermentation,  and 
partly  by  the  fact  that,  as  soon  as  the  protein  molecule  is  broken 
down  by  the  digestive  enzymes,  its  building-stone  amino  acids  are  ab- 
sorbed. There  are  probably  also  bacteria  in  the  small  intestine  capable 
of  splitting  fat  into  fatty  acid  and  glycerine,  but  practically  nothing  is 
known  of  their  action.  In  the  large  intestine  of  man,  along  with  the 
cellulose-digesting  bacteria  already  mentioned,  protein-digesting  bac- 
teria are  also  present.  These  bacteria  belong  to  the  class,  Bacillus  coli 
communis,  the  various  members  of  which  are  known  as  facultative  anae- 
robes because  they  can  grow  in  the  presence  or  absence  of  oxygen. 

If  bacterial  growth  is  excessive  or  there  is  an  insufficiency  of  carbohy- 
drates in  the  small  intestine,  the  bacteria  attack  the  amino  acids  pro- 
duced by  the  digestive  enzymes  and  decompose  them  into  products 
that  may  be  toxic  if  absorbed  into  the  blood. 


BACTERIAL  DIGESTION  IN  THE  INTESTINE  535 

Bacterial  Digestion  of  Protein 

From  a  pathological  standpoint,  the  most  important  action  of  bacteria 
is  that  which  takes  place  on  protein.  Under  anaerobic  conditions  the 
intestinal  bacteria  have  in  general  the  power  of  splitting  off  the  amino 
group  whereas  under  aerobic  conditions  they  split  off  the  carboxyl 
group.  This  splitting  off  of  the  carboxyl  group  as  carbon  dioxide  is  per- 
formed by  the  so-called  carboxylase  bacteria,  and  it  may  take  place  either 
before  or  after  deamidization  (see  page  649).  If  it  happens  after  this 
process,  the  products  are  not  highly  toxic  and  include  phenol,  cresoL 
indole  ar^  ftfcat.nlA,  whir*Vi  are  partly  absorbed  into  the  blood  and  partly 
excreted  with  the  feces. 

The  fractions  of  those  substances  that  are  absorbed  into  the  blood 
have  their  toxicity  removed  by  conjugation  mainly  with  sulphuric  acid 
to  form  the  so-called  ethereal  sulphates.  A  part  is  also  combined  with 
p'lycuronic  acid  (see  page  665).  In  the  case  of  phenol  and  cresol  this 
conjugation  occurs  immediately  after  absorption,  but  in  the  case  of 
indole  and  skatole  it  is  preceded  by  an  oxidative  process,  converting 
these  substances  into  indoxyl  and  skatoxyl  respectively.  The_jleiaxica- 
tion  process  occurs  in  the  liver,  as  has  been  shown  by  experiments  in 
which  this  organ  was  artificially  perfused  outside  the  body.  They  are 
then  removed  from  the  blood  by  the  kidneys  and  excreted  in  the  urine. 
The  proportion  of  ethereal  sulphates  in  this  fluid  therefore  gives  an  esti- 
mate of  the  extent  of  intestinal  putrefaction  of  protein  (see  page  665). 
The  indican,  being  readily  detectable  by  the  well-known  color  reaction 
of  Jaffe,  serves  as  an  indicator  of  excessive  intestinal  putrefaction. 
The  indole  and  skatole  which  are  not  thus  absorbed  and  detoxicated  are 
excreted  with  the  feces,  to  which  they  give  the  characteristic  odor. 

The  source  of  the  phenol  is  tyrosine  and  that  of  the  indole  is  trypto- 
phane.  The  chemical  processes  involved  are  shown  in  the  following 
equations,  in  which  the  by-products  of  the  reactions  are  in  brackets. 

COH  COH 

HC         CH  HC         CH 


C.OH 

COH 

COH 

HC         CH 

/\ 

HC         CH 

HC         CH 

1          II 

1          II 

1          II 

HC         CH 

HC         CH 

HC         CH 

V 

V 

v 

C 

1        * 

1     —  > 

1 

CH2 

CH2 

CH2 

HC         CH  HC         CH 

\/  \x 

C  CH 
CH3(CO2 


!  (NH.)      |  (C02+H20)     |  (C02) 

CHNH2  CH2  COOH 

I  I 

COOH  COOH 

(tyrosine)  (p-oxyphenyl-  (p-oxyphenyl-  (paracresol)  (phenol) 

propionic  acid)  acetic  acid) 


536 


DIGESTION 


Putrefaction   of  tryptophane   is   probably   preceded   by   deamidization : 

CH 

C C— CH2CH2.COOH 


(NH,) 


CH 
H/V 


I  I 

HC         C         CH 

\X\X 
CH      NH 

(indole-propionic  acid) 
CH 


(C(X  +  H20) 


-CH 


HC 


(+CH3) 


\/  \/ 

CH      NH 


(CO2+H.,0)  HC         C         CH 

\X\X 
CH      NH 
(indole-acetic  acid)  (indole)  (skatole) 

If,  however,  the  carboxylase  bacteria  remove  the  carboxyl  group  be- 
fore the  amino  group  has  been  removed,  highly  toxic  substances  called 
amines  are  produced.  They  are  the  so-called  ptomaines.  From  alanine, 
ethylamine  is  formed;  from  tyrosine,  phenoleTTryTamine ;  from  histidine, 
which  it  will  be  remembered  is  an  important  protein  building-stone, 
histamine,  (imidazyl ethylamine)  and  so  on.  The  process  of  formation  is 
illustrated  in  the  accompanying  formulae: 

1.  CH3.CH(NH2).COOH  —  CO2  -f-  CH3.CH2(NH,) 

Alanine  Ethylamine 

2.  C6H,(OH).CH,.CH(NH2).COOH  —  CO2  -f  C6H4(OH) .CH,.CH2.NH2 

Tyrosine  Phenylethylamine 

3.  CsN,H3.CH2.CH(NH2).COOHz=CO, +  C3H3N2.  CH2.CH2.NH, 

Histidine.  Histamine. 

Similar  substances  are  very  common  in  the  metabolic  products  of 
plants;  for  example,  they  constitute  the  active  principle  of  ergot.  They 
are  also  no  doubt  produced  in  the  tissues  of  mammals,  imidazylethyla- 
mine,  commonly  called  histamine,  being  thus  produced,  as  well  as  the 
closely  related  epinephrine,  which  is  the  active  principle  of  the  supra- 
renal gland  (see  page  773),  and  may  be  described  as  a  methylated  ethyla- 
mine derivative  of  tyrosine. 

Phenylacetic  acid  produced  by  a  similar  process  from  tyrosine  may 
be  excreted  in  the  urine,  where  it  forms  the  mother  substance  of  homo- 
gentisic  acid,  to  which  the  dark  brown  color  of  the  urine  in  alkaptonuria 
is  due. 

The  great  importance  attached  to  these  decomposition  products  of  proteins 
depends  on  the  fact  that  they  have  powerful  pharmacological  actions.  These 
actions  are  developed  very  largely  upon  the  vascular  system;  histamine, 
(pages  253  and  307)  for  example,  produces  marked  vasodilatation  and 
lowers  the  coagulability  of  the  blood,  whereas  other  substances  of  the 
same  class,  like  epinephrine,  have  the  property  of  raising  the  blood  pres- 
sure. In  larger  doses,  serious  nervous  symptoms  and  a  condition  of  pro- 


BACTERIAL    DIGESTION    IN    THE    INTESTINK  537 

found  collapse  are  produced.  These  observations  have  led  several  inves- 
tigators to  believe  that  the  persistent  occurrence  of  bacterial  fermen- 
tation and  the  absorption  of  the  resulting  decomposition  products  of 
protein  into  the  blood  ultimately  cause  arteriosclerosis  and  the  other  symp- 
toms that  accompany  senescence.  It  is  difficult  at  the  present  time  to 
knoAv  how  much  of  this  one  ought  to  believe,  although  it  can  not  be 
doubted  that  putrefaction  has  an  unfavorable  action  on  the  arteries, 
and  that  an  excessive  degree  of  it  causes  the  symptoms  of  ptomaine 
poisoning. 

If  the  ptomaines  have  formed  in  the  food  before  it  is  eaten,  the  symp- 
toms develop  in  from  one^to'five  hours  after  the  meal,  but  if  the  decomposi- 
tion occurs  in  the  intestine  on  account  of  bacteria  that  are  taken  at  the  same 
time  as  the  food,  the  ptomaines  may  not  have  developed  sufficiently  to 
cause  symptoms  until  from  twelve  to  forty-eight  hours ;  sometimes,  how- 
ever, they  develop  in  an  hour  or  so.  Prominent  among  the  symptoms  is 
usuallj_jli4rrhea,  which  develops  for  the  purpose  of  getting  rid  of  the 
offending  bacteria  and  ptomaines. 

Actual  infection  of  food  with  bacteria  of  the  paratyphoid-enteritidis 
type  is  much  more  common  than  poisoning  by  substances  (ptomaines)  that 
have  been  generated  in  food  before  it  is  taken  (Jordan27).  Meat,  milk 
and  other  protein  foods  are  usually  the  carriers  of  the  bacilli,  and  in  most 
of  the  accurately  recorded  cases  the  meat  or  milk  was  found  to  be 
derived  from  animals  suffering  from  enteritis  or  some  other  infection. 
Sometimes,  however,  perfectly  good  food  may  become  infected  by 
handling.  Although  the  symptoms  are  usually  acute,  they  may  closely 
simulate  those  of  typhoid  fever,  and  the  effects  of  the  attack  may  linger 
for  weeks  or  months. 

BOTULISM 

The  commonest  type  of  poisoning  by  substances  actually  present  in  the 
food  is  that  known  as  botulism.  In  this  the  gastrointestinal  symptoms,  as  a 
rule  are  not  pronounced, — indeed,  paralysis  of  the  intestinal  tract  with  con- 
stipation is  the  rule, — but  those  affecting  the  nervous  system,  dizziness, 
diplopia  and  other  visual  disturbances,  with  difficulty  in  swallowing, 
are  very  prominent.  The  temperature  is  usually  normal;  the  pulse  some- 
times slowed.  In  practically  all  of  the  reported  cases,  the  source  of  infec- 
tion has  been  food  which  after  having  been  subjected  to  some  preliminary 
treatment,  such  as  smoj^nj^jrickling,  or  canning,  had  been  allowed  to  stand 
for  some  time  and  then  eaten  without  cooking.  The  Bacillus  botulinus, 
which  is  responsible  for  the  production  of  the  poisons  or  toxins,  is  a 
strict  anaerobe  and  is  readily  destroyed  by  cooking,  as  are  also  the 
poisons.  Antitoxins  are  formed  by  snblethal  injections.  Another  but 


538  DIGESTION 

now  very  rare  example  of  poisoning  by  products  formed  in  food  is 
that  caused  by  "ergotoxin." 

The  treatment  in  such  cases  is  to  encourage  diarrhea  by  giving  pur- 
gatives. If  the  intoxication  is  of  a  more  chronic  character,  the  symptoms 
are  vague,  consisting  of  drowsiness,  lassitude,  headache,  and  general  de- 
pression. The  treatment  here  also  is  to  clear  out  the  intestines  by  a 
good  purge.  There  can  be  little  doubt  that  many  of  the  unhealthy  condi- 
tions of  the  skin  leading  to  the  formation  of  pimples,  acne,  and  boils, 
are  also  caused  by  chronic  intoxication  with  protein  decomposition  prod- 
ucts. Again,  purgation  is  the  proper  treatment. 

It  is  unnecessary  in  a  work  of  this  character  to  go  further  into  these 
highly  important  questions.  It  is  probable,  however,  that  the  importance 
of  the  relationship  of  excessive  protein  putrefaction  in  the  intestine  to 
many  of  the  so-called  minor  diseases  cannot  be  overemphasized.  On  the 
other  hand,  we  must  be  careful  not  to  attribute  every  sort  of  chronic 
condition  to  this  putrefaction.  Toxemia  is  often  a  shibboleth  of  the 
profession.  When  a  chronic  disease  cannot  be  diagnosed,  it  is  put  down 
as  a  toxemia.  This,  however,  is  not  medical  science — it  is  medical  shirk- 
ing. It  is  certainly  unsafe  at  the  present  time  to  conclude  that  the 
ordinary  symptoms  of  senescence,  such  as  hard  arteries  or  increased  blood 
pressure,  are  invariably  to  be  attributed  to  this  cause.  It  will  be  re- 
membered that  Metchnikoff  is  largely  responsible  for  such  a  view,  and 
also  that  he  suggested,  as  the  surest  way  to  ward  off  the  chance  of  such 
intoxication,  the  taking  of  buttermilk,  which  would  supply  bacteria 
through  whose  growth  in  the  intestine  the  protein-destroying  bacteria 
would  not  be  able  to  thrive.  It  is  probable  that  the  same  result  could  be 
attained  in  patients  showing  undoubted  signs  of  suffering  from  intestinal 
putrefaction  by  a  change  in  diet  in  the  direction  of  giving  more  carbo- 
hydrate, for,  as  we  have  seen,  if  there  is  a  plentiful  supply  of  this  food- 
stuff in  the  small  intestine,  the  bacteria  do  not  tend  to  attack  the  protein. 

Before  leaving  this  subject  it  is  interesting  to  consider  for  a  moment 
the  cause  of  the  severe  symptoms  that  follow  intestinal  obstruction. 
This  question  has  recently  been  diligently  investigated  by  Whipple,28  who 
found  that  the  nonprotein  nitrogen  of  blood  (page  641)  becomes  greatly 
increased  in  intestinal  obstruction.  The  cause  for  this  increase  in  non- 
protein  nitrogen  is  found  to  be  an  excessive  breakdown  of  tissue  protein 
caused  by  the  absorption  into  the  blood  of  a  proteose.  When  this  pro- 
teose  isolated  from  obstructed  loops  of  intestine  was  injected  into  fast- 
ing dogs,  profound  symptoms  of  depression  were  produced,  followed,  in 
cases  in  which  the  dose  was  sublethal,  by  recovery  in  from  twenty-four 
to  forty-eight  hours.  Along  with  these  symptoms  the  nitrogen  elimina- 
tion by  the  urine  increased  by  100  per  cent.  A  very  interesting  fact  is 


BACTERIAL    DIGESTION    IN    THE    INTESTINE  539 

that  animals  can  be  rendered  immune  to  this  proteose  by  progressively 
increasing  periodic  administration.  When  they  are  thus  immunized, 
the  toxic  symptoms  do  not  follow  upon  its  injection,  nor  are  the  symp- 
toms produced  by  artificially  creating  an  intestinal  obstruction.  Con- 
versely, when  a  chronic  toxic  condition  is  kept  up  by  a  partial  obstruc- 
tion, such  as  that  produced  by  making  a  gastrojejunal  fistula  and  occlud- 
ing the  duodenum,  the  animals  are  less  susceptible  than  normal  ones  to 
proteose  injection. 

We  have  here  and  there  incidentally  referred  to  the  reaction  of  various 
parts  of  the  gastrointestinal  contents,  but  we  would  call  attention  once 
again  to  this  important  subject,  especially  since  many  points  of  uncer- 
tainty have  recently  been  cleared  up  by  the  accurate  observations  of 
Long  and  Fenger,29  who  used  the  electrometric  method  for  measuring 
the  hydrogen-ion  concentration.  The  contents  of  the  duodenum  removed 
by  means  of  the  Eehfuss  tube  in  man  showed  a  reaction  varying  from  dis- 
tinctly acid  to  slightly  acid,  depending  upon  the  proximity  of  the  tube 
to  the  pylorus  or  papilla,  this  position  being  determined  by  x-ray  exam- 
ination. The  slight  degree  of  alkalinity  is  surprising.  Lower  down  in 
the  duodenum  the  reaction  was  as  frequently  acid  as  alkaline,  the  de- 
gree of  acidity,  however,  being  so  slight  as  to  favor  rather  than  retard 
the  digestive  powers  of  the  pancreatic  juice. 

To  determine  the  reaction  lower  down,  the  observations  were  made  on 
recently  slaughtered  animals  (pigs,  calves,  and  lambs),  the  small  intes- 
tine being  tied  off  in  loops  of  the  upper,  middle,  and  lower  thirds.  The 
contents  of  the  last  loop  were  often  alkaline,  but  might  be  more  acid  even 
than  those  of  the  first,  which  were  usually  faintly  of  this  reaction.  Con- 
siderable variations  were,  however,  the  rule.  The  mixed  intestinal  con- 
tents of  a  recently  fed  dog,  removed  immediately  after  death,  gave 
PH  =  6.79 ;  i.  e.,  very  faintly  acid. 

DIGESTION  REFERENCES 
(Monographs) 

iPavlov,  J.  P.:     The  Work  of  the  Digestive  Glands.     Trans,  by  Sir  W.  H.   Thomp- 
son, London,  Griffin,  ed.  2,  1910. 

2Starling,  E.  H. :     Recent  Advances  in  the  Physiology  of  Digestion,  W.  T.  Keene  & 
Co.,  Chicago,  1907. 

sCannon,  W.  B.:     The  Mechanical  Factors  of  Digestion,  Internat.  Med.  Monographs, 
London,  Ed.  Arnold,  1911. 

^Carlson,  A.  J.:     The  Control  of  Hunger  in  Health  and  Disease,  Univ.  of  Chicago 
Press,  1917. 

sTodd,  T.  Wingate:     The  Clinical  Anatomy  of  the  Gastrointestinal  Tract,  Manches- 
ter, Univ.  Press,  1915. 

eMacallum,  A.  B.:     Ergeb.  der  Physiol.,  xi,  598-657. 

'Cannon,  W.  B.,  and  Cattell,  McKeen:     Am.  Jour.  Physiol.,  1916,  xli,  39. 
E.:     Proc.  Am.  Physiol.  Soc.,  Am.  Jour.  Physiol.,  1918,  xlv,  559. 


540 


DIGESTION 


,  H.  H.,  and  Laidlaw,  P.  F. :     Proc.  Phys.  Soc.,  Jour.  Physiol.,  1912,  xliv,  12  and 

13. 
ioBabkin,  B.  P.,  Bubaschkin,  W.  J.,  and  Ssawitsch,  W.  W. :     Arch,  f .  mikr.  Anat.,  1909, 

Ixxiv,  68. 

"Miller,  F.  E.:     Quart.  Jour.  Exper.  Physiol.,  1913,  vi,  57. 
isKeeton,  E.  W.,  and  Koch,  F.  C. :     Am.  Jour.  Physiol.,  1915,  xxxvii,  481 ;  also  Popiel- 

ski,  L.:     Arch.  f.d.  ges.  Physiol.,  1901,  Ixxxvi,  215. 
isEdkins,  J.  S.:     Jour.  Physiol.,  1906,  xxxiv,  133-144. 
"Meltzer,  S.  J. :     Am.  Jour.  Physiol.,  1899,  ii,  266. 
ic-Cannon,  W.  B.:     Am.  Jour.  Physiol.,  1898,  i,  359. 
isGrey,  E.  G.:     Am.  Jour.  Physiol.,  1917,  xlv,  272. 
^Carlson,  A.  J.:     Am.  Jour.  Physiol.,  1917,  xlv,  81. 

isGinsburg,  Tumpowsky,  and  Hamburger:     Jour.    Am.  Med.  Assn.,  1916,  Ixviii,  990. 
^Cannon,  W.  B.,  Blake,  J.  B. :     Ann.  Surg.,  1905,  xli,  686,  Cf .  No.  3. 
soAlvarez,  W.  C.:     Am.  Jour.  Physiol.,  1918,  xlvi,  238. 
2iCannon,  W.  B.:     Proc.  Eoy.  Soc.,  1918,  xc,  B,  283. 

22Macallum,  A.  B.:     See  Fitzgerald  M.  P.:     Proc.  Eoy.  Soc.,  Ixxxiii,  B,  56. 
ssHarvey,  B.  C.  H.,  Bensley,  E.  E.:     Biol.  Bull.  Woods  Hole,  1912,  xxiii,  225. 
24Long,  J.  H.,  et  al.:     Jour.  Am.  Chem.  Soc.,  1917,  xxxix,  162  and  1493;   also  ibid., 

1916,  xxxviii,  38. 

25Whipple,  C.  H.,  Hooper,  C.  W.:     Am.  Jour.  Physiol.,  1916,  xl,  332  and  349;   ibid., 

1917,  xlii,  257  and  264;  Hoope;  ibid,  p.  280. 
26Meltzer,  S.  J.:     Am.  Jour.  Med.  Sc.,  1917,  cliii,  469. 
27jordan,  E.  V.:     Food  Poisoning,  Univ.  Chicago  Press,  1917. 

28Whipple,  G.  H.,  Cooke,  J.  V.,  and  Stearns,  T.:     Jour.  Exper.  Med.,  1917,  xxv,  479. 

Also  Whipple,  G.  H.,  Stone,  and  Bernheim:     Ibid.,  1913,  xvii,  286  and  307. 
29Long,  J.  H.,  and  Fenger,  F. :     Jour.  Am.  Chem.  Soc.,  1917,  xxxix,  1278. 
soCole,  L.   G.:     Jour.  Am.  Med.  Assn.,  1912,  lix,  1947.     Ibid.,  1913,  Ixi,  762;  Arch. 

Eoentgen  Eay,  December,  1911,  April,  1912,  Am.  Jour.  Physiol.,  1917,  xlii,  61S. 
-iLuckhardt,  A.  B.,  Phillips,  H.  T.,  and  Carlson,  A.  J.:     Am.  Jour.  Physiol.,  1919, 

1,  57. 

«2Wheelon,  H.,  and  Thomas,  J.  E.:     Jour.  Lab.  &  Clin.  Med.,  1920,  vi,  124. 
asWheelon,  H.,  and  Thomas,  J.  E.:     Am.  Jour.  Physiol.,  1922,  lix,  72. 
a*McClure,  C.  W.,  Eeynolds,  L.,  and  Swartz,  C.  O.:     Arch.  Int.  Med.,  1920,  xxvi,  410. 


PART  VI 
THE  EXCRETION  OF  URINE 

CHAPTER  LX 

THE  EXCRETION  OF  URINE 
(Partly  contributed  by  R.  G.  PEARCE) 

It  will  be  advisable  to  introduce  the  subject  by  a  brief  review  of  the 
essential  structural  features  of  the  kidney,  in  so  far  as  they  apply  to 
the  excretory  function  of  the  orj^m. 

STRUCTURE  OF  THE  KIDNEY 

The  kidney  is  mainly  derived  from  the  surface  of  the  celom,  and  is  a 
mesodermal  structure.  In  this  respect  it  differs  from  ordinary  secreting 
glands,  which  are  endodermal  in  origin.  Just  as  it  is  more  or  less 
unique  in  its  development  as  a  gland,  it  is  also  unique  in  its  method 
of  functioning.  The  physiological  theories  of  the  mechanism  of  urinarj^ 
secretion  are  closely  related  to  the  highly  characteristic  structure  of  the 
kidney.  For  this  reason  a  ftrief  survey  of  the  structure  of  the  different 
parts  of  the  uriniferous  tubules  and  the  epithelial  cells  with  which  these 
are  lined,  is  advisable. 

The  uriniferous  tubule,  which  is  the  secreting  unit  of  the  kidney, 
takes  its  origin  in  the  capsule  of  Bowman,  which  may  be  likened  to  a 
hollow  sphere  of  very  delicate  epithelium,  one  side  of  which  is 
invaginated  by  a  very  much  convoluted  capillary  mass,  the  glomerulus. 
The  capsule  opens  up  by  a  narrow  twisted  neck  into  a  tubule,  which  is 
rather  tortuous  in  the  cortex  (the  proximal  convoluted  tubule),  but  soon 
takes  a  sharp  descending  course  in  the  medulla  towards  the  pelvis  of  the 
kidney,  and  doubles  back  (loop  of  Henle)  in  a  straight  course  again  to 
the  cortex,  where  it  again  makes  a  twisted  course  (the  distal  convoluted 
tubule),  and  terminates  in  a  collecting  tubule,  which,  uniting  with  other 
tubules,  collects  the  urine  and  conducts  it  to  the  pelvis  of  the  kidney  (Fig. 
170).  The  capsule  is  lined  with  very  thin  epithelial  cells,  especially  over 
the  capillaries  comprising  the  glomerulus.  The  proximal  and  distal  tubules 

541 


542 


THE   EXCRETION    OF    URINE 


contain  epithelium  showing  a  prominent  striation.  These  striations  are 
rows  of  granules,  which  run  towards  the  lumen  of  the  cell,  becoming 
less  distinct  as  they  approach  it  and  apparently  standing  in  close  rela- 
tionship to  the  rather  prominent  internal  (lumen)  striated  border  of 
the  cell.  Some  histologists  believe  that  the  striations  at  the  border  are 


Fig.    170. — Diagram    of   the    liriniferous    tubules    (C) ,    the    arteries    (A),    and    the    veins    (5)    of    the 

kidney. 

really  cilia,  which  are  described  as  being  immobile.  The  cilia  are  shown 
in  Fig.  171.  The  descending  limb  of  Henle's  loop  is  lined  with  a  thin 
pavement  epithelium  with  large  bulging  nuclei.  The  distal  convoluted 
tubule  is  lined  with  cells  not  unlike  those  found  in  the  proximal  tubules, 
except  that  the  inner  border  is  not  striated.  The  diameter  of  the  lumen 


THE   EXCRETION    OF    URINE 


543 


of  the  capsule  varies  with  the  activity  of  the  kidney,  as  is  shown  in 
the  following  figures  given  by  Brodie  and  Mackenzie.1 


RESTING 
KIDNEY 
MM. 

KIDNEY  DURING 
DIURESIS 
MM. 

Mean  diameter  of  capsule 
"           "         "   glomerulus 
'•'           tl         tl  space  of  capsule 
Lumen  of  proximal  convoluted  tubule 
"       "    distal             "                 " 

93.4 
90.4 
3.0 
0.0 

7.2 

123.8 

100.0 
23.8 
17.6 
20.6 

The  urinary  tubule  has jLj-emarl^able  blood  supply.  The  renal  arteries 
arise  directly  from  the  abdominal  aorta  and  are  very  short.  They  run 
through  the  medulla  to  the  cortex,  and  join  with  neighboring  arteries  to 


B. 


Fig.   171. — Cross  sections  of  convoluted  tubules  from  kidney  of  rat.     A,   during  slight  secretion;  B, 
during  maximal   secretion.      (From   Sauer.) 

form  arches  from  which  proceed  branches,  that  radiate  into  the  cortex 
and  give  off  smaller  branches  each  of  which  very  shortly  breaks  up  into  a 
small  capillary  tuft, — the  glomerulus, — which  lies  in  the  invaginated  sphere 
of  Bowman's  capsule.  By  concentration  of  a  beam  of  light  on  the  kidney 
of  the  living  frog  Richards  and  his  co-workers  have  succeeded  in  rendering 
the  capillary  blood  flow  in  the  glomeruli  readily  visible  under  the 
microscope.  The  capillaries  collect  into  an  efferent  vessel,  which  ap- 
pears to  be  smaller  than  the  efferent  artery,  and  this  vessel  in  emerging 
from  the  capsule  again  breaks  up  to  form  a  capillary  network  about  the  con- 
voluted tubules,  forming  their  sole  blood  supply.  These  capillaries 


544  THE    EXCRETION    OF    URINE 

coalesce  to  form  the  renal  vein.    The  blood  of  the  kidney  must,  accord- 
ingly, pass  through  two  sets  of  capillaries. 

The  kidney  is  richly  supplied  with  nerves,  which  are  for  the  most  part 
derived  from  the  celiac  ganglion  and  are  in  connection  with  the  splanch- 
nic and  the  vagus.  Other  branches  from  plexuses  in  the  region  of  the 
suprarenal  body  and  the  aorta  join  with  those  coming  from  the  celiac 
ganglion  to  form  what  is  known  as  the  renal  plexus,  which  is  arranged 
in  a  network  along  the  blood  vessels  and  on  the  walls  of  the  pelvis  of 
the  kidney.  These  fibers  are  distributed  to  the  very  smallest  blood  ves- 
sels, and  nerve  fibers  have  been  observed  among  the  cells  of  the  tubules. 

THE  MECHANISM  OF  THE  EXCRETION  OF  THE  URINE 

The  great  number  as  well  as  the  variety  of  substances  which  are  pres- 
ent in  both  the  blood  and  the  urine  makes  it  appear  improbable  that 
urine  excretion  is  dependent  upon  chemical  combinations  within  the 
renal  cells,  and  leads  us  to  seek  a  physicochemical  mechanism  to  explain 
the  phenomenon.  Can  we  discover  the  processes  by  which  the  kidney 
manufactures  a  highly  concentrated  solution  of  salts  from  a  very  dilute 
solution  of  the  same  salts  in  the  blood  plasma  ?  The  problem  is  compli- 
cated by  the  fact  that  the  ratios  existing  between  the  concentration  of 
each  urinary  salt  in  the  urine  and  the  concentration  of  the  same  salt 
in  the  blood  are  different.  In  other  words,  the  urine  is  not  merely 
concentrated  blood  plasma  freed  from  protein. 

The  passage  of  water  and  salts  through  the  capillary  wall  and  through 
the  basement  membrane  surrounding  the  renal  cell  probably  takes  place 
by  simple  diffusion.  If  it  were  otherwise,  an  expenditure  of  energy 
would  be  required,  and  it  is  difficult  to  understand  how  a  basement 
membrane  could  bring  about  energy  changes.  Any  substance  to  which 
the  cell  membrane  is  permeable  will  diffuse  into  the  cell  until  an  equi- 
librium is  established  between  its  concentration  within  the  cell  and 
that  of  the  lymph  or  blood  plasma.  A  nondiffusible  substance  will  not 
enter  the  cell  because  it  can  not  pass  through  the  cell  membrane,  and 
if  it  exerts  an  osmotic  pressure,  it  will  also  tend  to  keep  the  water  in 
which  it  is  dissolved  from  entering.  If  water  does  pass  into  the  cell 
under  these  conditions,  it  is  due  to  the  expenditure  of  energy  opposed 
to  and  greater  than  that  which  is  offered  by  the  osmotic  pressure  of  the 
nondiffusible  substances.  Possible  sources  for  such  energy  are  the  pres- 
sure of  the  blood  in  the  renal  capillaries,  which  would  exert  a  force  op- 
posite to  that  of  its  osmotic  pressure,  and  the  presence  within  the  cell  of 
a  concentration  of  salts  greater  than  is  present  in  the  blood,  and  able  to 
exercise  a  sufficient  osmotic  force  to  draw  fluid  into  the  cell  against  the 
osmotic  force  of  the  nondiffusible  salts.  The  passage  of  the  urinary 


THE   EXCRETION   OF   URINE  545 

constituents  through  the  cell  might  also  be  due  to  simple  diffusion,  the 
substances  passing  through  the  cell  to  be  extruded  on  the  other  side  in 
the  same  concentration  as  in  the  blood.  In  this  case,  the  renal  cells 
would  act  merely  as  a  filter,  the  urine  having  the  same  concentration 
of  each  urinary  salt  as  is  present  in  the  blood. 

A  comparison  of  the  concentrations  of  the  urinary  salts  in  the  urine 
and  the  blood  shows,  however,  that  the  urine  is  not  merely  a  deprotein- 
ized  blood  plasma,  so  that  other  factors  must  be  sought  to  explain  the 
excretion.  Since  the  concentration  of  the  urine  requires  the  expenditure 
of  much  more  energy  than  is  provided  by  the  known  physical  factors, 
it  is  generally  accepted  that  the  renal  cell  in  some  manner  supplies  this 
energy  by  its  metabolic  activity.  It  is  impossible  at  present  even  to 
surmise  the  nature  of  the  process.  Two  possibilities  may  be  considered. 
One  is  that  the  urine  is  a  filtrate  of  the  blood  which  has  passed  through 
a  portion  of  the  renal  epithelium  into  the  tubules  as  a  very  dilute  fluid, 
resembling  the  blood  plasma  minus  its  colloidal  substances,  and  that 
this  dilute  fluid  is  concentrated  by  the  reabsorption  of  fluid  and  of  salts 
by  other  cells  of  the  kidney,  and  again  replaced  in  the  blood  stream.  The 
other  is  that  the  salts  and  fluid  are  each  actively  and  individually  ex- 
creted by  the  kidney.  Whichever  condition  is  the  true  one,  the  fact 
remains  that  the  change  in  the  concentration  entails  the  expenditure 
of  a  great  amount  of  energy  on  the  part  of  the  renal  cells. 

The  energy  which  the  kidney  must  use  in  the  actual  work  of  concen- 
trating the  urine  from  the  fluid  of  the  blood  plasma  can  not  be  com- 
puted from  a  comparison  of  the  concentration  of  the  urinary  salts  as  a 
whole  in  both  the  blood  and  the  urine.  Each  constituent  must  be  con- 
sidered apart.  We  can  not,  for  example,  determine  the  molecular  con- 
centration of  the  blood  plasma  and  the  urine  (by  measuring  A)  (page 
10)  and  estimate  the  work  which  is  expended  in  producing  the  con- 
centration from  the  observed  difference.  On  the  basis  of  such  comparisons, 
however,  it  is  said  that  the  excretion  of  100  c.c.  of  urine  requires  at  the 
minimum  500  kilogrammeters  of  work  (Cushny2).  Even  this  conserva- 
tive estimate  may  be  wrong,  for  it  does  not  take  into  consideration  the 
possibility  that  the  excretion  of  water  by  the  kidney  requires  energy 
expenditure  on  the  part  of  the  renal  cells. 

Theories  of  Renal  Function 

For  many  years  two  rival  hypotheses  have  dominated  the  teaching  of 
the  mechanism  of  renal  function.  Bowman  and  Heidenhain  postulated 
that  the  constituents  of  the  urine  are  secreted  by  the  vital  activity  of 
the  epithelium  of  the  capsule  and  the  tubules.  The  glomerular  capsule 
secretes  the  water  and  the  easily  diffusible  salts  in  a  dilute  solution,  and 


T)46  THE    KXCRKT1OX    OF    l-KLN'K 

the  uriniferous  tubules  add  to  this  fluid  the  various  organic  and  inor- 
ganic salts  to  bring  the  urine  to  the  necessary  concentration.  This 
theory  has  been  termed  the  -vital  theory.  Ludwig,  on  the  other  hand, 
advanced  what  is  termed  the  physical  theory,  which  holds  that  the 
glomerulus  and  capsule  act  simply  as  a  filter,  which  allows  the  fluid 
of  the  blood  plasma  to  pass  through  in  a  very  dilute  solution  and  in 
large  amounts.  This  fluid  is  concentrated  by  physicochemical  processes 
on  its  passage  along  the  urinary  tubules  to  the  pelvis  of  the  kidney. 

Both  of  these  theories  are  inadequate  and  fall  to  explain  the  phenom- 
ena which  research  has  shown  to  occur  in  the  kidney,  but  they  have 
served  to  develop  what  Cushny  terms  a  modern  theory  of  urinary 
excretion. 

The  Modern  Theory  of  Urine  Formation. — This  theory  accepts  the 
general  scheme  offiltration  and  reabsorption  of  Ludwig,  but  pays  due 
respect  to  the  fact  that  the  known  physical  forces  are  not  adequate 
to  explain  the  reabsorption  which  must  occur  in  the  tubules.  It  therefore 
supplements  Ludwig 's  theory  by  assuming  a  vital  activity  on  the  nart 
of  the  epithelium  of  the  tubules  in  reabsorbing  fluids  and  salts  from 
the  dilute  filtrate  coming  from  the  glomerulus  and  capsule.  A  large 
amount  of  plasma  fluid  is  filtered  through  the  Avails  of  the  glomerular 
vessels.  This  fluid  has  the  same  concentration  of  the  salts  to  which  the 
capsule  is  permeable  as  does  the  blood  plasma,  but  it  is  free  of  the  col- 
loidal substances  normally  present  in  the  plasma.  The  blood  leaving  the 
glomerulus  is  therefore  a  somewhat  concentrated  solution  of  plasma  col- 
loids, and  must  have  returned  to  it  the  proper  amount  of  water  and 
salts  to  make  it  an  optimum  fluid  for  the  body  cells.  This  is  accomplished 
by  active  absorption  from  the  glomerular  filtrate.  The  salts  that  are  of 
no  use  to  the  body  are  not  reabsorbed  and  therefore  appear  in  highly 
concentrated  form  in  the  urine.  These  salts  are  termed  nonthreshold  sub- 
stances, and  since  their  presence  in  the  plasma  is  unnecessary,  they  con- 
tinue to  be  excreted  as  long  as  they  are  present  in  any  concentration  in 
the  blood.  The  salts  that  are  necessary  for  the  plasma  are  termed 
threshold  substances,  and  are  reabsorbed  until  they  are  again  present  in 
the  plasma  in  optimal  strength.  For  example,  urea  continues  to  be  ex- 
creted as  long  as  any  is  present  in  the  blood,  while  glucose  is  almost  com- 
pletely reabsorbed  so  long  as  its  concentration  remains  under  a  more  or  less 
fixed  level. 

The  volume  of  deproteinizcd  blood  plasma  which  the  capsule  would  require  to  filter 
oft'  from  the  blood  in  order  to  furnish  the  amount  of  the  various  salts  excreted  each 
day,  and  the  volume  of  water  which  would  have  to  be  absorbed  by  the  epithelium  of 
the  tubules  to  account  for  the  concentration  in  which  the  salts  are  found  in  the  urine, 
has  been  calculated  as  follows:  in  order  to  produce  20  grams  of  urea  in  1000  c.c.  of 
urine,  62  liters  of  the  water  of  the  blood-plasma,  containing  0.033  per  cent  of  urea, 


THK    KXCKHT10N    OF    L'KINE  547 

would  have  to  be  filtered  through  the  capsule,  and  (51  liters  of  water  returned  to  the 
blood  from  the  uriniferous  tubules.  This  amount  of  water  would  be  derived  from  67 
liters  of  plasma  (see  table  on  page  551).  Since  the  bloodflow  through  the  kidneys  is 
very  great,  at  least  500  liters  per  day,  only  about  13  per  cent  of  the  fluid  contained  in 
the  blood  passing  through  the  glomerulus  would  pass  by  nitration  through  the  capsule  of 
Bowman.  The  fact  that  such  a  large  amount  of  fluid  would  have  to  be  reabsorbed  from 
the  uriniferous  tubules  is  a  possible  a  priori  criticism  of  the  theory,  but  Cushney  points 
out  that  the  amount  each  tubule  would  have  to  absorb  per  hour  would  be  very  small 
(in  his  experiment  on  a  cat  amounting  to  less  than  0.014  c.c.  per  hour). 

According  to  the  modern  view,  there  are  therefore  two  fundamentally 
different  processes  occurring  in  the  kidney;  filtration  in  the  capsule  and 
selective  reabsorption  in  the  tubules.  It  is  important  to  consider  some 
of  the  evidence  which  is  considered  to  indicate  that  both  of  these  pro- 
cesses occur. 

The  Filtration  Process. — The  filtration  of  the  protein-free  blood  fluid 
through  the  renal  capsule,  like  that  through  any  other  membrane,  depends 
on  several  factors.  (1)  There  must  be  a  difference  in  the  pressure  between 
the  blood  and  the  urinary  filtrate.  In  the  laboratory  the  pressure  used  in 
filtering  is  usually  supplied  by  gravity,  but  in  the  case  of  the  filtration  of 
the  urine  through  the  capsule  the  force  is  furnished  by  the  pressure  of  blood 
in  the  glomerular  vessels.  (2)  The  character  of  the  filter  determines  what 
substances  shall  pass.  The  renal  capsule  is  a  membrane  normally  im- 
pervious to  the  proteins  of  the  blood,  but  pervious  to  the  other  constitu- 
ents. Under  certain  conditions  it  loses  this  character.  (3)  The  char- 
acter of  the  fluid  determines  how  readily  it  will  filter  through  the  mem- 
brane. If  the  fluid  contains  a  substance  which  can  not  pass  through  the 
filter  and  which  exerts  an  osmotic  pressure  in  opposition  to  the  filtering 
force,  the  rate  of  filtration  as  well  as  the  amount  filtered,  will  be  reduced. 

If  the  capsule  acts  as  a  filter  it  should  be  possible  to  alter  the  rate  of 
urine  excretion  by  varying  any  of  the  above  mentioned  factors,  and 
experimentally  this  is  true.  The  factors  can  be  varied  in  several  ways.  If 
the  blood  pressure  is  raised  by  tying  off  several  of  the  branches  of  the  aorta, 
the  urine  is  appreciably  increased,  or  if  the  blood  pressure  is  lowered,  as  can 
be  done  by  cutting  the  spinal  cord  the  amount  of  urine  is  decreased.  In  the 
artificially  perfused  kidney,  the  fluid  exuding  from  the  ureter  increases 
as  the  pressure  of  the  perfusion  fluid  is  raised,  and  decreases  as 
the  pressure  is  decreased,  and  Richards  and  Plant17  have  recently  shown 
that  this  urine  formation  may  run  parallel  with  the  pressure  without 
their  being  any  alteration  in  blood  flow.  This  strongly  supports  the 
view  that  filtration  is  the  function  of  the  glomerulus.  Apparently,  excre- 
tion can  continue  only  as  long  as  the  colloids  of  the  plasma  are  not  notably 
increased,  for,  as  the  osmotic  pressure  due  to  indiffusible  colloids  rises,  the 
pressure  in  the  capillaries  is  no  longer  able  to  overcome  it.  The  same  point 
has  been  shown  by  Starling  and  his  pupils,  who  found  that  the  excretion  of 


548  THE    EXCRETION    OF    URINE 

urine  ceased  when  the  capillary  pressure  in  the  glomerulus  fell  below  that 
exerted  by  the  osmotic  pressure  of  the  blood  proteins,  the  critical  pressure 
being  from  30  to  40  mm.  Hg.  They  also  found  that  dilution  of  the  blood 
with  saline  solution  by  reducing  the  osmotic  pressure  of  the  proteins  in  the 
plasma,  was  accompanied  by  an  increase  in  the  rate  of  excretion;  excre- 
tion in  such  cases  being  maintained  at  a  blood  pressure  below  the  normal 
critical  pressure.  If  the  dilution  of  the  blood  was  made  with  saline  con- 
taining gelatin  or  gum  arabic,  on  the  other  hand,  the  diuretic  effect  was 
greatly  diminished,  and  any  fall  in  the  blood  pressure  was  followed  by  a 
suppression  of  the  urine  (Knowlton9).  These  experiments  evidently 
indicate  that  saline  causes  diuresis  by  diluting  the  plasma  proteins  and 
lowering  their  osmotic  pressure,  since  no  diuresis  occurs  when  the  os- 
motic pressure  of  the  blood  is  maintained  by  the  addition  of  colloids 
having  an  osmotic  pressure.  The  significance  of  these  facts,  in  connec- 
tion with  the  raising  of  lowered  blood  pressure  after  hemorrhage,  has 
already  been  alluded  to  (page  140). 

The  view  that  saline  diuresis  is  caused  by  physical  changes  alone 
is  confirmed  by  the  experiments  of  Barcroft  and  Straub,10  who  showed 
that  the  oxygen  consumption  is  often  not  appreciably  raised  during  the 
diuresis  which  occurs  after  the  injection  of  saline.  If  the  diuresis  were 
due  to  an  actual  increase  in  the  work  of  the  kidney,  the  oxygen  con- 
sumption would  have  been  increased. 

In  the  frog,  the  glomerulus  and  the  tubules  are  supplied  with  blood 
by  the  renal  artery,  as  is  the  case  in  the  mammal,  but  the  tubules 
are  also  supplied  with  some  of  the  blood  coming  from  the  lower  ex- 
tremities and  the  trunk  through  a  vessel  which  has  no  counterpart 
in  the  mammal — the  renal  portal  vein.  The  blood,  therefore,  which 
is  supplied  to  the  tubule  is  a  mixture  from  the  glomerulus  and  the  renal 
portal  system.  By  ligating  the  renal  vessels  it  is  possible  to  cut  off  the 
blood  supply  of  the  glomerulus  while  leaving  the  tubules  supplied  by  the 
renal  portal  vein.  Normally  the  pressure  in  the  renal  portal  system  is 
not  sufficient  to  force  blood  back  through  the  glomerular  vessels.  Liga- 
tion  of  the  renal  vessels  at  once  results  in  a  suppression  of  the  urine. 

If  the  glomerular  vessels  are  perfused  with  Ringer's  solution  at  a 
pressure  equal  to  that  found  in  the  aorta,  a  considerable  flow  of  fluid 
may  be  secured  from  the  ureters,  but  no  fluid  is  obtained  when  the  renal 
portal  vein  is  perfused  at  a  pressure  equal  to  that  normally  present  in 
this  vein.  Rowntree  and  Geraghty11  found  that  phenolsulphonephthalein 
added  to  the  fluid  perfused  through  the  renal  portal  vein,  did  not 
cause  secretion,  but  when  urea  was  added,  fluid  containing  the  dye  was 
obtained  from  the  ureter.  Unfortunately  the  pressure  employed  in  these 
experiments  may  have  allowed  some  fluid  to  be  forced  backward  into  the 


THE   EXCRETION   OF   URINE 


549 


glomerulus,  so  that  the  results  may  be  due  to  filtration  through  the 
capsule.  Microscopical  examination  of  the  glomeruli  has  revealed  the 
important  fact  that  all  are  not  equally  active  at  the  same  time.  As  judged 
from  the  blood  flow  in  them,  the  glomeruli  would  appear  to  work  in 
relays. 

The  Reabsorption  Process, — It  is  generally  accepted  that  the  proof  that 
the  capsule  acts  as  a  filter  is  fairly  complete.  Unfortunately  such  decisive 
experimental  facts  can  not  be  offered  to  prove  the  assumption  that  the  epi- 
thelium of  the  tubules  reabsorbs  the  excess  of  water  and  salts  which  are  fil- 
tered off  through  the  capsule.  If  the  modern  theory  of  urine  excretion  is  cor- 
rect, the  cells  of  the  tubules  must  not  only  absorb  large  amounts  of  water, 


Renal 
arfery 


Malpighian 
corpuscle 


Renal-portal  vein 


Fig.   1/2. — Diagram  of  blood  supply  of  Malpighian  corpuscle  and  of  convoluted  tubules  in  amphibian 

kidney.      (Redrawn    from    Cushny.) 

but  they  must  also  allow  for  the  reentrance  into  the  blood,  either  completely 
or  partially,  of  certain  salts,  while  they  must  reject  others  entirely. 

We  have  called  attention  above  to  the  fact  that  the  glomerular  filtrate  is 
very  different  from  the  urine  that  is  finally  passed.  The  urine  contains  a 
very  high  percentage  of  small  molecules,  and  the  proportion  in  which  they 
are  present  is  entirely  different  from  that  in  the  blood  plasma  or  in  the 
glomerular  filtrate. 

This  is  shown  in  the  following  table,  in  which  the  figures  in  the  first  two  columns 
represent  the  average  number  of  grams  of  urea,  uric  acid,  chlorine,  and  glucose  in 
100  c.c.  of  protein-free  blood  plasma  and  in  100  c.c.  of  urine.  In  the  third  column  is 
given  the  change  in  concentration  which  must  occur  in  the  kidney. 


550  THE   EXCRETION    OF    URINE 


100  C.C.  PKOTEIN- 

100  C.C.  URINE 

CHANGE  IN 

FREE  BLOOD 

CONTAINS 

CONCENTRATION 

PLASMA  CONTAINS 

IN  THE  KIDNEY 

Urea 

.033 

2. 

60 

Uric  Acid 

.0022 

.05 

22.7 

Chlorine 

.41 

.6 

1.5 

Glucose 

.1 

— 

Among  the  experiments  that  have  been  offered  in  support  of  the  absorption  of  fluid 
and  salts  by  the  tubules,  are  those  in  which  the  pressure  of  the  urine  in  the  tubules  is 
slightly  increased  by  partial  closure  of  the  ureter  (Cushny).  In  these  experiments  the 
ureter  of  one  kidney  is  partly  closed  with  a  clamp  and  the  excretion  obtained  from 
this  kidney  is  compared  with  that  of  the  opposite  normal  kidney.  Considerable  ob- 
struction of  the  ureter  results  in  a  decrease  in  the  amounts  of  water,  chloride  and 
urea  excreted,  but  the  urea  content  is  decreased  relatively  less  than  is  the  chloride 
and  water  content.  These  results  can  be  explained  on  the  basis  that  a  pressure  that 
is  sufficient  to  oppose  the  head  of  pressure  producing  filtration  in  the  giomerulus  will 
reduce  the  amount  of  the  glomerular  filtration,  and  accordingly  the  time  allowed  for 
the  passage  of  this  filtrate  along  the  tubules  is  increased  and  absorption  becomes  more 
complete.  Since  urea  is  probably  not  absorbed  at  all  and  chloride  is,  the  discrepancy 
in  the  effects  on  the  excretion  of  urea  and  chlorine  in  the  partially  obstructed  kidney 
can  be  explained.  When  the  obstruction  of  the  ureter  is  only  slight,  however,  opposite 
results  to  that  just  mentioned  are  obtained  (Brodie  and  Cullis).  This  observation  is 
difficult  to  harmonize  with  the  reabsorption  hypothesis. 

When  very  large  amounts  of  water  are  taken  by  mouth,  it  often  happens  that  the 
urine  excreted  has  a  concentration  of  salts  less  than  that  present  in  the  fluid  of  the 
blood.  Some  investigators  believe  that  such  a  condition  is  possible  only  on  the  as- 
sumption that  water  is  actively  excreted,  but  a  more  plausible  explanation  based  on 
the  modern  theory  is  that  the  water  that  is  absorbed  from  the  alimentary  tract  reaches 
the  kidney  as  a  dilute  saline  solution,  and  is  rapidly  filtered  off  in  a  form  somewhat 
more  dilute  than  the  optimal  solution  which  blood  plasma  must  have  for  the  well-being 
of  the  tissues.  The  tubules  reabsorb  the  amounts  of  water  and  of  substances,  such  as 
chlorides  and  sugar,  that  are  necessary  to  restore  the  plasma  to  the  optimal  concentra- 
tion, but  they  do  not  reabsorb  the  nonthreshold  substances,  such  as  sulphates  and  urea. 

Many  attempts  have  been  made,  by  destroying  the  capsules  or  the 
tubules  by  means  of  poisons  or  by  operation,  to  determine  directly  or 
indirectly  the  question  of  the  function  of  the  tubules.  In  such  experi- 
ments, however,  the  number  of  factors  involved  confuses  the  issue  and 
makes  the  results  practically  valueless  so  far  as  determining  the  normal 
function  of  the  tubules.  Progress  is  however  to  be  expected  in  the 
near  future  since  Richards  and  \Yeani  have  succeeded  in  developing  a 
method  by  which  sufficient  jfiltraU1  can  be  removed  from  the  capsule  of 
Bowman  in  living  frogs,  to  make  inicrocheinical  analyses  possible. 

Most  important  results  supporting  the  reabsorption  hypothesis  have 
already  been  obtained  in  the  case  of  glucose  and  chlorides.  Thus,  when 
glucose  was  injected  subcutaneously  some  appeared  in  the  capsular 
filtrate  but  none  in  the  bladder  urine;  likewise  chloride  was  found  in 
the  filtrate  but  none  in  the  bladder.19 


THE   EXCRETION   OF   URINE 


551 


Other  experimenters  have  attempted  to  show  absorption  in  the  tubules  by  injecting 
diffusible  substances,  such  as  chemicals  and  dyes,  into  the  ureter  under  what  they 
deemed  sufficient  pressure  to  force  the  solution  into  the  tubules,  and  by  an  examination 
of  the  blood  or  the  tissues  to  determine  whether  or  not  the  injected  substances  had  been 
absorbed.  The  results  obtained  by  this  method  are  not  convincing,  probably  chiefly 
because  of  the  difficulty  in  reaching  the  tubules.  Indeed,  it  is  very  questionable 
whether  it  is  possible  to  inject  a  substance  into  the  tubules  from  the  ureter. 

Years  ago  Heidenhain,  the  exponent  of  the  vital  theory  of  excretion,  believed  that 
he  had  demonstrated  the  ability  of  the  renal  cells  to  excrete  dye  substances  injected  in- 
travenously. Since  he  failed  to  find  evidence  of  dye  excretion  in  the  capsule,  but 
found  masses  of  dye  in  the  tubules  and  stained  granules  in  the  cells  of  the  tubules, 
he  concluded  that  the  cells  of  the  tubules  had  the  power  to  excrete  the  dye,  and  from 
analogy  he  believed  that  the  tubules  must  likewise  excrete  the  water  and  the  various 
urinary  salts.  Subsequent  work,  however,  has  failed  to  confirm  his  belief  that  the 
capsule  is  not  concerned  in  the  excretion  of  the  dye,  and  it  is  as  reasonable  to  explain 
the  results  of  the  experiments  with  the  dyes  by  assuming  that  the  masses  of  dye  sub- 
stances found  in  the  tubules  and  in  the  cells  are  due  to  the  reabsorption  of  water  and 
perhaps  of  some  of  the  dye  from  the  dilute  glornerular  filtrate,  as  to  accept  Heiden- 
hain 's  hypothesis. 

Iii  the  following  table  taken  from  Cushny  the  movements  of  the  con- 
stituents of  the  plasma  may  be  followed  through  the  kidney.  The  ulti- 
mate destination  of  each  is  indicated  in  the  enclosures. 


67  LITERS  PLASMA 
CONTAIN 

62  LITERS 
FILTRATE 

61    LITERS 
REABSORBED   FLUID 
CONTAIN 

I    LITER   URINE 
CONTAINS 

PER 
CENT                TOTAL 

CONTAIN 
IN  ALL 

PER 
CENT               TOTAL 

PER 
CENT               TOTAL 

Water 

92               62  1. 

62    1. 

61    1. 

95          950  c.c. 

Colloids 

|  8           5360     gm.| 



—                — 

—              — 

Dextrose 

0.1            67     gm. 

67     gm. 

0.11          67     gm. 

—              — 

Uric  acid 
Sodium 
Potassium 
Chloride 

0.002          1.3 
0.3          200 
0.02          13.3 
0.37        248 

1.3    " 
200      " 
13.3   " 
248      " 

0.0013        0.8    " 
0.32       196       " 
0.019        11.8    " 
0.40        242       " 

0.05      0.05  gm. 
0.35     3.5     " 
0.15     1.5     " 
0.6       6.0     " 

Urea 
Sulphate 

0.03          20 
0.003          1.8 

20      " 
1.8   " 

2.0       2.0     " 
0.18      1.8     " 

(From  Cushny.2) 

It  will  be  noted  that  the  dextrose  alone  is  completely  absorbed,  and 
that  the  urea  and  the  sulphate  are  not  absorbed  at  all  from  the  glom- 
erular  filtrate.  The  other  salts  are  partly  absorbed. 

Although  at  present  it  is  probably  most  useful  for  practical  purposes 
to  accept  Cushny 's  hypothesis,  it  should  be  remembered  that  we  are  far 
from  being  in  a  position  to  explain  all  the  known  facts  of  the  renal 
function  by  means  of  it.  There  can  be  no  doubt  that  a  process  that  is 
closely  analogous  if  not  identical  with  filtration  plays  an  essential  part 
in  the  formation  of  urine,  and  that  it  is  assisted  by  a  more  obscure 
process  depending  on  a  selective  action  of  the  renal  cells.  But  whether 
this  latter  process  is  essentially  one  of  reabsorption  of  certain  molecules 


552  THE   EXCRETION    OF    URINE 

from  tubule  to  blood,  or  one  of  secretion  from  blood  to  tubule  is  problem- 
atical. As  G-.  N.  Stewart  points  out,  the  reabsorption  hypothesis  is  no 
simpler  to  comprehend  than  the  older  hypothesis  of  Bowman  and  Heiden- 
hain,  for  according  to  both  views  the  renal  cells  are  assumed  to  exercise 
discriminative  powers. 

DIURETICS 

As  already  mentioned,  Barcroft  and  Straub10  have  shown  that  the 
diuresis  which  results  from  the  injection  of  saline  into  the  blood  is  not 
accompanied  by  any  increase  in  the  oxygen  consumption  of  the  kidney. 
This  observation,  coupled  with  the  fact  that  the  total  amount  of  chloride, 
urea,  and  sulphate  which  is  excreted  during  saline  diuresis  is  greater  than 
under  normal  conditions,  indicates  that  the  excretion  of  these  salts  is 
not  due  to  any  active  secretory  process  in  the  kidney,  but  rather  to  a 
greater  filtration  because  of  increased  heart  action. 

The  diuresis  which  is  caused  by  adding  urea  or  sodium  sulphate  to  the 
blood,  on  the  other  hand,  is  accompanied  by  an  increase  in  the  oxygen 
consumption  of  the  kidney.  Since  there  is  no  increase  in  oxygen  con- 
sumption accompanying  the  increased  excretion  of  practically  the  same 
salts  during  saline  diuresis,  the  greater  oxygen  consumption  must  be 
due  to  more  work  being  done  in  separating  the  water  from  the  sulphate 
etc.,  to  return  it  to  the  blood. 

The  diuresis  resulting  from  certain  doses  of  adrenalin  and  from  pituitrin 
is  apparently  due  to  constriction  of  the  vasa  efferentia  for,  in  the  isolated 
kidney  perfused  outside  the  body,  the  addition  of  these  drugs  causes 
the  volume  of  theor^a^jtoJnjsrease,  the  perfusion  pressure  to  rise  and 
diuresis  to  occur?15"" 

According  to  the  modern  theory  the  polyuria  in  diabetes  is  caused 
by  the  excessive  amount  of  water  taken  and  by  the  inability  of  the 
kidney  to  concentrate  the  urine  (by  reabsorption)  against  the  osmotic  pres- 
sure offered  by  the  concentrated  sugar  solution  in  the  tubules.  The  diuresis 
following  the  injection  of  sugar  is  therefore  of  the  same  type  as  that  pro- 
duced by  sulphate  and  urea.  The  diuretic  action  of  the  digitalis  group  is 
dependent  upon  its  influence  on  the  circulatory  system.  If  the  circulation 
is  already  sufficient,  digitalis  does  not  cause  diuresis.  The  cause  of  the 
diuresis  produced  by  pituitary  extract  is  not  definitely  known.  It  may  be 
owing  in  part  to  its  action  on  the  circulation  and  in  part  to  a  direct 
action  on  the  kidney  (see  page  811). 

ALBUMINURIA 

The  plasma  proteins  ordinarily  do  not  obtain  entrance  into  the  tubules 
of  the  kidney.  In  disease  such  as  acute  nephritis  and  cardiac  fail- 
ure, the  plasma  colloids  are  filtered  off  through  the  capsule,  proba- 


THE   EXCRETION    OF    URINE 


553 


bly  because  of  some  change  that  has  occurred  in  the  permeability 
of  its  membrane  due  to  inflammation  or  asphyxia.  In  these  cases  the 
urine  is  usually  reduced  in  amount.  Probably  there  is  no  purely  glom- 
erular  or  tubular  type  of  nephritis,  both  structures  sharing  in  the  dis- 
ability. When  foreign  proteins  such  as  egg  albumin  gain  entry  to  the 
blood,  they  appear  in  the  urine.  This  is  also  the  case  when  hemoglobin 
is  liberated  from  the  blood  corpuscles.  In  both  cases  masses  of  the  ex- 
creted protein  in  the  capsule  may  be  detected  by  microscopical  examina- 
tion when  the  kidney  is  excised  and  hardened  during  the  excretion. 
There  is  also  some  evidence  that  the  capsule  is  damaged  during  the  fil- 
tration of  the  foreign  protein,  for  it  has  been  found  after  injecting  egg 


Si 


Fig.  173. — Nerve  supply  of  the  kidney.     K,  kidney;   Si,  S2,  major  and  minor  splanchnic  nerves;    V, 
vagus;    C.G.,   Celiac   ganglion;  A,   aorta.      (From   Cushny.) 

albumin,  that  more  protein  may  appear  in  the  urine  in  24  hours  than  the 
amount  injected. 

Albuminuria  is  also  readily  induced  experimentally  by  clamping  the 
blood  vessels  of  the  kidney.  After  occlusion  of  the  renal  artery  for 
30  seconds,  the  urine  for  some  time  ceases  entirely  to  flow,  and  when 
it  returns  (in  about  an  hour)  it  is  loaded  with  protein  which  gradually 
disappears.  In  all  cases  of  albuminuria  the  albuminous  nitrate  in  its 
passage  along  the  tubules  is  concentrated  by  the  reabsorption  process, 
and  this  may  occur  to  such  an  extent  that  the  protein  is  precipitated 
so  as  to  form  a  cast  to  which  detritus  from  the  tubular  epithelium  may 
become  added,  the  exact  type  of  cell  composing  this  detritus  depending 
on  the  point  at  which  the  protein  solidifies. 


554 


THE    EXCRETION    OF    URINE 


The  Influence  of  the  Nervous  System  on  the  Excretion  of  Urine. — In 

spite  of  numerous  and  repeated  attempts  to  demonstrate  that  a  nervous 
mechanism  governs  the  excretion  of  urine,  no  proofs  which  are  above 
criticism  have  been  forthcoming.  Stimulation  of  the  splanchnic  nerves 
results  in  a  diminution  in  the  excretion  of  urine,  probably  because  of  a 
diminution  in  the  blood  supply  of  the  renal  vessels  owing  to  the  vasocon- 
striction.  Stimulation  of  the  vagus  nerves  below  the  level  of  the  cardiac 
branches  has  been  said  to  result  in  the  augmentation  of  the  rate  of  urine 
excretion  (Asher  and  Pearce12).  The  results  are  doubtful,  however,  since 
there  is  no  increase  in  the  oxygen  absorption  under  the  above  conditions 
(Pearce  and  Carter13). 

There  is  no  doubt  that  the  renalnerves  profoundly  affect  the  excretion 
of  urine,  but  that  they  do  so  directly  is  very  improbable,  since  perfectly 
adequate  renal  -function  can  be  maintained  in  animals  that  have  had  the 
kidneys  entirely  removed  and  then  replaced.  There  are  numerous  re- 
flexes that  affect  the  rate  of  urine  excretion  by  constriction  of  the  renal 
vessels.  Injury  to  the  bladder  or  ureter,  abdominal  injuries  to  the  kid- 
ney, or  even  cold  applied  to  the  skin,  may  result  in  incomplete  suppres- 
sion of  the  urine. 


CHAPTER  LX1 

THE  AMOUNT  AND  COMPOSITION  OF  THE  URINE  IN  HEALTH 

AND  DISEASE 

(Partly  contributed  by  R.  G.  PEARCE) 

In  the  chapters  on  digestion  and  metabolism,  we  have  followed  the 
course  which  food  takes  with  especial  reference  to  the  nutrition  of  the 
body.  The  excretion  of  these  elements  of  nutrition  is  taken  up  under  a 
number  of  the  subdivisions  of  physiology,  viz.,  respiration,  digestion, 
kidney  function  and  the  skin.  In  the  chapters  on  digestion  attention  was 
called  to  the  fact  that  the  feces,  besides  containing  the  indigestible  resi- 
due of  the  aliment,  contain  several  excretory  products  which  at  one 
time  or  another  have  actually  been  within  the  body  proper.  These  in- 
clude normally  the  pigments  of  the  body  and  many  of  the  heavier  mineral 
salts,  such  as  iron,  magnesium,  lime  and  phosphates;  and  under  abnormal 
conditions,  as  when  the  metals  are  given  as  medicine,  bismuth  and  mer- 
cury. The  respiratory  system  excretes  most  of  the  oxygen  and  carbon. 
In  this  chapter  we  shall  take  up  the  manner  in  which  the  body  rids  itself 
of  the  nitrogenous,  and  some  of  the  mineral  waste  materials.  Even  at 
the  risk  of  repetition,  it  will  be  advantageous  to  recapitulate  certain  facts 
concerning  the  essential  chemical  structure  of  the  urinary  constituents, 
so  that  we  may  be  in  a  position  to  appreciate  the  kidney  function  in 
health  and  disease. 

We  now  know  that  the  kidney  does  not  form  any  of  the  specific  con- 
stituents of  its  secretion  (except  hippuric  acid).  These  substances  are 
formed  in  the  various  tissues  of  the  body,  and  are  brought  to  the  kidneys 
by  the  blood,  where  they  are  eliminated.  But  while  the  constituents  in  the 
urine  are  unchanged  in  chemical  composition  from  that  in  which  they 
are  found  in  the  blood,  they  do  occur  in  greatly  changed  proportions. 
It  is  this  variation  in  the  concentration  of  the  urinary  constituents  in 
the  blood  and  the  urine  which  presents  the  most  important  and  at  the 
same  time  the  most  difficult  question  in  the  physiology  of  the  kidney. 
In  the  following  table  the  percentage  composition  of  the  blood  plasma  is 
compared  with  that  of  an  average  sample  of  human  urine.  The  third 

555 


556 


THE    EXCRETION    OF    URINE 


column  gives  the  change  in  concentration  which  each  constituent  under- 
goes in  passing  through  the  renal  filter. 


BLOOD  PLASMA 
PER  CENT 

URINE 
PER  CENT 

CHANGE  IN 
CONCENTRATION 

Water 

90-93 

95 



Proteins,  fats  and  other  colloids 

7-9 

— 

— 

Dextrose 

0.1 

— 

— 

Urea 

0.03 

2 

60 

Uric  acid 

0.002 

0.05 

25 

Creatinine 

Ammonia 

0.001 

0.04 

40 

Sodium 

0.32 

0.35 

1 

Potassium 

0.02 

0.115 

7 

Calcium 

0.008 

0.015 

2 

Magnesium 

0.0025 

0.006 

2 

Chlorine 

0.009 

0.27 

30 

Phosphates  (PO4) 

0.003 

0.18 

60 

Sulphates  (SO4) 

Amino  acids 

The  Amount  of  Urine 

The  amount  of  urine  passed  in  twenty-four  hours  varies  with  the 
amount  of  fluid  ingested  and  the  proportion  of  fluid  retained  by  the  body 
or  excreted  by  other  channels.  Under  ordinary  conditions  a  twenty-four- 
hour  sample  amounts  to  from  1000  to  1800  c.c.  of  urine.  On  a  constant 
water  intake  the  volume  of  urine  is  extremely  variable  for  any  single 
day  or  part  of  the  day  (Addis  and  Watanabe3).  The  average  volume  of 
urine  excreted  by  twenty  individuals  on  the  third,  fourth  and  fifth  days 
of  a  constant  diet  in  which  the  fluid  intake  was  2,070  c.c.,  varied  from 
1,013  to  1,712  c.c.  for  a  twenty-four-hour  period,  from  684  to  1,195  c.c. 
for  the  first  twelve  hours  of  the  day,  and  from  501  to  788  c.c.  for  the 
first  eight  hours  of  the  day.  In  normal  subjects  the  amount  of  urine 
excreted  during  the  night  is  usually  less  than  that  during  the  day.  This 
is  such  a  constant  finding  that  in  cases  where  more  than  50  per  cent  of 
the  urine  is  excreted  in  the  twelve  hours  of  the  night,  suspicions  of  renal 
disease  should  be  aroused. 

With  a  constant  intake  of  food  and  water,  the  specific  gravity  of  samples 
of  urine  collected  at  frequent  intervals  throughout  the  twenty-four 
hours  exhibits  considerable  variations.  The  night  urine  is  usually  of 
higher  specific  gravity  than  that  of  samples  passed  every  two  hours 
during  the  day,  the  variation  often  amounting  to  as  much  as  ten  points. 
If  the  variation  does  not  occur,  but  the  different  specimens  show  a  fixed 
specific  gravity,  either  at  a  high  or  a  low  level,  it  is  usually  indicative 
of  renal  trouble.  This  is  illustrated  in  the  following  table: 


AMOUNT   AND    COMPOSITION   OF   THE   URINE 


557 


DAY 

NIGHT 

8-10 

A.M. 

10-12 

A.M. 

12-2 

P.M. 

2-4 

P.M. 

4-6 

P.M. 

6-8 

P.M. 

8-8 

P.M.  -A.M. 

Normal   person 
In  Hypertensive  Nephritis 
In  Myocardial  Decompensation 

1.016 
1.010 
1.018 

1.019 
1.009 
1.020 

1.012 
1.010 
1.019 

1.014 
1.009 
1.018 

1.020 
1.009 
0.020 

1.010 
1.010 
1.021 

1.020 
1.009 
1.022 

(Compiled  from  Mosenthal's  figures.) 

The  proportion  of  water  to  total  solids  is  often  very  similar  in  plasma 
and  urine,  but  when  water  is  taken  in  large  quantities  the  urine  shows 
much  greater  changes  than  does  the  blood,  and  the  solids  may  sink  to  a 
very  low  concentration.  On  the  other  hand,  when  little  fluid  is  taken  or 
when  the  skin  and  bowel  eliminate  a  large  amount  of  fluid,  the  urine 
may  become  very  concentrated  without  any  change  in  the  blood  plasma. 
The  total  solids  in  urine  can  be  determined  with  approximate  accuracy 
by  multiplying  the  last  two  figures  of  the  specific  gravity  by  the  con- 
stant coefficient  0.233  (Haeser). 

The  Depression  of  Freezing  Point. — While  the  solids  of  the  blood  con- 
sist, for  the  most  part,  of  proteins  and  colloids,  those  of  the  urine  are 
made  up  of  inorganic  salts  and  small  organic  molecules.  The  mole- 
cular concentration — that  is,  the  total  number  of  molecules  in  a  given 
quantity  of  fluid — is  under  ordinary  conditions  much  greater  in  the 
urine  than  in  the  blood.  The  molecular  concentration  may  be  deter- 
mined by  the  depression  of  the  freezing  point  of  a  fluid  below  that  of  dis- 
tilled water  (see  page  10).  Blood  freezes  almost  constantly  at  -0.56°  C., 
while  urine  may  freeze  at  temperatures  which  vary  between  -1°  C.  and 
-2.5°  C.;  if  very  concentrated  it  may  freeze  at  a  temperature  as  low  as 
-5°  C.,  or  if  dilute  the  freezing  point  may  be  as  high  as  -0.075°  C. 

The  variability  of  the  freezing  point  and  the  specific  gravity  of  the 
urine  lead  us  to  a  consideration  of  the  relationship  of  the  urinary  volume 
to  its  concentration.  In  the  first  place,  the  volume  of  water  ingested  is 
more  frequently  than  otherwise  in  excess  of  the  minimum  absolutely  re- 
quired by  the  body,  and  is  subject  to  greater  variation  than  the  sub- 
stances excreted  in  the  urine.  The  kidney  is  able  to  eliminate  one  con- 
stituent of  the  plasma  which  may  be  present  in  excess  without  involving 
any  changes  in  others.  For  example,  when  salt  is  added  to  the  food  and 
excreted  in  the  urine,  the  total  chlorides  are  increased,  but  the  amount 
of  urine  and  the  other  constituents  may  remain  unchanged ;  or,  again,  as 
may  happen,  excess  of  salt  leads  to  an  increase  in  the  volume  of  the 
urine,  but  the  salt  concentration  remains  constant  while  that  of  the 
other  urinary  bodies  is  decreased.  Similarly,  although  the  rate  of  urea 
excretion  is  not  demonstrably  augmented  by  an  increase  in  the  volume 
of  the  urine,  an  increase  in  the  rate  of  urea  excretion  induced  by  the 


558 


THi:    KXrKKTJOX    OF    I'HLNK 


ingestion  of  urea  is  accompanied  by  a  larger  volume  of  urine.  That  these 
two  factors  may  not  stand  in  a  causal  relationship  to  each  other  is  sug- 
gested by  recent  work  of  Addis  and  Watanabe,3  who  find  no  quantitative 
relationship  between  the  rate  of  increase  in  urea  excretion  and  the  increase 
in  urine  volume,  and  who  believe  that  the  apparent  relationship  is  due  to  a 
common  cause,  such  as  alteration  in  the  rate  of  circulation  or  change  in  the 
activity  of  the  kidney  cells.  Nevertheless,  there  appears  to  be  a  limit  set  to 
the  power  of  the  kidney  to  take  the  urinary  salts  or  water  from  the  plasma 
and  to  place  them  in  the  urine  in  quite  different  proportions.  The  definite 
amount  of  water  required  to  hold  the  urinary  salts  has  been  termed  the 
"  volume  obligative"  (Ambard5).  These  limits  of  concentration  may  be 
fixed  by  the  energy  which  the  kidney  can  bring  to  act  against  the  osmotic 
resistance. 

The  inconstancy  in  the  behavior  of  the  kidney  toward  ingested  salts  is 
probably  due  to  the  fact  that  the  salts  reach  the  kidney  in  the  concen- 
tration in  which  they  are  held  by  the  blood  plasma,  and  not  as  they  were 
ingested.  If  salt  is  absorbed  rapidly  enough  to  disturb  the  salt  equilib- 
rium of  the  tissues  and  plasma,  then  water  will  be  abstracted  from  the 
tissues,  and  the  plasma  on  reaching  the  kidney  will  eliminate  the  salt 
and  water  together.  The  difference  in  the  reaction  arises  from  the 
varied  activity  in  the  tissues  in  general  rather  than  in  the  kidney  itself. 

THE  REACTION  OF  THE  URINE 

In  man  and  the  carnivora  the  reaction  of  the  urine  is  generally  acid 
to  litmus  or  phenolphthalein,  but  alkaline  to  methyl  orange.  The  acid 
responsible  for  the  reaction  is  phosphoric,  not  in  a  free  state,  but  as  a 
mixture  of  the  salts  Na2,  HP04  and  £jaH2P04,  in  which  there  is  an  excess 
of  the  latter.  If  alkali  be  added  to  a  solution  of  H3P04,  containing  a 
little  methyl  orange,  the  tint  changes  from  red  to  yellowish  when  the 
H3P04  has  all  been  changed  into  NaH2P04;  if  more  alkali  be  added,  and 
the  indicator  be  now  changed  to  phenolphthalein  the  tint  turns  red  when 
the  H3P04  has  been  changed  to  Na2HP04.  The  reaction  of  urine  lies  be- 
tween these  two  points.  In  the  herbivorous  animals  the  alkaline  re- 
action is  due  to  the  fact  that  vegetables  and  fruits  contain  salts 
of  dibasic  or  polybasic  acids,  such  as  acid  potassium  malate,  citrate, 
acetate,  and  tartrate.  Oxidation  of  these  in  the  body  gives  rise  to 
carbonates.  Some  of  the  carbonic  acid  is  excreted  through  the  lungs, 
and  hence  the  associated  base,  generally  sodium  or  potassium,  is  com- 
bined so  as  to  form  a  weak  basic  salt. 

The  measurement  of  the  acidity  of  the  urine  in  terms  of  the  H-ion  con- 
centration like  the  same  measurement  in  blood,  requires  the  use  of  the 


AMOUNT    AND    COMPOSITION    OF    THK    TRINE  559 

rather  difficult  electrical  or  indicator  method,  the  principle  of  which  has 
been  described  in  Chapter  V.  Expressed  in  terms  of  CH,  the  acidity 
varies  between  4.7  x  10-7  and  100  x  10"7.  The  total  potential  acidity — 
that  is,  the  number  of  H  ions  which  will  be  formed  in  the  face  of  a  con- 
tinual neutralization  of  those  in  solution — may  be  obtained  fairly  accu- 
rately by  titrating  the  urine  with  Vio  normal  alkali  in  the  presence  of 
neutral  potassium  oxalate,  using  phenolphthalein  as  an  indicator  (Folin) . 
The  results  may  be  expressed  in  acidity  per  cent  in  terms  of  c.c.  N/10 
NaOH  required  to  neutralize  100  c.c.  of  urine.  If  the  ammonia  excretion 
is  added  to  the  titration  results,  the  total  potential  acidity  is  very  closely 
measured.  In  normal  subjects  the  acidity  is  high  in  the  relatively  scanty 
urine  that  is  excreted  during  the  night.  In  the  forenoon  more  urine  is 
excreted  and  the  acidity  is  muchjeas,  i- ft-,  alkalinity  Trmo.h  greater.  This 
alkaline  tide  in  the  forenoon  is  not  dependent  upon  the  accompanying 
diuresis,  and  it  is  the  only  alkaline  tide  during  the  24  hours.  The  old  idea 
of  an  alkaline  tide  following  the  ingestion  of  food  is  not  correct.  These 
facts  are  taken  advantage  of  in  a  test  of  renal  efficiency  in  which  the 
conditions  are  standardized  by  having  the  patient,  after  awaking  in  the 
morning,  drink  a  definite  volume  of  water,  but  take  no  food.  The  night 
urine  (from  11  p.  M  to  7  A.  M.)  and  hourly  specimens  between  7  A.  M.  and 
12  noon  are  collected  and  their  volume  and  alkalinity  (c.c.  N/10  NaOH  per 
100  c.c.)  measured.  Typical  results  after  drinking  500  c.c.  water  are 
exhibited  in  the  following  table: 


No.  OF  CASES 

FROM  WHICH 

DIURESIS 

ALKALINITY   PER   CENT 

THE   MEAN 

c.c. 

PER     HOUR 

MAXIMUM 

FIGURES   ARE 

MAXIMUM 

AT 

AT    10    OR 

CALCULATED 

BEFORE 

AFTER 

NIGHT 

11    A.    M. 

I 

49 

55 

336 

27 

84 

II 

51 

61 

182 

23 

74 

III 

5(5 

63 

221 

22 

42 

(Adapted  from  Leathes.) 

In  this  table,  I  represents  the  response  of  normal  subjects  in  whom 
diuresis  and  alkalinity  both  increased;  II,  that  of  nephritic  patients  in 
whom  the  diuresis  reaction  was  subnormal,  but  the  alkalinity  normal, 
and  III,  more  severe  cases  in  whom  both  the  diuresis  and  the  alkalinity 
were  subnormal. 

Leathes  has  been  able  to  show  that  this  morning  alkaline  tide  is  de- 
pendent upon  a  greater  excitability  of  the  respiratory  center  on  waking 
compared  with  that  during  the  night.  This  causes  pulmonary  ventila- 
tion to  become  more  thorough  during  the  morning  hours  than  during 
the  night,  so  that  more  C02  is  washed  out  of  the  blood,  thus  lowering  its 
acidity  (alkalosis)  so  that  alkali  is  excreted  by  the  kidney.  The  C02  con- 


560  THE   EXCRETION    OF    URINE 

tent  of  the  alveolar  air  at  night  in  a  typical  case  was  7.4  per  cent  and  after 
rising  6.63.  Leathes  also  showed  that  forced  breathing  causes  a  marked 
increase  in  the  alkalinity  of  the  urine,  a  result  which  confirms  those  of 
Haldane,  Meakin,  etc.,  referred  to  elsewhere  in  this  volume  (page  381). 

THE  SOLID  CONSTITUENTS 

In  a  person  living  on  an  ordinary  diet  the  most  important  organic 
and  inorganic  constituents  of  the  urine  are  as  follows : 

TOTAL  SOLIDS  (40  TO  60  GRAMS)  IN  ONE  LITER  OF  NORMAL  URINE 
ORGANIC  CONSTITUENTS,  25-40  GM.  INORGANIC  CONSTITUENTS,  15-25  GM. 

Urea,  20-35  gm.  Sodium  chloride  (NaCl),  8-15  gm. 

Creatinine,  1.0-1.5  gm.  Phosphoric  acid  (P2O5),  2.5-3.5  gm. 

Uric  acid,  0.5-1.25  gm.  Sulphuric  acid,   (SO3),  2-2.5  gm. 

Hippuric  acid,  0.1-1.7  gm.  Potassium  (KjO),  2-3  gm. 

Other    constituents     (ethereal    sulphates,  Sodium  (Na2O),  4-6  gm. 

oxalic  acid,  urinary  pigments,  etc.),  Calcium  (CaO),  0.1-0.3  gm. 

1.5-2.3  gm.  Magnesium  (MgO),  0.2-0.5. 

Ammonia  (NH3),  0.3-1.2  gm. 
Iron  (in  pigment),  0.001-0.010. 

(Compiled  from  Mosenthal's*  figures.) 

These  urinary  salts  are  present  in  the  blood,  and  are  only  excreted  by 
the  kidney.  An  investigation  of  the  mechanism  of  renal  excretion  must 
therefore  include  a  study  of  the  relationship  existing  between  the  con- 
centration of  the  urinary  salts  in  the  blood  and  in  the  urine.  We  shall 
briefly  review  the  chief  biochemical  relationships  of  the  most  important  of 
these  constituents  and  then  give  tables  showing  the  quantitative  changes 
which  they  undergo  in  various  diseases. 

The  Organic  Salts  of  Normal  Urine 

Nitrogenous  Constituents. — The  greater  number  of  the  organic  salts  of 
the  urine  are  made  up  of  bodies  which  contain  nitrogen,  and  which  are 
derived  from  the  protein  element  of  nutrition.  The  proteins,  which  form 
the  chief  building  material  of  the  body,  are  broken  up  into  their  con- 
stituent amino  acids  in  the  intestinal  tract  and  absorbed  as  such  by  the 
blood.  Portions  of  these  acids  are  taken  up  by  the  tissues  to  repair  and 
to  replace  those  proteins  which  have  been  discarded,  and  the  remaining 
protein,  in  excess  of  the  body  need  for  amino  acids,  is  deamidized,  the 
major  portion  of  the  carbon,  oxygen  and  hydrogen  being  oxidized  to 
form  C02  and  water,  and  the  lesser  portion  of  these  elements  being  com- 
bined with  the  nitrogen  to  form  urea,  ammonia,  uric  acid,  etc.  A  similar 
fate  later  awaits  the  nitrogen  moiety  which  found  a  place  in  the  tissues, 
and  which  is  replaced  in  turn  by  new  nitrogenous  bodies.* 

*For    further    details    see    page    645. 


AMOUNT   AND    COMPOSITION    OF    THE   URINE  561 

Since  all  the  ingested  nitrogen,  except  a  small  and  rather  constant 
amount  which  is  lost  by  the  feces  and  the  sweat,  is  excreted  in  the  urine, 
the  total  nitrogen  of  the  urine  has  been  taken  as  a  measure  of  the  nitro- 
gen or  protein  metabolism  of  the  body.  In  normal  conditions  the  protein 
metabolism  is  adjusted  in  such  a  manner  that  the  nitrogen  intake  is 
equal  to  the  nitrogen  output,  a  condition  known  as  nitrogenous  equilib- 
rium. If  the  nitrogen  intake  is  reduced  below  the  actual  body  needs, 
the  excretion  of  nitrogen  is  greater  than  the  intake  which  indicates  that 
the  body  protein  is  replacing  the  protein  usually  furnished  by  the  food. 
The  minimum  amount  of  protein  that  the  body  must  have  to  maintain 
equilibrium  varies  in  individuals,  and  with  the  nature  of  the  protein 
(page  605).  With  the  ordinary  mixed  diet  it  is  usually  between  12  and 
20  grams  a  day,  corresponding  to  from  75  to  125  grams  of  protein.  Ordi- 
narily, nitrogen  is  not  retained  and  an  increase  in  the  protein  ingested  is 
followed  by  an  increase  of  nitrogen  in  the  urine.  In  periods  of  growth  and 
after  undernutrition,  however,  protein  is  stored  in  the  body.  For  this 
reason,  unless  the  amount  of  nitrogen  ingested  is  known,  the  study  of  the 
total  nitrogen  of  the  urine  gives  no  information  concerning  the  nature  of 
the  nitrogen  metabolism  of  the  body.  The  total  output  of  nitrogen  per  day 
usually  amounts  to  10  to  15  grams — from  1  to  2  per  cent  of  the  urine  by 
weight. 

Urea. — The  chifijLjo£-tho  nitrogcaeu&-b^4i^^  of  the  urine  is  urea,  the 
origin  of  which  has  been  fully  described  in  the  chapters  on  metabolism. 
No  constituent  of  the  urine  is  subject  to  greater  variation  both  in  abso- 
lute and  in  relative  amounts.  On  an  average  diet  containing  120  grams 
of  protein  per  day,  the  absolute  urea  excretion  may  amount  to  about  30 
grams ;  on  a  low  protein  diet  it  may  be  only  a  few  grams.  When  the  pro- 
tein intake  is  high,  the  nitrogen  eliminated  as  urea  may  be  90  per  cent 
of  the  total  nitrogen;  but  when  the  protein  intake  is  low,  this  proportion 
may  fall  to  60  per  cent.  The  difference  is  because  on  a  low  protein  diet 
the  greater  percentage  of  nitrogen  eliminated  is  endogenous  in  origin, 
and  urea,  which  is  the  chief  constituent  of  the  exogenous  nitrogen  moiety 
of  the  urine,  is  accordingly  decreased  on  low  diets. 

In  recent  years  the  importance  of  the  relationship  between  the  con- 
centration of  the  urinary  constituents  in  the  blood  and  the  urine  has 
been  much  insisted  upon,  and  since  the  estimation  of  the  amount  of 
urea  in  the  blood  and  the  urine  is  relatively  simple,  most  of  the  work 
has  been  done  by  using  these  values.  Ambard  and  Weil5  believe  that  a 
quantitative  relationship  exists  between  the  rate  of  urine  excretion  and 
the  concentration  of  urea  in  the  blood  and  the  urine,  since  the  urea  in 
the  blood  acts  as  a  stimulus  to  the  renal  cells.  By  comparing  the  rate 
of  urea  excretion  and  the  concentration  of  urea  in  the  blood  and  urine 


562  THE    EXCRETION    OF    URINE 

in  a  mathematical  formula,  they  have  obtained  a  value  which  they  be- 
lieve is  more  or  less  fixed  for  the  normal  kidney.  This  expression  is 
known  as  Ambard's  coefficient  and  formula*  and  has  been  used  as  a 
means  of  evaluating  the  functional  capacity  of  the  kidney. 

Whatever  may  be  the  value  of  the  formula  in  expressing  the  relation- 
ship existing  between  the  rate  of  urea  excretion  and  the  concentration  of 
this  substance  in  the  blood,  it  is  certain  that,  in  diseased  conditions  where 
there  is  impairment  of  the  kidney  the  concentration  of  urea  in  the 
blood  remains  permanently  at  an  abnormally  high  average  level,  al- 
though the  amount  of  urea  excreted  during  twenty-four  hours  may  bo 
exactly  the  same  as  under  normal  conditions.  Probably  the  increased  con- 
centration of  urea  in  the  blood  under  these  conditions  is  a  compensatory 
measure  to  provide  sufficient  pressure  to  cause  its  excretion  through  a 
damaged  outlet.  It  is  this  increase  in  iirea  of  the  blood  which  is  indicated 
by  the  term  urea  retention  in  nephritis. 

The  upper  limit  of  blood  urea-nitrogen  is  about  20  mg.  per  100  c.c., 
which  would  correspond  to  about  0.45  gm.  of  urea  per  liter  of  blood. 
The  average  figure  is  half  of  this  amount.  The  maximum  concentration 
of  urea  in  the  urine  is  seldom  over  8  per  cent,  On  this  basis  the  kidney 
can  raise  the  concentration  of  the  urea  in  the  urine,  at  a  conservative 
estimate,  from  100  to  200  times.  Normally  the  daily  output  of  urea 
nitrogen  may  range  from  8  to  12  gm.,  and  the  nitrogen  which  it  contains 
is  roughly  80  per  cent  of  the  total  excretion  for  the  day. 

Ammonia. — The  chief  source  of  ammonia  in  the  body  is  the  ni- 
trogenous portion  of  the  deamidized  ammo  acids.  The  ammonia  found 
in  excess  in  the  portal  blood  is  derived  from  ingested  ammonium  salts 
and  from  ammonia  resulting  from  bacterial  action  on  proteins  in  the 
intestinal  tract.  The  ammonia  of  the  body  is  present  chiefly  in  the  form 
of  ammonium  carbonate,  and  it  is  this  salt  that  is  the  precursor  of  urea. 
Because  ammonium  carbonate  is  so  readily  converted  into  urea  by  the 
tissues  of  the  body,  little  ammonia  is  normally  present  in  the  systemic 
blood.  The  greater  portion  of  the  ammonia  that  finds  its  way  into  the 
urine  serves  as  a  base  to  transfer  acid  radicles  either  invested  or  formed 


*Ambard  and  Weil's  formula  is: 

Ui 


70 
D  x  —  x 


P         V25 

K    r=  coefficient  of  urea  excretion   (Constant  of  Ambard). 
Ur  =  grams  of  urea  per  liter  of  blood. 
D    :=  output  of  urea  in  grams  per  24  hours. 
P    r=  weight  of  the  patient. 
C    =  grams  of  urea  per  liter  of  urine. 
70  r=  standard   weight. 
25   =  standard  concentration  of  the  urine. 

The  average  value  for  this  constant  in  normal  individuals  is  said  to  lie  between  .06  and   .09. 
Critical    reviews    of    the    work    have    been    published    recently    by    Maclean6    and    by    Addis    and 
Watanabe.3 


AM  Of  N'T    AND    COMPOSITION    OF    THE    URINE  563 

within  the  body.  The  amount  of  ammonia  in  the  urine,  therefore,  is  a 
measure  of  the  acid  bodies  of  the  blood.  For  the  latter  reason  the  deter- 
mination of  the  ammonia  excretion  in  urine  is  of  some  clinical  importance. 
The  ingestion  of  mineral  acids  increases  the  ammonia  excretion,  while 
alkalies  tend  to  reduce  it.  During:  fasting  and  in  diseases  such  as 
diabetes,  where  there  is  an  abnormal  metabolism,  the  amount  of  ammonia 
in  the  urine  is  increased.  Ordinarily  the  daily  output  of  ammonia  nitro- 
gen does  not  exceed  0.5-0.6  gm.,  constituting  3-5  per  cent  of  the  total 
amount  of  nitrogen.  According  to  Nash20  and  Benedict  the  formation 
of  the  urinary  ammonia  occurs  in  the  kidneys.  Thus,  there  is  more  am- 
monia in  the  blood  of  the  renal  vein  than  in  that  of  the  systemic  circula- 
tion, and  the  latter  does  not  become  increased  by  intravenous  injection 
of  acid.  That  the  kidney  produces  ammonia  is  further  shown  by  the  fact 
that  this  decrease*  in  the  blood  after  complete  nephrectomy. 

Creatinine. — On  a  meat-free  diet  the  daily  excretion  of  creatinine  is 
remarkably  constant,  amounting  to  from^T  to  11  nig.  per  kilogram  of 
body  weight.  For  this  reason  its  determination  is  accepted  as  an  in- 
dispensable feature  in  metabolism  investigations  involving  urine  analy- 
sis. Any  gross  variation  from  the  normal  amount  indicates  the  certain 
failure  of  the  attendants  to  collect  all  of  the  twenty-four-hour  specimen 
of  urine. 

The  creatinine  is  one  of  the  last  of  the  urinary  constituents  to  accumu- 
late  in  the  blood  during  renal  insufficiency,  and  for  this  reason  affords 
a  reliable  prognostic  indication  concerning  the  patients'  condition.  A 
rise  in  the  creatinine  concentration  of  the  blood  is  evidence  of  serious 
renal  disease,  patients  with  concentrations  of  5  mg.  never  recovering 
(Chase  and  Myers).7  The  concentration  of  creatinine  in  the  urine  is 
about  100  times  greater  than  in  the  blood,  in  which  there  is  1-2  mg.  per 
100  c.c. 

In  adult  man  creatine  does  not  appear  in  the  urine  save  during  starva- 
tion or  wasting  diseases.  In  woman  it  is  absent  save  after  postpartum 
resolution  of  the  uterus.  Children  commonly  excrete  creatine  along 
with  creatinine  until  the  middle  years  of  childhood. 

The  Purine  Bodies  and  Uric  Acid. — The  most  important  purine  in 
human  urine  is  uric  acid.  Xanthine  is  the  next  in  importance,  and  small 
amounts  of  hypoxanthine,  guanine,  and  adenine  are  found. 

The  human  body  has  the  almost  unique  distinction  among  mammals 
of  not  being  able  to  destroy  any  of  the  uric  acid  it  produces,  and  hence 
all  the  uric  acid  formed  during  metabolism  must  be  excreted  in  the  urine. 
Unfortunately  the  kidney  appears  to  be  less  competent  to  rid  the  body 
of  this  waste  than  it  is  of  the  other  urinary  metabolites,  and  one  of  the 


564  THE   EXCRETION   OF   URINE 

earliest  signs  of  renal  insufficiency  is  now  held  to  be  a  failure  of  the 
kidney  to  prevent  the  uric  acid  of  the  blood  from  increasing.  Perhaps 
the  reason  for  the  inability  of  the  kidney  to  excrete  uric  acid  readily 
lies  in  the  fact  that  its  salts  are  among  the  least  soluble  of  those  in  the 
urine.  It  is  on  this  account  that  when  the  urine  cools,  a  red  sediment  of 
urates  containing  certain  pigments  often  separates  out. 

The  uric  acid  of  the  urine  is  possibly  derived  entirely  from  the  purine 
metabolism  of  the  body,  in  which  the  nucleins  either  of  the  body  cells  or 
of  the  exogenous  food  take  part.  It  is  decreased  during  starvation  and 
increasedL_by  eating  food  rich  in  nucleins,  such  as  liver  and  sweet- 
breads. 

Under  ordinary  conditions  the  excretion  of  uric  acid  amounts  to  from 
0.3  to  1.2  gm.  per  day  (0.02  to  0.10  per  cent),  the  variation  being  de- 
pendent upon  the  state  of  health,  diet,  or  personal  idiosyncrasy.  The 
blood  of  a  normal  individual  contains  on  the  average  1.8  mg.  of  uric 
acid  per  100  c.c.  The  kidneys  are  therefore  able  to  concentrate  the 
uric  acid  in  the  urine  from  30  to  60  times  over  its  concentration  in  the 
blood  plasma. 

The  purines  found  in  coffee  and  tea  (caffeine,  etc.)  are  excreted  in 
the  urine  as  salts  not  of  uric  acid  but  of  methylated  xanthines. 

Hippuric  Acid. — This  is  a  constanj^  constituent  of  the  urine  of  her- 
bivorous animals,  and  is  usually  present  in  small  amounts  in  human 
urine.  The  amount  rarely  exceeds  0.7  gm.  a  day,  but  on  a  diet  rich  in 
fruits  and  vegetables  it  may  exceed  2  gm.  It  is  interesting,  since  it  is 
the  only  urinary  constituent  that  is  synthesized  by  the  renal  cells. 

Amino  acids  are  always  present  in  small  amounts  in  the  urine,  con- 
stituting, according  to  D.  D.  Van  Slyke,  about  1.5  per  cent  of  the  total 
nitrogen.  The  estimation  of  the  amino-acid  nitrogen  of  the  urine  has 
not  been  found  to  be  of  any  clinical  significance.8 

The  aromatic  oxyacids  are  normally  present  in  the  urine  in  varying 
amounts.  These  include  phenol,  indoxyl,  skatoxyl,  and  phenylacetic, 
paraoxyphenyl,  propionic,  oxymandelic  and  homogentisic  acids.  These 
bodies  are  derived  from  phenylamino  acids,  such  as  tyrosine,  tryptophane, 
and  phenylalanine.  It  is  believed  that  the  putrefactive  decomposition 
of  proteins  in  the  large  intestine  results  in  the  production  of  these  toxic 
bodies.  The  body  protects  itself  by  oxidizing  them  and  uniting  them 
to  sulphuric  acid  to  form  the  ethereal  or  conjugated  sulphates,  which 
are  found  in  the  urine  in  the  form  of  sodium  or  potassium  salts.  The 
determination  of  the  amounts  of  these  bodies  in  the  urine  has  therefore 
been  taken  as  an  index  of  the  putrefaction  going  on  within  the  bowel. 

The  chief  of  these  bodies  is  urinary  indican,  which  is  found  usually  as 


AMOUNT   AND    COMPOSITION   OF   THE   URINE  565 

a  potassium  salt.  The  test  for  indican  in  the  urine  consists  in  oxidiz- 
ing the  indoxyl  in  an  acid  solution  by  means  of  ferric  chloride  to  indigo 
blue,  and  shaking  out  the  indigo  blue  with  chloroform.  The  depth  of 
the  color  of  the  chloroform  affords  a  rough  means  of  determining 
the  amount  of  indican  present.  The  fact  that  the  indican  test  is  nega- 
tive must  not  be  taken  to  mean  that  the  intestinal  processes  are  normal, 
for  if  the  intestine  fails  to  contain  phenylated  amino  acids,  or  the  proper 
bacteria  are  not  present,  no  indican  will  be  found.  On  the  other  hand, 
the  putrefactive  process  of  the  large  bowel  may  not  be  very  extensive, 
yet  the  amount  of  indican  in  the  urine  be  increased,  because  of  greater 
absorption  due  to  constipation. 

Skatole,  ajejsaLsmetHng  substance,  is  formed  by  certain  kinds  of  bac- 
teria. The  greater  proportion  of  this  substance  is  excreted  by  the  bowel, 
but  if  the  person  is  constipated,  some  of  it  may  find  its  way  into  the 
blood  to  impart  a  fecal  odor  to  the  breath  and  urine.  Its  presence 
therefore  has  some  diagnostic  importance. 

A  very  interesting  body  which  is  sometimes  found  in  the  urine  is 
homogentisic  acid.  It  is  thought  to  be  an  intermediate  step  in  the  metab- 
olism of  tyrosme,  and  is  found  in  the  urine  of  people  suffering  from 
alkaptonuria.  The  disease  is  remarkable  in  that  it  appears  to  run  in 
families  and  produces  no  ill  effects.  Homogentisic  acid  is  a  strong 
reducing  agent,  and  for  this  reason  may  be  confused  with  sugar  in 
Fehling's  test. 

The  inorganic  constituents  of  the  urine  include  the  acids:  chlorides, 
sulphates  and  phosphates;  and  the  bases:  sodium,  potassium,  magnesium, 
and  calcium. 

The  Salts  of  the  Normal  Urine 

The  Chlorides. — The  chlorides  compose  the  bulk  of  the  acid  rad- 
icles in  the  urine.  Although  they  appear  to  be  necessary  constituents 
of  the  living  cell,  they  do  not,  so  far  as  known,  enter  into  combinations 
with  the  organic  constituents.  The  tissues  appear  to  require  a  rather 
definite  concentration  of  sodium  chloride  in  order  to  carry  on  their 
work,  for  reduction  in  the  sodium-chloride  intake  of  the  body  results 
in  a  reduction  in  the  chloride  excretion  by  the  urine.  In  salt  starvation 
the  chlorides  may  disappear  entirely  from  the  urine,  the  amount  of 
chloride  excreted  appearing  to  be  closely  related  to  the  amount  of  salt 
ingested.  When  the  intake  is  constant,  the  rate  of  excretion  is  likewise 
more  or  less  constant,  but  a  sudden  reduction  in  the  salt  of  the  diet  may 
be  accompanied  by  a  slight  decrease  in  the  salt  content  of  the  blood, 
with  an  attendant  loss  of  water.  On  the  other  hand,  when  the  salt  is 


566  THE    EXCRETION    OF    URINE 

again  taken,  there  is  a  retention  of  salt  and  of  water,  with  a  consequent 
increase  in  body  weight,  until  equilibrium  is  re-established  on  the  old 
level.  While  the  above  is  the  usual  reaction,  a  considerable  retention  of 
salt  without  an  increase  in  the  water  content  of  the  body  may  occur  i 
some  apparently  normal  cases.  This  is  due  probably  to  the  deposition 
of  salt  in  the  tissues. 

Careful  studies  fail  to  confirm  the  idea  that  there  is  a  fixed  relation- 
ship between  the  salt  and  the  water  of  the  body.  As  with  the  nitroge- 
nous constituents,  however,  there  appears  to  be  a  relationship  between 
the  rate  of  excretion  of  chlorides  and  the  amount  of  chloride  in  the  blood. 
Ambard  believes  that  this  relationship,  like  that  of  the  excretion  of  urea 
to  the  blood  urea,  is  capable  of  being  expressed  mathematically  (see 
page  562),  if  allowance  is  made  for  the  fact  that  NaCl  is  not  excreted 
after  it  falls  below  a  certain  concentration  in  the  blood  equal  to  about 
5.62  gm.  per  1000  c.c.  This  level  is  more  or  less  constant  for  normal 
individuals,  but  is  considerably  increased  in  disease  of  the  kidney.  This 
is  known  as  the  threshold  of  chloride  excretion. 

The  amount  of  sodium  chloride  excreted  in  the  urine  in  twenty-four 
hours  varies  between  8  and  20  gm.  a  day,  according  to  the  intake.  It 
is  therefore  apparent  that  the  kidney  is  able  to  concentrate  the  salts 
of  the  plasma  from  ten  to  twenty  times. 

The  Sulphates. — Since  the  inorganic  sulphates  do  not  form  an  im- 
portant constituent  of  the  food,  the  greater  portion  of  the  sulphates  of 
the  urine  are  derived  from  the  sulphur  found  in  the  protein  molecule. 
For  this  reason  the  sulphates  of  the  urine,  like  the  nitrogen,  are  a  meas- 
ure of  protein  metabolism.  An  increase  in  the  nitrogen  excretion  is 
accompanied  by  an  increase  in  the  sulphur  excretion,  the  ratio  being 
about  5  to  1.  The  daily  output  of  sulphur  is  between  1  and  3  gm.  The 
greatest  output  is  in  the  form  of  the  alkaline  sulphates,  about  10  pev 
cent  in  combination  with  aromatic  bodies,  and  a  small  amount  in  com- 
bination with  amino  acids  and  neutral  organic  salts. 

The  phosphates  of  the  urine  are  derived  from  the  food  and  from  the 
oxidation  of  phosphorus-containing  bodies  in  the  tissues  such  as 
nuclein,  lecithin,  etc.  The  daily  excretion  varies  between  1  and  5  gm., 
calculated  as  P20:V  When  calcium  or  magnesium  is  present  in  the 
food,  they  are  excreted  by  the  bowel  as  phosphate,  and  proportionately 
less  is  found  in  the  urine.  The  amount  usually  excreted  in  the  feces 
canals  about  30  per  cent  of  the  total. 

Since  phosphates  in  the  urine  exist  as  a  mixture  of  the  mono-  and  di- 
sodium  hydrogen  phosphates,  they  have  an  important  bearing  on  the 


AMOUNT   AND    COMPOSITION    OF    THE    URINE  567 

reaction  of  the  urine,  the  amount  of  each  varying  with  the  degree  of 
the  acidity  of  the  urine  (see  page  558). 

On  a  heavy  protein  diet  the  urine  is  acid  on  account  of  the  sulphuric 
and  other  acids  formed  from  the  meat,  and  in  this  case  there  is  a  greater 
amount  of  phosphoric  acid  and  the  mono-sodium  hydrogen  phosphate. 
When  the  urine  is  alkaline  or  less  acid,  as  it  is  on  a  vegetable  diet,  there 
is  a  large  amount  of  the  disodium  hydrogen  phosphate.  Since  calcium 
and  magnesium  phosphates  are  more  soluble  than  the  diphosphates  of 
the  same  metals,  deposits  of  the  earthy  phosphates  are  often  found  in 
neutral  or  alkaline  urines.  When  the  urine  is  heated,  the  diphosphate 
of  calcium  breaks  up  into  the  mono-calcium  and  a  tri-calcium  phos- 
phate, which  accounts  for  the  fine  turbidity  often  taken  for  albumin  in 
the  flame  test.  Addition  of  acid  will  cause  this  to  disappear.  The  crys- 
tals of  triple  phosphates  which  occur  in  alkaline  urine  are  ammonium 
magnesium  phosphate,  NH4MgP04. 

Quantitative  Changes  in  the  Blood  and  Urine  in  Disease 

The  precise  diagnosis  of  many  diseases  is  being  greatly  assisted  by 
quantitative  determinations  of  the  various  nitrogenous  metabolites,  of 
sugar  and  of  inorganic  salts,  not  only  in  the  urine  but  also  in  the  blood. 
Although  the  details  of  this  work  must  be  sought  for  in  the  texts  deal- 
ing with  clinical  diagnosis,  it  may  be  of  value,  as  indicating  the  practical 
nature  of  the  work  if  we  give  one  of  the  tables  (page  568)  recently  pub- 
lished by  Myers16  which  illustrates  the  nature  of  the  results  that  have 
been  obtained. 

COMPARATIVE  NITROGEN  PARTITION   OF  URINE  AND  BLOOD. 
(In  per  cent  of  total  nonprotein  nitrogen) 


FLUID                                                       URIC^ACID 

UREA      CREATININE 

N                     N 

AMMONIA 

N 

REST 

N 

Normal  Urine                                     <X^L5 
Normal  Blood                                            2 
Blood  in  Gout  and  Early  Nephritis  6 
Blood  in  Parenchymatous 
Nephritis    (Nephrosis)                    2 
Blood  in  Terminal  Interstitial 
Nephritis                                             2  to  3 

85 
50 
50 

55 
75 

5 
2 
o 

2 
2.5 

4 
0.3 
0.3 

0.3 
0.5 

4.5 
46 
42 

40 
•20 

In  the  foregoing  table  is  given  a  comparison  of  the  partition  of  the  non- 
protein  nitrogenous  constituents  of  the  blood  and  urine  as  well  as  that  of 
the  blood  in  nephritic  conditions.  A  useful  description  of  .the  most  prac- 
tical and  simple  of  the  methods  employed  for  making  the  necessary  an- 
alyses will  be  found  in  the  papers  of  Myers. 


568 


THE   EXCRETION   OF   URINE 


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AMOUNT   AND    COMPOSITION   OF   THE   URINE  569 

KIDNEY  KEFERENCES 

(Monographs) 

Beddard,  A.  P.:     Recent  Advances  in  Physiology,  Longmans,   Green  &  Co.,   London, 

1906. 
Cushny,  A.  E.:     Secretion  of  Urine,  Longmans,  Green  &  Co.,  London,  1917. 

(Original  Papers) 

iBrodie,  T.  G.,  and  Mackenzie,  J.  J.:     Proc.  Eoy.  Soc.,  1914,  Ixxxvii,  B,  593. 

sCushny,  A.  E.:     Secretion  of  Urine,  1917,  p.  48. 

sAddis  and  Watanabe:     Jour.  Biol.  Chem.,  1916,  xxiv,  203. 

4Mosenthal,  H.  O.:     Arch.  Int.  Med.,  1915,  xvi,  733. 

sAmbard  and  Weil:     Physiologic  normals   et  pathologique   des  reins,   Paris,   1914, 
J.  B.  Bailliere  et  fils. 

sMaclean,  F.  C.:     Jour.  Exper.  Med.,  1915,  xxii,  212. 

7Chase  and  Meyers:     Jour.  Am.  Med.  Assn.,  1916,  Ixvii,  931. 

s Van  Slyke,  D.  D.,  and  Meyer,  G.  M.:     Jour.  Biol.  Chem.,  1912,  xii,  399;  and  1913, 
xvi,  197,  213  and  231. 

»Knowlton,  F.  P.:     Jour.  Physiol.,  1911,  xliii,  219. 
iQBarcroft,  J.,  and  Straub,  H.:     Jour.  Physiol.,  1910,  xli,  145. 
nEowntree  and  Geraghty:     Jour.  Pharm.  and  Exper.  Thefap.,  1910,  i,  579. 
isAsher  and  Pearce,  E.  G.:     Zeitschr.  f.  Biol.,  1913,  Ixiii,  83. 
isPearce,  E.  G.,  and  Carter,  E.  P.:     Am.  Jour.  Physiol.,  1915,  xxxviii,  350. 
"Stewart,  G.  K:     Text  Book  of  Physiology,  1918. 
isLeathes,  J.  B.:     Brit.  Med.  Jour.,  Aug.  9,  1918,  p.  165. 
leMyers,  V.  C. :     Jour.  Lab.  and  Clin.  Med.,  1920,  v,  343,  418,  490. 
iniichards,  A.  K,  and  Plant,  O.  H.:     Am.  Jour.  Physiol.,  1922,  lix,  144,  184,  191. 
isEichards,  A.  N.,  and  Schmidt,  C.  F.:     Proc.  Am.  Physiol.  Soc.,  Am.  Jour.  Physiol., 

1922,  lix,  489. 
iQWearn,  J.  T.:     ibid,  490. 

,  T.  P.,  and  Benedict,  S.  E. :     Jour.  Biol.  Chem.,  1921,  xlviii,  463. 


PART  VII 
METABOLISM 


CHAPTER  LXII 

METABOLISM 

Introductory. — The  object  of  digestion,  as  we  have  seen,  is  to  render 
the  food  capable  of  absorption  into  the  circulatory  liuids — the  blood  and 
lymph.  The  absorbed  food  products  are  then  transported  to  the  various 
organs  and  tissues  of  the  body,  where  they  may  be  either  used  at  once 
or  stored  away  against  future  requirements.  After  being  used,  certain 
substances  are  produced  from  the  foods  as  waste  products,  and  these  pass 
back  into  the  blood  to  be  carried  to  the  organs  of  excretion,  by  which  they 
are  expelled  from  the  body.  By  comparison  of  the  amount  of  these  ex- 
cretory products  with  that  of  the  constituents  of  food,  we  can  tell  how 
much  of  the  latter  has  been  retained  in  the  body,  or  lost  from  it.  This 
constitutes  the  subject  of  general  metabolism.  On  the  other  hand,  we  may 
direct  our  attention,  not  to  the  balance  between  intake  and  output,  but  to 
the  chemical  changes  through  which  each  of  the  foodstuffs  must  pass  be- 
tween absorption  and  excretion.  This  is  the  subject  of  special  metabolism. 
In  the  one  case  we  content  ourselves  with  a  comparison  of  the  raw  ma- 
terial acquired  and  the  finished  product  produced  by  the  animal  factory; 
in  the  other  we  seek  to  learn  something  of  the  particular  changes  to  which 
each  crude  product  is  subjected  before  it  can  be  used  for  the  purpose  of 
driving  the  machinery  of  life  or  of  repairing  the  worn-out  parts  of  the 
body. 

In  drawing  up  a  balance  sheet  of  general  metabolism,  we  must  select 
for  comparison  substances  that  are  common  to  both  intake  and  output.  In 
general  the  intake  comprises,  besides  oxygen,  the  proteins,  fats  and  car- 
bohydrates; and  the  output,  carbon  dioxide,  water  and  the  various  nitrog- 
enous constituents  of  urine.  This  dissimilarity  in  chemical  structure  be- 
tween the  substances  ingested  and  those  excreted  limits  us,  in  balancing  the 
one  against  the  other,  to  a  comparison  of  the  smallest  fragments  into  which 
each  can  be  broken  by  chemical  agencies.  These  are  the  elements,  and  of 
them  carbon  and  nitrogen  are  the  only  ones  whifli  it  is  possible  to  measure 

570 


METABOLISM  571 

with  accuracy  in  both  intake  and  output.  From  balance  sheets  of  intake 
and  output  of  carbon  and  nitrogen  and  from  information  obtained  by  ob- 
serving the  ratio  between  the  amounts  of  oxygen  consumed  by  the  animal 
and  of  carbonic  acid  excreted,  we  can  draw  far-reaching  conclusions  re- 
garding the  relative  amounts  of  protein,  fat  and  carbohydrate  that  have 
been  involved  in  the  metabolism. 

As  has  already  been  stated,  the  essential  nature  of  the  metabolic  proc- 
ess in  animals  is  one  of  oxidation — that  is,  one  by  which  large  unstable 
molecules  are  broken  down  to  those  that  are  simple  and  stable.  Dur- 
ing this  process  of  catabolism,  as  it  is  called,  the  potential  energy  locked 
away  in  the  large  molecules  becomes  liberated  as  actual  or  kinetic  energy— 
that  is,  as  movement  and  heat.  It  therefore  becomes  of  importance  to 
compare  the  actual  energy  which  an  animal  expends  in  a  given  time  with 
the  energy  which  has  meanwhile  been  rendered  available  by  metabolism. 
We  shall  first  of  all  consider  this  so-called  energy  balance  and  then  pro- 
ceed to  examine  somewhat  more  in  detail  the  material  balance  of  the  body. 


ENERGY  BALANCE 

The  unit  of  energy  is  the  large  calorie  (written  0.),  which  is  the  amount 
of  heat  required  to  raise  the  temperature  of  one  kilogram  of  water  through 
one  degree  (Centigrade)  of  temperature.*  We  can  determine  the  calorie 
value  by  allowing  a  measured  quantity  of  a  substance  to  burn  in  com- 
pressed oxygen  in  a  steel  bomb  placed  in  a  known  volume  of  water  at  a 
certain  temperature.  Whenever  combustion  is  completed,  we  find  out 
through  how  many  degrees  the  temperature  of  the  water  has  become 
raised  and  multiply  this  by  the  volume  of  water  in  liters.  Measured 
in  such  a  calorimeter,  as  this  apparatus  is  called,  it  has  been  found  that 
the  number  of  calories  liberated  by  burning  one  gram  of  each  of  the  proxi- 
mate principles  of  food  is  as  follows : 

Carbohydrates  j  ^ardl ' "   ^ 

|  Sugar    4.0 

Protein    5.0 

Fat 9.3 

The  same  number  of  calories  will  be  liberated  at  whatever  rate  the  com- 
bustion proceeds,  provided  it  results  in  the  same  end  products.  When 
a  substance,  such  as  sugar  or  fat,  is  burned  in  the  presence  of  oxygen,  it 
yields  carbon  dioxide  and  water,  which  are  also  the  end  products  of  the 
metabolism  of  these  foodstuffs  in  the  animal  body ;  therefore,  when  a  gram 
of  sugar  or  fat  is  quickly  burned  in  a  calorimeter,  it  releases  the  same 

*The  distinction  between  a  calorie  and  a  degree  of  temperature  must  be  clearly  understood.  The 
former  expresses  quantity  of  actual  heat  energy;  the  latter  merely  tells  us  the  intensity  at  which  the 
lieat  energy  is  being  given  out. 


572 


METABOLISM 


amount  of  energy  as  when  it  is  slowly  oxidized  in  the  animal  body.  But 
the  case  is  different  for  proteins,  because  these  yield  less  completely  oxi- 
dized end  products  in  the  animal  body  than  they  yield  when  burned  in 
oxygen;  so  that,  to  ascertain  the  physiological  energy  value  of  protein,  we 
must  deduct  from  its  physical  heat  value  the  physical  heat  value  of  the 
incompletely  oxidized  end  products  of  its  metabolism.  It  is  obvious  that 
we  can  compute  the  total  available  energy  of  our  diet  by  multiplying  the 
quantity  of  each  foodstuff  by  its  calorie  value. 

Methods. — In  order  to  measure  the  energy  that  is  actually  liberated  in  the  animal 
body,   we  must  also  use  a  calorimeter,  but  of   somewhat   different   construction  from 


Fig.  174. — Respiration  calorimeter  of  the  Russell  Sage  Institute  of  Pathology,  Belleyue  Hospital, 
New  York.  At  the  right  is  seen  the  table  with  the  absorption  tubes;  and  in  the  middle,  at  the 
back,  the  electric  control  table  for  regulating  the  temperature  of  the  double  walls  of  the  calorimeter. 
At  the  extreme  left  is  the  oxygen  cylinder.  (Lusk's  Science  of  Nutrition.) 

that  used  by  the  chemist,  for  we  have  to  provide  for  long-continued  observations  and 
for  an  uninterrupted  supply  of  oxygen  to  the  animal.  Animal  calorimeters  are  also 
usually  provided  with  means  for  the  measurement  of  the  amounts  of  carbon  dioxide 
(and  water)  discharged  and  of  oxygen  absorbed  by  the  animal  during  the  observation. 
Such  respiration  calorimeters  have  been  made  for  all  sorts  of  animals,  the  most  perfect 
for  use  on  man  having  been  constructed  in  America  (see  Fig.  174).  As  illustrating  the 
extreme  accuracy  of  even  the  largest  of  these,  it  is  interesting  to  note  that  the  actual 
heat  given  out  when  a  definite  amount  of  alcohol  or  ether  is  burned  in  one  of  them 
exactly  corresponds  to  the  amount  as  measured  by  the  smaller  bomb-calorimeter.  All 


METABOLISM  573 

of  the  energy  liberated  in  the  body  does  not,  however,  take  the  form  of  heat.  A 
variable  amount  appears  as  mechanical  work,  so  that  to  measure  in  calories  all  of  the 
energy  that  an  animal  expends,  one  must  add  to  the  actual  calories  given  out,  the 
calorie  equivalent  of  the  muscular  work  which  has  been  performed  by  the  animal  dur- 
ing the  period  of  observation.  This  can  be  measured  by  means  of  an  ergometer, 
a  calorie  corresponding  to  425  kilogram*  meters  of  work.  That  it  has  been  possible  to 
strike  an  accurate  balance  between  the  intake  and  the  output  of  energy  of  the  animal 
body,  is  one  of  the  achievements  of  modern  experimental  biology.  It  can  be  done  in 
the  case  of  the  human  animal;  thus,  a  man  doing  work  on  a  bicycle  ergometer  in  the 
Benedict  calorimeter  gave  out  as  actual  heat  4,833  C.,  and  did  work  equalling  602  C., 
giving  a  total  of  5,435  C.  By  drawing  up  a  balance  sheet  of  his  intake  and  output 
of  food  material  during  this  period,  it  was  found  that  the  man  had  consumed  an  amount 
capable  of  yielding  5,459  C.,  which  may  be  considered  as  exactly  balancing  the  actual 
output. 

It  would  be  out  of  place  to  give  a  full  description  of  the  respiration  calorimeter  here. 
The  general  construction  will  be  seen  from  the  accompanying  figure  of  the  form  of 
apparatus  in  use  for  patients  in  the  Eussell  Sage  Institute,  New  York.  One  of  the  most 
icteresting  details  of  its  construction  concerns  the  means  taken  to  prevent  any  loss  of 
heat  from  the  calorimeter  to  the  surrounding  air.  This  is  accomplished  in  the  follow- 
ing way:  The  innermost  layer  of  the  wall  is  of  copper;  then,  separated  from  this  by 
an  air  space,  is  another  wall  of  copper,  outside  of  which  are  two  wooden  walls  separated 
from  each  other  and  from  the  outer  copper  walls  by  air  spaces.  The  two  copper  walls 
are  connected  through  thermoelectric  couples,  so  that  an  electric  current  is  set  up  when- 
ever there  is  any  difference  in  their  temperatures.  The  current  is  observed  by  means  of 
a  galvanometer  placed  outside  the  calorimeter,  and  from  its  movements  the  observer 
either  heats  up  or  cools  down  the  outer  copper  walls  so  as  to  correct  the  difference  of 
temperature  causing  the  current.  This  is  done  by  an  electric  heating  device  or  by  cold 
water  tubes  placed  between  the  outermost  copper  and  the  innermost  wooden  walls. 
Since  the  temperature  of  the  two  copper  walls  is  the  same,  there  can  be  no  exchange  of 
heat  between  them,  and  consequently  none  of  the  heat  that  is  absorbed  by  the  inner  cop- 
per walls  is  allowed  to  be  carried  away.  All  the  heat  given  out  by  the  animal  is  ab- 
sorbed by  the  stream  of  cold  water  flowing  through  the  coils  of  pipe  in  the  chamber. 
The  heat  used  to  vaporize  the  moisture  from  skin  and  lungs  must  of  course  also  be 
measured.  This  is  done  by  collecting  the  water  vapor  in  a  sulphuric-acid  bottle  placed 
in  the  ventilating  current.  By  multiplying  the  grams  of  water  by  the  factor  for  the 
latent  heat  of  vaporization,  we  obtain  the  calories  of  heat  so  eliminated. 

' '  The  calorimeter  contains  a  comfortable  bed  and  is  provided  with  two  windows,  a 
shelf,  a  telephone,  a  fan,  a  light  and  a  Bowles  stethoscope  for  counting  the  pulse. 
The  ordinary  experiment  takes  about  as  long  as  a  trip  from  New  York  to  New  London. 
Patients,  as  a  rule,  doze  from  time  to  time  or  else  try  to  work  out  some  scheme  by 
which  they  can  amuse  themselves  without  moving.  After  three  or  four  hours  they  are 
rather  bored  by  the  quiet,  and  the  observations  are  not  prolonged  beyond  this  time. 
They  are  allowed  to  turn  over  in  bed  once  or  twice  an  hour,  but  reading  and  telephon- 
ing are  discouraged,  since  these  increase  the  metabolism.  The  air  in  the  box  is  fresh 
and  pure,  the  patient  suffers  no  discomfort,  and  objections  to  the  procedure  are  very 
infrequent.  Most  of  the  patients  are  only  too  glad  of  the  extra  attention,  and  they 
insist  that  the  calorimeter  has  a  marked  therapeutic  value."  (Du  Bois.) 

Normal  Values. — Having  thus  satisfied  ourselves  as  to  the  extreme 

*A  kilogram  meter  is  the  product  of  the  load  in  kilograms  multiplied  by  the  distance  in  meters 
through  which  it  is  lifted. 


574 


.M  i  :TA  HOI.  i  S.M 


accuracy  of  the  method  for  measuring  energy  output,  we  shall  now  con- 
sider some  of  the  conditions  that  control  it.  To  study  these  we  must  first 
of  all  determine  the  basal  heat  production — that  is,  the  smallest  energy 
output  that  is  compatible  with  health.  This  is  ascertained  by  allowing  a 
man  to  sleep  in  the  calorimeter  and  then  measuring  his  calorie  output 
while  he  is  still  resting  in  bed  in  the  morning,  fifteen  hours  after  the  last 
meal.  When  the  results  thus  obtained  on  a  number  of  individuals  are 
calculated  so  as  to  represent  the  calorie  output  per  kilogram  of  body  weight 
in  each  case,  it  will  be  found  that  1  C.  per  kilo  per  hour  is  discharged 
—that  is  to  say,  the  total  energy  expenditure  in  24  hours  in  a  man  of  70 
kilos,  which  is  a  good  average  weight,  will  be  70X24  =  1,680  C. 

When  food  is  taken  the  heat  production  rises,  the  increase  over  the 
basal  heat  production  amounting  for  an  ordinary  diet  to  about  10  per 
cent.  Besides  being  the  ultimate  source  of  all  the  body  heat,  food  is  there- 
fore a  direct  stimulant  of  heat  production.  This  specific  dynamic  action, 
as  it  is  called,  is  not,  however,  the  same  for  all  groups  of  foodstuffs,  being 
greatest  for  proteins  and  least  for  carbohydrates.  Thus,  if  a  starving 
animal  kept  at  33°  C.  is  given  protein  with  a  calorie  value  which  is  equal 
to  the  calorie  output  during  starvation,  the  calorie  output  will  increase  by 
30  per  cent,  whereas  with  carbohydrates  it  will  increase  by  only  6  per 
cent.  Evidently,  then,  protein  liberates  much  free  heat  during  its  as- 
similation in  the  animal  body;  it  burns  with  a  hotter  flame  than  fats  or 
carbohydrates,  although  before  it  is  completely  burned  it  may  not  yield 
so  much  energy  as  is  the  case,  for  example,  when  fats  are  burned.  This 
peculiar  property  of  proteins  accounts  for  their  well-known  heating  qual- 
ities. It  explains  why  protein  composes  so  large  a  proportion  of  the  diet  of 
peoples  living  in  cold  regions,  and  why  it  is  cut  down  in  the  diet  of  those 
who  dwell  near  the  tropics.  Individuals  maintained  on  a  low  protein  diet 
may  suffer  intensely  from  cold. 

If  we  add  to  the  basal  heat  production  of  1,680  C.  another  168  C.  (or 
10  per  cent)  on  account  of  food,  the  total  1,848  C.  nevertheless  falls  far 
short  of  that  which  we  know  must  be  liberated  when  we  calculate  the 
available  energy  of  the  diet,  which  we  may  take  as  2,500  C.  What  be- 
comes of  the  extra  fuel  ?  The  answer  is  that  it  is  used  for  muscular  work. 
Thus  it  has  been  found  that  if  the  observed  person,  instead  of  lying  down 
in  the  calorimeter,  is  made  to  sit  in  a  chair,  the  heat  production  is  raised 
by  8  per  cent,  or  if  he  performs  such  movements  as  would  be  necessary  for 
ordinary  work  (writing  at  a  desk)  it  may  rise  about  30  per  cent,  that  is  to 
say,  to  90  C.  per  hour.  There  is,  however,  practically  no  difference  in  the 
energy  output  of  a  person  lying  flat  or  lying  in  a  semi-reclining  posi- 
tion, as  in  a  steamer  chair.  Allowing  eight  hours  for  sleep  and  sixteen 
hours  for  work,  we  can  account  for  about  2.168  0.,  the  remaining  300  odd 


METABOLISM  575 

C.  that  are  required  to  bring  the  total  to  that  which  we  know,  from  statis- 
tical tables  of  the  diets  of  such  workers,  to  be  the  actual  daily  expenditure, 
being  due  to  the  exercise  of  walking.  If  the  exercise  is  more  strenuous, 
still  more  calories  will  be  expended;  thus,  to  ascend  a  hill  of  1,650  feet  at 
the  rate  of  2.7  miles  an  hour  requires  407  extra  calories.  Field  workers 
may  expend,  in  24  hours,  almost  twice  as  manj^  calories  as  those  engaged 
in  sedentary  occupations. 

Standard  for  Comparison 

When  the  energy  output  per  kilo  body  iveiglit  is  determined  in  animals 
of  varying  size,  the  values  are  greater  the  lighter  the  animal.  This  is 
evident  from  the  following  results  obtained  on  dogs: 

Weight  of  docf  Heat  production  in  calories 

per  Icilo  per  day 

(1)  31.2  35.68 

(2)  18.2  4(5.2 

(3)  9.6  65.16 

(4)  0.5  66.07 

(5)  3.19  88.07 

(Eubner) 

When,  on  the  other  hand,  instead  of  body  weight,  the  area  of  the  sur- 
face of  the  body  is  taken  as  the  basis  of  calculation,  results  that  are  almost 
constant  are  obtained.  Following  are  the  results  in  the  above  animals  on 
this  basis: 

Heat  production  in  calories 

Surface  in  square  cm.  per  square  meter  of  sur- 

face per  day 

(1)  10,750  1036 

(2)  7,662  1097 

(3)  5,286  1183 

(4)  3,724  1153 

(5)  2,423  1212 

(Eubner) 

Such  results  have  prompted  observers  to  conclude  that  the  determining 
factor  in  the  calorie  output  of  warm-blooded  animals  is  the  relative  sur- 
face of  the  animal.  This  is  greater  the  smaller  the  animal,  with  the  con- 
sequence that  heat  is  more  rapidly  lost  to  the  surrounding  air  from  the 
surface,  thus  requiring  more  active  combustion.  Until  quite  recently  it  has 
been  generally  believed  that  such  a  relationship  between  body  surface  and 
heat  production  did  actually  exist,  but,  thanks  to  the  work  of  F.  G-.  Bene- 
dict7 and  E.  F.  and  D.  Du  Bois6,  it  is  now  known  that  the  calculations  were 
based  upon  incorrect  computations  of  the  body  surface.  In  the  older  re- 
searches the  ca^ulation  was  made  by  using  a  formula  known  as  Meeh's,  in 
which  weight  was  multiplied  by  a  certain  factor  (viz.,  12.312  x  -^weight). 
Du  Bois,  however,  has  shown  that  an  average  error  of  16  per  cent  is  in- 
curred in  using  this  formula.  For  more  accurate  measurement  of  the 


576 


METABOLISM 


surface  area  in  man  this  worker  covered  the  body  with  thin  underwear, 
which  was  then  impregnated  with  melted  paraffin  and  reinforced  with 
paper  strips  to  prevent  it  from  changing  in  area  when  removed.  This 
model  of  the  surface  was  afterwards  cut  up  into  flat  pieces  and  photo- 
graphed on  paper  of  uniform  thickness,  the  patterns  being  then  cut  out, 
and  weighed.  From  the  results  it  was  easy  to  calculate  the  actual  sur- 
face area. 

Where  the  height  and  weight  are  known,  a  fairly  accurate  computation 
of  the  surface  can  be  secured  by  using  the  following  formulas :  A=W°-425 
XH°-725X71.84;  A  being  the  surface  area  in  square  centimeters;  H  the 
height  in  centimeters;  and  W,  the  weight  in  kilograms.  Based  on  this 
formula,  a  chart  has  been  plotted  from  which  the  surface  area  may  be  de- 


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I.I 

0         30         40         50         60         70         80         90         100        t 

WEIGHT-KILOGRAMS 

Fig.  175. — Chart  for  determining  surface  area  of  man  in  square  meters  from  weight  in  kilo- 
grams (Wt.)  and  height  in  centimeters  (Ht.)  according  to  the  formula:  Area  (Sq.  Cm.)  =  Wt. 
0.425  XHt.  0.725  X71.84.  (From  Dubois  and  Dubois,  Arch.  Int.  Med.,  1917,  vol.  17.) 

termined  at  a  glance  (Fig.  175).  Another  method  recently  employed  by 
Benedict  is  based  on  measurements  made  from  photographs  of  the  subject 
in  various  poses. 

By  the  use  of  these  more  accurate  measurements  of  body  surface,  it  is 
now  known  that,  although  the  surface-area  law  gives  us  constant  results 
for  the  energy  output  of  different  individuals  of  similar  build,  and  offers 
us  a  much  more  accurate  basis  than  body  weight  for  comparing  those  of  dif- 
ferent laboratory  animals,  yet  it  breaks  down  when  applied  to  men  in  widely 
differing  states  of  body  nutrition.  Thus,  in  the  case  of  a  man  who  starved 
for  a  month,  the  calorie  output  per  square  meter  of  surface  decreased  to- 
wards the  end  of  the  fast  by  28  per  cent.  Obviously,  therefore,  it  would  be 
incorrect  to  draw  conclusions  regarding  possible  changes  in  energy  output 


METABOLISM  577 

of  a  series  of  emaciated  or  corpulent  individuals  by  comparison  of  their 
calorie  output  per  square  meter  of  surface  with  that  of  normal  individuals. 

The  determining  factor  of  energy  output  is  undoubtedly  the  general 
condition  of  bodily  nutrition — the  active  mass  of  protoplasm  of  the  body 
(Benedict).  That  there  is  a  relationship  between  the  body  surface  and 
metabolism  is  undoubted,  but  the  relationship  is  not  a  causal  one.  At 
present,  therefore,  the  only  safe  method  to  employ  in  comparing  the 
metabolism  of  normal  and  diseased  individuals  is  that  called  by  Benedict 
"the  group  method,"  in  which  the  metabolism  of  groups  of  persons  of 
like  height  and  weight  is  compared,  it  being  assumed  that  such  individuals 
have  the  same  general  growth  relations.  . 

Benedict,  in  collaboration  with  Harris,  has  carried  this  idea  into  effect 
by  the  preparation  of  standard  tables  which  give  the  values  for  basal 
metabolism  for  both  men  and  women  for  the  commoner  ranges  of  weight, 
stature  and  age.  The  values  in  the  tables  are  based  on  the  statistical 
constants  of  a  sufficient  number  of  accurate  normal  data  so  that  they 
can  be  used  as  the  standards  for  comparison  with  results  obtained  under 
various  physiological  and  pathological  conditions. 

Two  sets  of  tables  are  employed,  one  for  body  weight  and  the  other 
for  stature  and  age,  the  values  of  the  two  tables  being  added  together, 
and,  since  women  have  a  lower  metabolism  than  men,  sets  of  tables  for 
both  sexes  are  necessary.  To  determine  whether  there  is  a  significant 
modification  of  metabolism  in  clinical  cases,  it  is  necessary  to  compare 
the  actually  measured  calories  with  those  calculated  from  the  tables  on 
the  assumption  that  the  patient  is  in  normal  health.  It  has  been  found 
by  this  method  that  athletes  have  a  somewhat  higher  metabolism  than 
untrained  persons,  and  that  living  on  a  vegetarian  diet  does  not  funda- 
mentally alter  it. 

Influence  of  Age  and  Sex 

The  energy  output  is  low  in  the  newly  born ;  it  increases  rapidly  during 
the  first  year,  reaching  a  maximum  at  about  three  to  six  years  of  age,  and 
then  rapidly  declining  to  about  twenty,  after  which  it  declines  much  more 
slowly.  The  decline  in  the  earlier  years  does  not  proceed  steadily,  how- 
ever, for  at  the  period  just  preceding  the  onset  of  puberty  a  decided  in- 
crease becomes  evident,  indicating  that  at  this  period  the  metabolism  of 
the  growing  organism  is  being  stimulated.  Females  have  a  lower  energy 
output  than  males,  and  the  stimulating  influence  of  puberty  is  less  marked 
in  them. 

In  round  numbers,  40  C.  per  square  meter  of  surface  per  hour  is  the 
energy  output  of  normal  men,  a  15  per  cent  deviation  being  considered 
as  decidedly  abnormal.  The  average  metabolism  of  fat  and  thin  subjects  is 


578  METABOLISM 

the  same,  but  that  of  women  is  6.8  per  cent  lower  than  that  of  men.  The 
basal  metabolism  of  a  group  of  men  and  women  between  the  ages  of  forty 
and  fifty  was  4.3  per  cent  below  the  average  for  the  larger  group  between 
the  ages  of  twenty  and  fifty;  and  that  of  a  group  between  fifty  and  sixty 
years  was  11.3  per  cent  lower. 

Influence  of  Diseases 

The  measurements  have  been  made  by  the  direct  method  which  has  just 
been  described,  but  since  the  much  simpler  indirect  method  (page  589) 
yields  comparable  results,  it  is  being  adopted  for  clinical  purposes.  These 
results  were  obtained  by  making  parallel  determinations  of  energy  out- 
put by  both  methods,  in  disease  as  well  as  in  health.  Some  of  the  ob- 
servations that  have  been  made  on  the  energy  output  in  various  diseases 
are  as  follows:  In  very  severe  cases  of  exophthalmic  goiter,  heat  produc- 
tion may  be  increased  from  50  to  75  per  cent  over  the  normal.  The 
warmth  of  the  skin  and  the  sweating,  which  are  prominent  symptoms 
of  this  disease,  are  therefore  accounted  for  by  the  increased  elimina- 
tion of  heat,  and  it  is  considered  possible  that  the  other  symptoms 
would  be  caused  in  any  normal  individual  were  his  metabolism 
maintained  for  months  or  years  at  the  high  level  which  it  occupies  in 
goiter.  In  the  opposite  condition  of  myxedema,  the  energy  output  is 
markedly  reduced,  but  rises  slowly  during  treatment  with  thyroid  extract, 
or  much  more  rapidly  with  the  very  active  thyroid  hormone  recently  iso- 
lated by  Kendall  (page  798).  In  diabetes  it  has  often  been  thought  that 
the  rapid  emaciation  and  loss  of  strength  were  dependent  upon  an  excit( 
state  of  metabolism,  or  a  useless  burning  up  of  the  energy  material.  Al- 
though an  increase  could  not  be  shown  when  the  surface  area  was  used  as  a 
basis  for  calculation  (Du  Bois)  the  group  method  shows  an  increased 
energy  metabolism  in  many  cases  of  diabetes  amounting  sometimes  to 
12  per  cent  (Benedict).  In  uncompensated  cases  of  cardiorenal  dis- 
'ease,  there  is  increased  energy  output.  In  pernicious  anemia  metabolism 
is  normal,  although  in  severe  cases  there  may  be  an  increased  demand  for 
oxygen. 

Even  at  the  risk  of  repetition,  it  is  important  to  point  out  that  in  all 
these  diseases  the  energy  output  is  the  same  whether  measured  directly  or 
by  the  indirect  method  about  to  be  described. 

The  value  of  following  the  basal  metabolism  in  the  therapy  of  exoph- 
thalmic goiter  has  been  demonstrated  in  recent  work  by  Means  and 
Aub,  who  have  followed  the  metabolism  and  clinical  condition  of  a  series 
of  cases  over  a  period  of  several  years.  They  found  in  the  majority  of 
cases  that  the  results  with  the  x-ray  treatment  are  as  good  as  those  se- 
cured by  surgical  methods.  The  basal  metabolism  shows  a  rapid  pre- 


METABOLISM  579 

liminary  fall  after  surgical  removal,  but  a  secondary  rise  occurs,  whereas 
with  x-rays  the  metabolism  gradually  declines  throughout  the  treatment. 
There  is  practically  no  mortality  with  the  x-ray  treatment,  and  the 
risks  of  surgical  interference  in  very  acute  cases  is  decidedly  amelio- 
rated by  a  preliminary  treatment  with  the  rays.  They  conclude  that  "in 
the  management  of  exophthalmic  goiter  periodic  determination  of  the 
basal  metabolism  should  be  quite  as  much  a  routine  as  the  examination 
of  the  urine  for  sugar  in  diabetes  mellitus." 

THE  MATERIAL  BALANCE  OF  THE  BODY 

We  must  distinguish  between  the  balances  of  the  organic  and  the  in- 
organic foodstuffs.  From  a  study  of  the  former  we  shall  gain  information 
regarding  the  sources  of  the  energy  production  whose  behavior  under 
various  conditions  we  have  just  studied.  From  a  study  of  the  inorganic 
balance,  although  we  shall  learn  nothing  regarding  energy  exchange — 
for  such  substances  can  yield  no  energy — we  shall  become  acquainted 
with  several  facts  of  extreme  importance  in  the  maintenance  of  nutrition 
and  growth. 

To  draw  up  a  balance  sheet  of  organic  intake  and  output  requires  an 
accurate  chemical  analysis  of  the  food  and  of  the  excreta  (urine  and  ex- 
pired air). 

Methods  for  Measuring  Output 

The  principle  by  which  the  output  is  measured  will  be  understood  by  referring  to 
Fig.  176,  from  which  it  will  be  seen  that  the  calorimeter  is  connected  with  a  closed 
system  of  tubes  provided  with  an  air-tight  rotary  blower  or  pump  to  maintain  a  con- 
stant current  of  air,  as  indicated  by  the  arrows.  Following  the  air  stream  as  it  leaves 
the  chamber,  we  note  a  side  tube  connecting  with  a  meter  to  indicate  changes  in  vol- 
ume of  the  air  in  the  system.  Beyond  this  and  the  pump  is  a  specially  constructed 
bottle  containing  concentrated  H2SO4,  then  one  containing  soda  lime,  and  lastly  another 
H2SO4  bottle.  The  first  H2SO4  bottle  absorbs  all  the  water  vapor  contained  in  the 
air  coming  from  the  chamber;  the  soda  lime  bottle  absorbs  the  CO2,  and  the  second 
H,S04  bottle  absorbs  water  that  is  produced  in  the  chemical  reaction  involved  in  the 
absorption  of  the  CO2  by  the  soda  lime  (2NaOH  +  CO2  =  H2O +  Na2CO3).  By  weigh- 
ing* these  absorption  bottles  before  and  after  an  animal  has  been  for  some  time  in 
the  chamber,  the  weight  of  H  O  and  of  CO  given  out  can  be  determined.  Another 
side  tube  leads  to  an  oxygen  cylinder,  the  valve  of  which  is  manipulated  so  as  to  cause 
oxygen  to  be  discharged  into  the  system  at  such  a  rate  as  to  compensate  exactly  for 
that  used  up  by  the  animal,  as  indicated  by  the  behavior  of  the  meter.  The  amount  of 
oxygen  required  is  determined  either  by  weighing  the  oxygen  cylinder  before  and  after 
the  observation  or  by  measuring  the  volume  of  oxygen  used  by  passing  it  through  a 
carefully  calibrated  and  very  sensitive  water  meter  inserted  on  the  side  tube  that  con- 
nects the  02  cylinder  with  the  main  tubing  of  the  system.  Since  muscular  activity 
causes  pronounced  changes  in  the  rate  of  metabolism,  means  are  usually  taken  to 
secure  graphic  records  of  any  movements  made  during  the  observation. 


580 


METABOLISM 


The  growing  importance  in  clinical  investigations  of  measurements  of 
the  respiratory  exchange  and  the  necessity  for  having  methods  that  are  as 
simple  as  is  consistent  with  accuracy,  have  led  to  the  introduction  of 
several  other  forms  of  apparatus,  of  which  those  of  F.  G.  Benedict  and  of 
Tissot  are  the  most  important.  In  these  methods  no  calorimeter  is  em- 
ployed but  the  energy  exchange  is  calculated  from  the  amount  of  02 
inspired  in  a  given  time.  In  Benedict's  method  a  tightly  fitting  mask  is 
applied  over  the  nose  and  mouth  and  connected,  by  a  short  T-piece,  with 
the  same  tubing  as  that  used  in  the  respiration  calorimeter.  The  patient 


I  V/////////////////////////////^^^  I 

-<L-    Water  to  absorb   heat  *<-) — 


Fig.  176. — Diagram  of  Atwater-Benedict  respiration  calorimeter.  As  the  animal  uses  up  the  O«, 
the  total  volume  of  air  shrinks.  This  shrinkage  is  indicated  by  the  meter,  and  a  corresponding 
amount  of  C>2  is  delivered  from  the  weighed  (^-cylinder.  The  increase  in  weight  of  bottles 
II  and  III  gives  the  COal  that  of  I,  the  water  vapor. 

thus  breathes  in  and  out  of  the  air  stream  that  is  passing  along  the  tubing 
without  any  of  the  obstruction  experienced  when  the  breathing  has  to  be 
performed  through  valves,  as  in  the  older  (Zuntz)  forms  of  portable 
respiratory  apparatus.  It  is  particularly  for  studies  on  man  that  this 
apparatus  has  been  devised.  The  Tissot  and  Douglas  methods  are  de- 
scribed in  Chapter  LXIV,  where  the  method  used  for  calculating  the  re- 
sults is  also  outlined. 

This  is  called  the  method  of  indirect  calorimetry,  and  it  has  been  clearly 
established  by  numerous  observations  that  the  results  agree  exactly  with 
those  secured  by  the  method  of  direct  calorimetry  described  above.  For 


METABOLISM  581 

most  purposes  the  indirect  method  is  quite  satisfactory,  and  it  is  espe- 
cially valuable  in  cases  in  which  there  are  considerable  and  sudden 
changes  in  body  temperature.  That  the  results  by  the  two  methods  should 
agree  shows  clearly  that  the  law  of  the  conservation  of  energy  must  apply 
in  the  animal  body,  for  it  is  evident  that  if  any  energy  were  derived  from 
outside  the  body  other  than  that  taken  with  the  food,  the  results  by  the 
direct  method  would  be  higher  than  those  by  the  indirect. 


CHAPTER  LXIII 

THE  CARBON  BALANCE 

Before  proceeding  to  discuss  the  special  metabolism  of  proteins,  fats 
and  carbohydrates,  it  will  be  advantageous  to  consider  briefly  some  gen- 
eral facts  concerning  the  excretion  of  carbon  dioxide  and  the  intake  of 
oxygen.  In  the  first  place,  it  is  important  to  note  that  the  extent  of  the 
combustion  process  in  the  animal  body  is  proportional  to  the  amount  of 
oxygen  absorbed  and  of  carbon  dioxide  produced,  whereas  the  nature  of 
the  combustion  is  indicated  by  the  ratio  existing  between  the  amounts  of 
carbon  dioxide  expired  and  of  oxygen  retained  in  the  body.  An  investi- 
gation of  the  carbon  balance,  in  other  words,  is  partly  quantitative  and 
partly  qualitative — quantitative  in  the  sense  that  it  indicates  how  in- 
tensely the  body  furnaces  are  burning,  and  qualitative  in  the  sense  that 
it  tells  us  what  sort  of  material  is  being  burned  at  the  time. 

THE  RESPIRATORY  QUOTIENT 

Influence  of  Diet. — The  respiratory  quotient  is  determined  by  com- 
parison of  the  volume  of  carbon  dioxide  expired  with  the  volume  of  oxy- 
gen meanwhile  retained  in  the  body  or,  as  a  formula, 

Vol.  C02  expired    ' 
VoT 02  retained* 

For  the  sake  of  brevity  the  respiratory  quotient  is  often  written  R.  Q.  That 
it  serves  as  an  indicator  of  the  kind  of  combustion  occurring  will  be  evi- 
dent from  the  following  equations: 

1.  Carbohydrate:    CfiH12O6  -K6O2  =  6CO2  +  6H2O 
(Dextrose.) 


2.  Fat:  C3H.(C]8H33O2)3  +  80O2  —  57CO2  +  52H2O 

(Olein.) 


3.  Protein  :  C72H112N18O22S  +  77O2  =  63CO2  +  38H,O  +  9CO  (NH2)2  +  SO, 

[Empirical  formula  for 
albumin  (Lieberkiihn).] 

.      T?  A  ^O2    _   ®^  n  Q9 

••B-Q-=  -57-77- 

582 


THE   CAEBON   BALANCE  583 

4.  Conversion  of  fat  into  carbohydrate: 

2C3H5(C18H3302)3  -f  6402  =  16C6H13O6  +  18CO2  +  8H2O 
(Olein.) 


5.  Conversion  of  carbohydrate  into  a  mixed  fat  : 

13C6H12O6  =  C55H104O6  +  23CO2  +  26H,O. 
(Oleostearopalmitin.) 

Taking  carbohydrates  first,  the  general  formula  may  be  written  CH20, 
from  which  it  is  plain  that,  to  oxidize  the  molecule,  oxygen  will  be  re- 
quired to  combine  with  the  carbon  alone,  according  to  the  equation, 
CH20  +  02  =  C02  +  H20.  In  other  words,  the  volume  of  carbon  dioxide  pro- 
duced by  the  combustion  will  be  exactly  equal  to  the  volume  of  oxygen 
used  in  this  process,  in  obedience  to  the  well-known  gas  law  that  equi- 
molecular  quantities  of  different  gases  occupy  the  same  volume.  The 
respiratory  quotient  is  therefore  unity  (Equation  1).  With  fats  and  pro- 
teins, however,  the  general  formula  must  be  written  CH2-{-0,  indicating 
therefore  that  for  its  complete  oxidation  the  molecule  must  be  supplied 
with  oxygen  in  sufficient  amount  to  combine  not  only  with  all  of  the  car- 
bon, but  also  with  some  of  the  hydrogen,  forming  water;  so  that  the  vol- 
ume of  C02  produced  will  be  less  than  the  volume  of  oxygen  retained, 
and  the  respiratory  quotient  will  be  less  than  unity.  As  a  matter  of  fact, 
as  the  above  equations  show  (2  and  3),  the  respiratory  quotient  for  fats 
is  0.7  and  for  protein  0.82.* 

That  the  conditions  hypothecated  in  the  equations  exist  in  the  animal 
body  during  the  combustion  of  the  foodstuffs  can  easily  be  shown  by  ob- 
serving the  respiratory  quotient  of  animals  on  different  diets.  An  her- 
bivorous animal,  such  as  a  rabbit,  when  it  is  well  fed  gives  invariably  a 
respiratory  quotient  of  about  1,  whereas  a  strictly  carnivorous  animal, 
such  as  the  cat,  gives  a  respiratory  quotient  of  about  0.7.  Even  more 
striking  perhaps  is  the  comparison  of  the  respiratory  quotients  in  an 
herbivorous  animal  while  it  is  well  fed  and  after  it  has  been  starved  for  a 
day  or  two.  In  the  latter  case  the  respiratory  quotient  will  fall  to  a  low 
level  because,  by  starvation,  the  animal  has  been  compelled  to  change  its 
combustion  material  from  the  carbohydrate  of  its  food  to  the  protein  and 
fat  of  its  own  tissues. 

As  already  explained  (page  582),  it  is  from  the  respiratory  quotient 
that  we  are  enabled  to  tell  what  proportions  of  fat  and  carbohydrate, 
respectively,  are  undergoing  metabolism.  A  useful  table  showing  the 
percentage  of  calories  produced  by  each  of  these  foodstuffs,  after  allow- 
ing for  protein,  is  given  by  Graham  Lusk  (see  page  598). 

^Vlore    recent   calculations   based   on    accurate   metabolism    observations   give    0.707    for    fats   and 
0.801    for    protein    (Lusk). 


584  METABOLISM 

Influence  of  Metabolism. — Apart  from  diet,  the  respiratory  quotient 
may  often  be  altered  by  changes  in  the  metabolic  habits  of  the  animal. 
These  are  most  conspicuously  exhibited  in  the  case  of  hibernating 
animals.  In  the  autumn  months,  when  the  animal  is  eating  voraciously 
of  all  kinds  of  carbohydrate  food  and  depositing  large  quantities  of 
adipose  tissue  in  his  body,  the  respiratory  quotient  may  be  considerably 
greater  than  unity,  indicating  therefore  either  that  relatively  more 
carbon  dioxide  is  being  discharged  or  less  oxygen  retained.  As  a  matter 
of  fact,  it  can  easily  be  shown  that  it  is  the  former  of  the  causes  that 
is  responsible  for  the  higher  quotient,  the  explanation  for  the  increased 
production  of  C02  being  that,  as  the  carbohydrate  changes  into  fat,  the 
relative  excess  of  carbon  in  the  former  is  got  rid  of  in  the  form  of  C02, 
as  indicated  in  Equation  5.  On  the  other  hand,  if  the  animal  is  examined 
while  in  his  winter  sleep,  it  will  be  found  that  the  respiratory  quotient  is 
extremely  low,  often  not  more  than  0.3  to  0.4,  which  may  be  interpreted 
as  indicating  either  an  excessive  absorption  of  oxygen  or  a  markedly 
decreased  excretion  of  carbon  dioxide.  As  a  matter  of  fact,  there  is  a 
great  diminution  in  both  the  excretion  of  carbon  dioxide  and  the  intake 
of  02,  because  the  whole  metabolic  activity  of  the  animal  is  extremely 
depressed,  but  this  diminution  affects  the  oxygen  to  a  much  less  degree, 
indicating  therefore  a  relative  increase  in  the  oxygen  retention.  The 
explanation  is  that  the  oxygen  is  being  used  in  the  chemical  process  in- 
volved in  the  conversion  of  the  fat  back  into  carbohydrate. 

Whatever  may  be  the  relationship  between  fat  and  carbohydrate  in 
the  nonhibernating  animal,  there  is  no  doubt  that  during  hiberna- 
tion, before  the  fat  stores  are  burned,  fat  is  converted  into  something 
closely  related  to  carbohydrates,  the  equation  for  the  process  being  rep- 
resented as  given  above  (No.  4). 

In  man  and  the  higher  mammalia,  the  only  condition  apart  from  diet 
which  can  affect  the  nature  of  the  combustion  process  is  disease;  thus 
in  total  diabetes  (page  709)  the  organism  loses  the  power  of  burning 
carbohydrate,  so  that  whatever  the  diet  may  be,  the  respiratory  quotient 
is  very  low,  never  higher  than  that  representing  combustion  of  fat  and 
protein.  It  has  been  claimed  by  certain  investigators  that  in  diabetes 
the  respiratory  quotient  may  fall  considerably  below  0.7,  indicating,  as 
in  hibernating  animals,  that  fat  is  being  converted  into  carbohydrate. 
The  most  recent  and  carefully  controlled  observations,  however,  deny 
this  claim,  and  for  the  present  we  must  assume  that  in  the  body  of  man 
fat  is  not  converted  into  carbohydrate  (see  page  696).  In  numerous  other 
diseases  investigated  by  Du  Bois  and  others6  no  qualitative  change  in 
the  combustion  processes  in  man  has  been  brought  to  light. 


THE    CARBON    BALANCE 


585 


THE  MAGNITUDE  OF  THE  RESPIRATORY  EXCHANGE 

It  is  evident  that  the  amount  of  carbon  dioxide  expired  and  of  oxy- 
gen retained  will  be  proportional  to  the  energy  liberation  in  the  animal 
body.  Even  at  the  risk  of  repetition  it  should  be  noted  that  the 
energy  exchange  can  be  very  accurately  calculated  from  the  result  of 
the  material  balance  sheet — indirect  calorimetry,  as  it  is  called  (page 
580).  On  account  of  the  comparative  simplicity  of  measuring  the  carbon 
dioxide  output  and  oxygen  intake,  it  is  natural  that  many  of  the  obser- 
vations that  have  been  made  on  energy  production  in  the  animal  body 
depend  on  the  use  of  this  method,  justification  for  which  is  found  in  the 
complete  agreement  between  the  results  of  direct  and  indirect  calorim- 
etry in  a  great  variety  of  diseases  and  conditions  in  man  (Du  Bois6).* 

In  the  first  place,  it  is  interesting  to  compare  the  respiratory  ex- 
changes of  different  animals  computed  per  kilo  body  weight.  This  is 
shown  in  the  following  table. 


ANIMAL 

WEIGHT 
GM. 

OXYGEN  AB- 
SORBED PER  KILO 
AND  HOUR 
GM. 

CARBON    DIOXIDE 
DISCHARGED 
PER   KILO 
AND  HOUR 
GM. 

VOL.    C02 
VOL.     02 

TEMPERA- 
TURE OF 
AIR 

Insecta 

Field  cricket 

0.25 



2.305 

— 

— 

Amphibia 

Edible  frog 

0.063 

0.060 

0.69 

15°-19° 

(44.2  c.c.) 

(30.76  c.c.) 

0.105 

0.1134 

0.78 

— 

(73.4c.c.) 

(57.7  c.c.) 

Aves 

Common  hen 

1280 

1.058 

1.327 

0.91 

19° 

(740  c.c.) 

(675  c.c.) 

Pigeon 

232-380 



3.236 

— 

— 

Sparrow 

22 

9.595 

10.492 

0.79 

18° 

(6710  c.c.) 

(5334.5  c.c.) 

Mammalia 

Ox 

638,000 



0.389-0.485 

— 

— 

660,000 

Sheep 

66,000 

0.490 

0.671 

0.99 

16° 

(343  c.c.) 

(341  c.c.) 

Dog 

6213 

1.303 

1.325 

0.74 

15° 

(911  c.c.) 

(674  c.c.) 

Cat 

2464 

1.356 

1.397 

0.75 

-3.2° 

3047 

(947  c.c.) 

(710  c.c.) 

)  f 

0.645 

0.766 

0.86 

29.6° 

(450  c.c.) 

(389  c.c.) 

Rabbit 

1433 

1.012 

1.354 

0.97 

18°-20° 

Guinea  pig 

444.9 

1.478 

1.758 

0.86 

22° 

Rat  (white) 

80.5 



3.518 

— 

7° 

(1789  c.c.) 

Mouse    " 

25 



8.4 



17° 

Man 

66,70 

0.292 

0.327 

— 

— 

(Modified  from  Pembrey.)" 

*For   the   convenience    of    those    who    may    desire   to   know    more    about    the    methods    of    analysis 
that  are  suitable  in  the  clinic,  a  chapter  on  the  subject  will  be  found  beginning  on   page   589. 


586  METABOLISM 

Several  factors  operate  to  explain  these  differences,  and  of  these  the 
following  are  of  importance: 

1.  The  Body  Temperature. — Increase  in  body  temperature  entails  in- 
creased combustion.     This  explains  why  the  metabolism  of  a  bird  is 
greater  than  that  of  a  mammal  of  the  same  size,  for,  as  is  well  known,  the 
temperature  of  a  bird  is  two  or  three  degrees  centigrade  above  that  of 
other  animals.    Rise  in  body  temperature  also  explains,  in  part  at  least, 
the  increased  metabolism  observed  in  fever. 

2.  The  Temperature  of  the  Environment. — In  considering  this  we  must 
distinguish  between  the  effect  produced  on  warm-blooded  and  on  cold- 
blooded animals.     Since  the  body  temperature  of  a  cold-blooded  animal 
is  only  one  or  two  degrees  Centigrade  above  that  of  its  environment,  it 
follows  that  the  metabolic  activity  will  be  directly  proportional  to  the 
temperature  of  the  latter.    In  a  warm-blooded  animal,  on  the  other  hand, 
the  body  temperature  remains  constant  whatever  changes  may  occur 
in  that  of  the  environment,  this  constancy  of  body  temperature  being 
dependent  on  the  fact  that  the  intensity  of  the  combustion  processes  is 
inversely  proportional  to  the  cooling  effect  of  the  atmosphere.     Thus, 
suppose  the  external  temperature  should  fall,  then  the  loss  of  heat  from 
the  body  will  tend  to  become  greater,  and  to  maintain  the  body  tempera- 
ture at  a  constant  level,  the  body  furnaces  must  burn  more  briskly,  with 
the  result  that  an  increased  excretion  of  carbon  dioxide  and  intake  of 
oxygen  will  occur. 

This  influence  of  the  surrounding  atmosphere  on  the  metabolic  activ- 
ity of  warm-blooded  animals  has,  as  already  pointed  out,  been  used  by 
several  investigators  to  explain  the  greater  combustion  per  kilo  body 
weight  of  small  as  compared  with  large  animals.  The  argument  is  that, 
since  the  surface  of  small  animals  relatively  to  their  mass  is  much  greater 
than  in  large  animals,  the  cooling  of  the  small  animals  will  be  proportion- 
ately greater.  The  relationship  between  surface  and  mass  is  shown  by  tak- 
ing two  cubes  and  putting  them  together;  the  mass  of  the  two  cubes  is 
equal  to  double  that  of  either  cube,  whereas  the  surface  is  less  than 
double,  since  two  aspects  of  the  cubes  have  been  brought  together.  To 
prove  the  contention,  the  respiratory  exchange  has  been  computed  per 
square  meter  of  surface  instead  of  per  kilo  body  weight,  with  the  result 
that  a  very  close  correspondence  in  the  metabolism  of  different  animals 
has  been  observed ;  but  this  question  has  already  been  discussed,  and  we 
now  know  that  the  law  of  cooling  can  not  be  the  only  one  that  determines 
the  extent  of  the  respiratory  exchange  (see  page  577). 

3.  Muscular  Exercise. — This  has  a  most  important  influence  on  the  ex- 
change and  it  is  particularly  in  connection  with  it  that  studies  in  carbon- 
dioxide  output  and  oxygen  intake  have  been  of  great  practical  value,  par- 


THE   CARBON   BALANCE  587 

ticularly  when  the  investigations  are  undertaken  on  men  doing  ordinary 
types  of  muscular  exercise,  such  as  walking  or  climbing.  It  is  true 
that  the  influence  of  muscular  exercise  on  the  energy  metabolism  may 
also  be  studied  by  having  a  person  in  the  calorimeter  do  exercises  on  an 
ergometer,  but  the  results  thus  obtained  are  in  many  ways  not  nearly  so 
valuable  as  those  which  can  be  secured  by  observing  the  respiratory 
exchange  of  persons  doing  ordinary  types  of  muscular  exercise  in  the 
open.  The  following  table  of  observations  on  horses  is  of  interest  in  this 
connection. 


CONDITION 

AIR  EXPIRED 

CARBON  DIOlXIDE 

OXYGEN  ABSORBED 

C02 

IN  LITERS 

DISCHARGED  IN 

IN  LITERS  PER 

02 

PER  MINUTE 

LITERS  PER 

MINUTE 

MINUTE 

Best 

44 

1.478 

1.601 

0.92 

Walk 

177 

4.342 

4.766 

0.90 

Trot 

333 

7.516 

8.093 

0.93 

It  will  be  observed  that  the  metabolism  increases  extraordinarily  for 
even  a  moderate  degree  of  work,  but  that  at  the  same  time  the  respiratory 
quotient  remains  constant.  From  observations  on  the  respiratory  ex- 
change of  working  men  and  animals,  extremely  important  facts  concern- 
ing the  efficiency  of  muscular  work  have  been  secured.  The  form  of 
respiratory  apparatus  (Zuiitz  or  Douglas)  employed  for  this  purpose 
must  be  capable  of  being  strapped  on  the  man's  back  without  causing 
any  embarrassment  to  his  bodily  movements.  By  a  comparison  of  the 
respiratory  exchange  with  the  amount  of  work  done,  the  efficiency  of  the 
work  can  readily  be  determined.  It  has  been  found,  for  example,  that 
the  efficiency  is  much  greater  after  the  man  or  animal  has  got  into  the 
swing  of  the  work,  his  energy  expenditure  per  unit  of  work  being  much 
greater  during  the  first  half  hour's  work  in  the  morning  than  it  is 
later  on.  This  indicates  that  after  a  little  practice  the  muscles  can  ex- 
ecute a  given  movement  and  perform  a  given  amount  of  work  much 
more  smoothly  than  when  they  are  not  in  training.  Another  interesting 
outcome  of  the  investigations  has  been  to  show  that  work  done  under  ab- 
normal conditions  that  tend  to  produce  any  kind  of  muscular  strain  is 
done  inefficiently.  It  has  been  found  in  marching  soldiers,  for  example, 
that  the  slightest  abrasion  of  the  foot  greatly  increases  the  energy 
expenditure,  for  the  man,  in  trying  to  avoid  the  pain  produced  by  the 
abrasion,  brings  into  operation  muscular  groups  that  are  really  not 
required  for  the  efficient  performance  of  the  movement,  but  are  used  in 
the  attempt  to  avoid  pressure  on  the  sore.  Fatigue  also  causes  inefficient 
performance  of  work;  that  is  to  say,  the  fatigued  person,  on  attempting 


588 


METABOLISM 


the  same  amount  of  work  as  he  performed  before  becoming  fatigued, 
will  do  so  at  a  much  greater  expenditure  of  energy. 

There  is  a  diurnal  variation  in  the  respiratory  exchange,  which  is  in 
(general  parallel  with  the  body  temperature;  it  rises  during  the  day,  the 
(time  of  activity  and  work,  and  falls  during  the  night,  the  time  of  rest 
'and  sleep.    Foodjilso  affects  respiratory  exchange,  but  it  will  be  unnec- 
essary to  go  into  this  further  after  what  has  been  said  on  page  582. 


CHAPTER  LXIV 

A  CLINICAL  METHOD  FOR  DETERMINING  THE  RESPIRATORY 

EXCHANGE  IN  MAN* 

(Contributed  by  R.  G.  PEARCE) 

Principle. — Since  the  determination  of  the  respiratory  exchange  in 
man  is  of  some  importance  in  the  study  of  certain  diseases  of  the  respira- 
tion, circulation  and  metabolism,  and  also  because  directions  for  carry- 
ing out  the  necessary  procedures  are  not  generally  available,  we  have 
thought  it  might  be  of  assistance  to  include  here  brief  directions  for  the 
Tissot  and  the  Douglas  methods.  These  methods  have  been  found  to 
compare  favorably  in  accuracy  with  others  in  use  at  present,!  and  be- 
cause of  their  adaptability  and  simplicity  they  are  specially  suited  for 
clinical  work. 

By  these  methods  the  energy  metabolism  of  the  body  is  calculated  from 
oxygen  consumption  or  carbon  dioxide  excretion  per  minute  (indirect 
calorimetry)  (page  580),  the  figures  for  which  are  determined  from  the 
volume  and  percentile  gaseous  composition  of  the  expired  air. 

The  subject  breathes  through  valves  which  automatically  partition  the 
inspired  and  expired  air.  The  expirations  from  a  number  of  respirations 
are  collected  in  a  spirometer  or  bag,  and  the  volume  of  the  respirations 
per  minute  is  determined.  The  gaseous  composition  of  the  expired  air 
is  determined  by  gas  analysis,  and  the  oxygen  consumption  and  energy 
output  of  the  body  are  calculated  from  the  data  obtained. 

Description  and  Use  of  Parts  of  the  Apparatus:  1.  THE  MOUTHPIECE  AND  VALVES. 
— The  mouthpiece  is  made  of  soft  pure  gum  rubber,  and  consists  of  an  elliptical  rub- 
ber flange  having  a  hole  in  the  center  2  cm.  in  diameter.  The  flange  is  attached  on 
one  side  to  a  short  rubber  tube.  On  the  other  side  at  right  angles  to  the  rubber  flange, 
are  attached  two  rubber  lugs.  The  rubber  flange  is  placed  between  the  lips,  and  the 
lugs  are  held  by  the  teeth.  The  rubber  tube  of  the  mouthpiece  is  connected  to  the 
tube  carrying  the  valves.  The  nose  must  be  tightly  closed  if  mouth  breathing  is  used. 
This  is  accomplished  by  a  nose  clip,  which  consists  of  a  V-shaped  metal  spring,  the 
ends  of  which  are  provided  with  felt  pads.  A  toothed  rachet  is  attached  to  the  ends  of 
the  spring,  and  serves  to  hold  the  spring  tightly  clamped  on  the  nostrils  in  the  proper 
position  (see  Fig.  177). 

Some  individuals  experience  great  distress  when  made  to  breathe  through  the  mouth. 

*This  chapter  is  added  for  the  convenience  of  workers  in  this  subject. 
tCarpenter:     Carnegie  Institution  of  Washington  Reports,  No.  216,  1915. 

589 


590 


METABOLISM 


For  these  it  is  best  to  use  a  face  mask.  Unfortunately  at  the  present  time  no  mask  is 
entirely  satisfactory.  Perhaps  the  best  is  one  sold  by  Siebe,  Gorman  &  Co.,*  which  is 
pictured  in  the  cut.  After  being  placed  in  position  the  face  mask  should  be  tested  for 
leaks,  which  can  be  done  by  putting  soap  around  the  edges. 


Fig.    177. — A,  Nose  clip;   B,   Face  mask;    C,   Mouth  piece. 


Fig.    178. — Diagram   of   respiratory   valves. 

2.  THE  VALVES. — The  valves  of  Tissot  are  probably  the  best  for  the  purpose,  but 
they  are  expensive  and  difficult  to  obtain.  We  have  made  perfectly  satisfactory  valves 
from  the  prepared  casings  used  in  the  manufacture  of  bologna  sausage.  These  can 

*This  mask  has  been  used  extensively  by  Carpenter.  The  agent  on  this  continent  is  H.  N.  Elmer, 
1140  Monadnock  Bldg.,  Chicago. 


METHOD   FOR  DETERMINING   RESPIRATORY   EXCHANGE   IN   MAN 


5S1 


be  obtained  preserved  in  salt,  and  they  will  keep  indefinitely  on  iee.  When  needed  a 
short  piece  is  taken,  washed  free  from  salt  by  allowing  water  from  the  tap  to  run 
through  it,  and  softened  in  a  weak  glycerine  solution.  The  gut  becomes  very  soft 
and  pliable,  and  does  not  dry  quickly.  A  piece  of  the  easing  about  10  cm.  long  is 
threaded  through  a  glass  tube  of  about  15  mm.  bore  and  4  to  6  cm.  long.  One  end 


Fig.    179. — The   Tissot   spirometer.      In    actual    experiment,    subject    is    reclining   or   lying   down   and 
the   valves   and   mouthpiece   are   held   with   a   clamp. 


of  the  casing  is  brought  around  the  outside  of  the  tubing  and  secured  by  means  of  a 
thread.  The  lower  end  of  the  membrane  is  pinched  off  and  the  casing  is  then  cut  a 
little  more  than  half  way  across  its  middle,  so  that  the  opening  will  lie  just  within 
the  free  end  of  the  tube  when  the  casing  is  drawn  back  through  it.  The  loose  end  of 
the  casing  is  slightly  twisted — an  essential  procedure — and  is  then  secured  by  a  thread 
on  the  outer  side  of  the  tube.  If  properly  made,  the  valve  will  work  freely  without 


592 


METABOLISM 


vibration,  and  the  opening  be  sufficiently  large  to  allow  a  good  current  of  air  to  pass. 
It  should  collapse  instantly  and  be  air-tight  when  the  current  of  air  is  reversed.  The 
back  lash,  or  lag  of  closure,  of  these  valves  is  extremely  small,  and  they  will  open  or 
close  with  a  pressure  of  air  not  exceeding  the  pressure  changes  in  normal  respiration. 
When  not  in  use,  the  valves  should  be  kept  in  glycrine  water  on  ice.  Valves  prepared 
in  this  way  have  been  in  use  a  month  without  loss  of  efficiency.  They  are,  however, 
made  with  so  great  ease  that  new  valves  are  provided  for  each  subject,  and  they  are 
therefore  especially  adapted  to  ward  work  (Fig.  178). 

The  valves  are  inserted  in     reverse  order  into  a  supporting  metal  T-piece,  and  the 
joints  made  air-tight  by  tape.     The  stem  of  the  T  is  connected  with  the  mouthpiece* 


Fig.  180. — The  Douglas  bag  method  for  determining  the  respiratory  exchange.  The  arrange- 
ment of  mouthpiece,  valves,  and  connecting  tubes  shown  here  has  been  found  to  be  more  con- 
venient than  that  recommended  by  Douglas. 

Through  a  rubber  tube  of  about  %  inch  bore,  the  expired  air  is  collected  in  the  spirom- 
eter,  or  Douglas  Bag. 

3.  THE  TISSOT  SPIROMETER  is  pictured  in  Fig.  179.  We  have  found  the  100-liter 
size  to  be  very  serviceable  in  the  clinic.  This  instrument  is  mounted  on  a  platform 
Having  rubber  wheels,  and  can  be  moved  about  the  wards  with  ease.  The  bell  of  the 
spirometer  is  made  of  aluminum  and  is  suspended  in  a  water-bath  between  the  double 
walls  of  a  hollow  cylinder  made  of  galvanized  iron.  The  height  of  the  bell  is  72  cm.  and 
the  diameter  42  cm.  An  opening  at  the  bottom  of  the  cylinder  connects  through  a 
three-way  stopcock  with  the  rubber  tube  leading  from  the  expiratory  valve  of  the 
mouthpiece  (see  Fig.  177).  The  bell  is  counterpoised  by  means  of  a  weight.  In  the 
original  Tissot  spirometer  an  automatic  adjustment  permitted  water  in  amount  equal 


METHOD    FOR    DETERMINING    RESPIRATORY   EXCHANGE   IN    MAN 


593 


to  the  water  displaced  by  the  bell  to  flow  from  the  spirometer  cylinder  into  a  counter- 
poise cylinder  as  the  bell  ascended  out  of  the  water.  The  bell,  being  heavier  out  of 
water  than  when  it  is  immersed,  is  accordingly  counterpoised  in  any  position,  although 
Carpenter  has  shown  that  this  refinement  is  unnecessary.  An  opening  in  the  top  of 
the  spirometer  permits  the  insertion  of  a  rubber  stopper,  through  which  are  passed  a 
thermometer,  a  water  manometer,  and  a  stopcock  with  tube  for  drawing  the  sample 
of  air.  A  scale  on  the  side  of  the  instrument  gives  the  volume  of  the  air. 

During  an  observation  the  subject  sits  in  a  reclining  position  or  lies  upon  a  couch. 
When  the  bell   of  the   spirometer  is   placed   at   zero,  the   mouthpiece   adjusted  in   the 


A  B. 

Fig.    181. — Haldane   gas   apparatus    (A)    and    Pearce   sampling   tube    (B). 


mouth,  and  the  nose  clamped,  respiration  is  started,  the  expirations  being  passed 
through  the  stopcock,  which  is  so  turned  as  to  allow  them  to  pass  to  the  outside  air. 
After  a  few  minutes  the  stopcock  is  turned  so  that  the  expirations  are  passed  into 
the  spirometer  for  a  definite  length  of  time.  At  the  end  of  the  period  the  cock  is 
again  turned,  and  after  the  barometric  pressure,  temperature,  and  volume  of  air  have 
been  noted,  the  composition  of  the  air  is  determined  in  the  Haldane  gas  analysis  ap- 
paratus. 

4.  THE  DOUGLAS  BAG. — The  Douglas  bag  is  made  of  rubber-lined  cloth,  and  is 
capable  of  holding  from  50  to  100  liters.  It  is  especially  useful  for  investigations 
during  exercise,  since  it  is  fitted  with  straps  so  that  the  bag  can  be  fastened  to  the 


594  METABOLISM 

shoulders  (Fig.  180).  It  is  then  connected  with  the  valves,  the  mouthpiece  of  which 
is  placed  between  the  lips.  Eespirations  are  commenced  with  the  three-way  valve 
turned  so  as  to  allow  the  expirations  to  pass  directly  outside.  After  respiratory  equi- 
librium is  established,  the  three-way  valve  is  turned  during  an  inspiratory  period  so 
that  the  succeeding  expirations  may  pass  into  the  bag.  The  time  required  to  fill  the 
bag  comfortably  is  determined  with  a  stop-watch.  The  air  which  has  been  collected 
in  the  bag  during  the  period  is  thoroughly  mixed  and  passed  through  a  meter,  the 
temperature  and  barometric  pressure  are  noted,  and  a  sample  analyzed  in  the  Haldane 
gas-apparatus.  The  bag  should  be  emptied  completely  by  rolling  it  up  when  nearly 
empty. 

5.  THE  HALDANE  GAS-ANALYSIS  APPARATUS.  PRINCIPLE. — The  Haldane  method  of 
analysis  of  expired  air  is  simple  and  easily  learned.  The  apparatus  (Fig.  181)  consists 
of  a  gas  burette,  a  control  burette  of  the  same  size  (both  surrounded  with  a  water 
jacket),  and  bulbs  containing  dilute  caustic  potash  or  soda  solution  for  the  absorp- 
tion of  the  carbon  dioxide  and  an  alkaline  pyrogallate  solution  for  the  absorption  of 
the  oxygen.  The  gas  burette  is  connected  with  the  bulbs  by  a  two-way  stopcock,  which 
allows  a  sample  of  gas  to  pass  into  either  bulb.  A  control  tube  (10)  is  put  into  con- 
nection with  the  burette  through  a  manometer  tube,  which  is  connected  with  the  alkali 
bulb,  and  can  be  made  to  compensate  for  any  changes  in  temperature  that  may  occur 
during  the  course  of  the  analysis.  For  an  analysis  the  gas  is  transferred  to  the  burette 
from  the  sampling  tube,  saturated  with  water  vapor  over  mercury,  and  then  measured, 
after  which  it  is  transferred  into  the  caustic  solution  to  free  it  from  CO2,  and  returned 
to  the  burette  to  determine  the  loss  of  volume  due  to  CO  absorption.  It  is  then  trans- 
ferred into  the  alkaline  pyrogallate  solution,  which  frees  it  from  oxygen,  after  which 
it  is  again  brought  back  to  the  burette  to  determine  the  loss  in  volume  due  to  the 
absorption  of  the  oxygen. 

THE  APPARATUS. — The  detail  of  the  Haldane  apparatus  is  shown  in  the  accompany- 
ing cut.  The  measuring  burette  (1)  holds  21  c.c.  The  bulb  is  of  15  c.c.  capacity, 
and  the  graduated  stem,  which  is  about  4  mm.  in  bore  and  60  cm.  in  length,  is  grad- 
uated to  0.01  c.c.  from  15  c.c.  to  21  c.c.  The  stopcock  at  the  top  of  the  burette  is 
double-bored,  so  that  in  one  position  air  can  be  drawn  in  from  a  gas  sampler  (2)  and 
in  another  sent  into  the  absorption  bulbs  (3).  The  lower  part  of  the  burette  extends 
through  the  rubber  cork  at  the  bottom  of  the  water  jacket  (4).  A  piece  of  rubber 
tubing  is  attached  to  the  bottom  of  the  burette  and  is  passed  through  a  metal  tube 
furnished  on  its  inside  with  a  metal  disc  which  presses  against  the  rubber  tubing,  the 
pressure  being  controlled  by  means  of  a  fine  adjusting  screw  (£).  Below  this  a  glass 
stopcock  (7)  connects  with  rubber  tubing  to  the  mercury  leveling  bulb  (5).  The 
absorption  bulb  for  CO2,  containing  20  per  cent  NaOH  or  KOH  (5),  is  put  in  con- 
nection with  the  burette  by  suitably  turning  stopcocks  (3  and  8)*  The  control  burette 
(10)  is  also  in  connection  with  this  bulb  through  the  manometer  tube  (11).^  Any 
variation  in  temperature  which  may  occur  during  the  analysis  will  cause  the  level  of  the 
alkaline  solution  in  the  manometer  to  change. 

When  final  readings  of  the  shrinkage  of  volume  are  made,  the  level  of  the  caustic 
solution  is  returned  to  the  level  of  that  in  the  manometer.  By  so  doing  any  error  due 
to  temperature  changes  is  avoided,  since  change  in  temperature  must  be  equal  in  the  two 
burettes. 

The  absorption  bulb  for  oxygen  (12)  is  filled  with  a  solution  made  by  dissolving 
10  grams  of  pyrogallic  acid  in  100  c.c,  of  a  nearly  saturated  KOH  solution.  The 


*The  stopcock  (5)   is  double-bored,  so  that  the  tube  leading  from  the  burette  can  be  brought  into 
connection  with  either  9  or  12. 

fThis  tube  also  has  a  three-way  stopcock  (79),  so  that  it  may  be  opened  to  the  outside. 


METHOD   FOR   DETERMINING   RESPIRATORY   EXCHANGE  IN    MAN  595 

specific  gravity  of  the  KOH  should  be  1.55,  which  is  obtained  approximately  by  dis- 
solving the  sticks  (pure  by  alcohol)  in  an  equal  weight  of  water.  The  mark  (13)  on 
the  stem  of  the  bulb  indicates  the  level  at  which  the  solutions  should  stand.  Enough 
pyrogallate  solution  is  introduced  through  tube  15  to  fill  bulbs  12  and  14  two-thirds 
full.  Then  pyrogallate  solution  is  poured  into  tube  16  until  the  difference  in  level 
of  fluids  is  sufficient  to  produce  enough  pressure  to  raise  the  level  of  the  pyrogallate 
solution  in  12  to  the  level  13  on  the  stem.  Stopcock  8  must  be  open  during  this  pro- 
'cedure.  It  may  be  necessary  to  add  or  take  away  a  little  pyrogallate  solution  through 
''15  to  attain  the  above  level. 

Care  must  be  taken  to  allow  for  complete  absorption  of  oxygen  from  the  air  that 
AS  entrapped  between  14  and  16  before  an  analysis  is  made;  otherwise  changes  will 
be  produced  in  the  level  of  the  pyrogallate  solution.  The  air  in  the  capillary  tubing 
connecting  the  burettes  with  the  absorption  bulbs  must  also  be  freed  of  CO2  and  O2. 
This  can  be  accomplished  by  making  a  dummy  analysis  of  atmospheric  air  before  the  real 
analysis.  Great  care  must  be  taken  to  have  atmospheric  pressure  in  all  the  tubes  at 
the  start  of  the  analysis.  This  is  accomplished  by  opening  the  stopcock  in  the  burette 
first  to  atmospheric  air  and  then  to  the  absorption  bulbs,  until  no  further  change 
in  the  level  of  the  fluids  in  the  stems  of  the  absorption  bulbs  occurs.  This  level  is 
then  marked  and  used  as  the  standard.  A  small  amount  of  water  in  the  burette  over 
the  mercury  assures  saturation  of  the  air  with  water  vapor.  Time  for  drainage  must 
be  allowed  before  making  readings. 

A  very  serviceable  sampling  tube  for  the  transfer  of  air  can  be  made  from  a  30 
c.c.  ground-glass  syringe,  to  which  is  attached  a  two-way  stopcock.  A  cut  of  this  is 
shown  in  Fig.  181.  The  dead  space  in  these  syringes  is  washed  out  by  working  the 
piston  back  and  forth  several  times.  A  thin  coating  of  vaseline  prevents  leakage  of 
the  gas.  We  have  found  that  these  sampling  tubes  will  retain  a  sample  of  expired 
air  without  change  up  to  eight  hours. 

MANIPULATION  OF  APPARATUS. — The  sampling  syringe  (20}  is  attached  to  opening  2 
of  the  burette,  and  its  stopcock  (17)  opened  to  atmospheric  air.  The  level  of  the 
mercury  is  raised  to  the  level  of  the  stopcock  of  the  syringe  and  is  then  turned  so  that 
syringe  and  burette  are  in  communication.  The  bulb  of  mercury  is  lowered  so  that 
the  mercury  falls  in  the  burette.  This  draws  the  piston  of  the  syringe  with  it,  and  fills 
the  burette  with  air  from  the  syringe.  It  is  advisable  to  put  a  little  positive  pressure 
on  the  piston  of  the  syringe  in  the  maneuver  to  prevent  possible  leakage.  When  all 
of  the  air  is  in  the  burette  a  slight  positive  pressure  is  produced  in  the  burette  by 
gently  pressing  on  the  piston,  and  immediately  thereafter  the  stopcock  on  the  syringe 
(17)  is  again  turned  to  the  original  position.  This  allows  the  pressure  of  air  in  the 
burette  to  come  to  that  of  the  atmosphere.  The  height  of  the  mercury  is  now  adjusted 
to  a  convenient  height  in  the  burette  by  closing  cock  7  and  turning  the  milled  screw 
6.  The  cock  18  is  now  made  to  communicate  with  the  absorption  bulbs.  If  the  air  in  the 
burette  is  at  atmospheric  pressure,  no  change  will  occur  in  the  level  of  the  fluids. 
The  reading  is  then  taken  on  the  burette. 

The  next  step  in  the  analysis  consists  in  turning  stopcock  8  to  communicate  with 
the  caustic  soda  solution  in  bulb  9,  and  the  leveling  tube  (5)  is  raised,  forcing  mercury 
into  the  burette  and  the  air  into  bulb  9.  The  gas  is  passed  back  and  forth  several 
times  until  absorption  is  complete,  as  can  be  determined  by  the  fact  that  the  level 
of  the  mercury  in  the  burette  remains  constant  when  the  fluid  in  the  bulb  is  returned 
to  its  original  level  (13)  on  the  stem.  In  this  adjustment  it  is  convenient  to  make 
the  gross  leveling  by  the  mercury  bulb  and  the  fine  leveling  by  closing  7  and  turning  6 
until  the  fluid  in  9  is  at  the  original  height.  The  reading  on  the  burette  indicates 
the  loss  in  volume  due  to  the  CO2  absorbed. 


596  METABOLISM 

The  oxygen  is  removed  by  a  similar  procedure,  the  gas  being  passed  into  the  alkaline 
pyrogallate  solution  by  turning  cock  8  to  communicate  with  bulb  12.  The  absorption 
of  oxygen  is  slower  than  for  CO2,  and  more  care  must  be  taken  to  get  complete 
absorption.  The  air  in  the  tubing  between  the  fluid  in  9  and  stopcock  8  must  be 
washed  out  several  times  in  order  to  get  the  oxygen  which  is  left  in  it  after  the 
absorption  of  the  CO2.  When  this  is  complete,  the  final  reading  on  the  burette  is 
made  and  the  loss  in  volume  from  the  second  reading  represents  the  oxygen. 


THE  CALCULATIONS 

The  calculation  of  the  percentage  composition  of  the  air  and  of  the  respiratory 
quotient  is  represented  in  the  following  example  of  an  actual  analysis: 

(The  temperature  and  barometric  pressure  as  taken  at  the  time  of  the  experiment 
were  20°  C.  and  747  mm.  Hg.) 

C02  analysis — 

1st  reading  of  burette    20.00 

2nd  reading  of  burette  after  absorption  of  CO2 19.20 

CO2    absorbed O80 

0.80  -^-  20  =  4.0  per  cent  CO2  in  expired  air. 

02  analysis — 

2nd  reading  of  burette 19.20 

3rd  reading  of  burette  after  absorption  of  O2 15.90 

O2  absorbed 3^30 

3.30  -f-  20  =  16.50  per  cent  of  02  in  expired  air. 

Determination  of  E.Q. — 

O2  in  atmospheric  air  =  20.94% 

O,  +  CO2  in  expired  air  (16.50  -t-  4)  =  20.50% 

100  -  20.94*  =  79.06%,  N  in  atmospheric  air. 
100-20.50    =79.50%,  N  in  expired  air. 

Since  nitrogen  is  an  inert  gas  in  the  body,  the  last  figure  shows  that  more  oxygen 
must  have  been  taken  in  during  inspiration  than  O2+  CO2  has  been  given  back  in  expira- 
tion. This  obviously  must  be  taken  into  account  in  the  calculations.  The  amount  of 
O2  actually  inspired  for  each  100  c.c.  of  air  expired  is  found  as  follows: 

20.94   (%  O2  in  atmospheric  air) 

79.06  (%  N2  in  atmospheric  air)  <  79'50  <%  N*  in  exPired  air)  >'  or  °'265  (con' 
stant  factor)  X  79-5  —  21.07.f 

The  amount  of  O2  actually  absorbed  by  the  animal  is  therefore: 

21.07—16.50—4.57%. 
and  the  amount  of  CO2  excreted  is: 

4.00  -  0.03   (CO2  in  inspired  air)  —3.97  %  CO2. 
The  respiratory  quotient,  or  ratio  of  CO2  excreted  to  O2  absorbed  is  therefore: 

3.97 
_=0.87. 

Total  Gas  Exchange. — The  volume  of  air  expired  in  15  minutes  into  the  Tissot 
spirometer  was  found  to  be  100  liters  measured  at  20°  C.  and  747  mm.  Hg.  (brass-scale 
barometer).  This  volume  of  gas  must  be  corrected  so  as  to  give  the  volume  of  dry 


*This  is  the  constant  Oa  percentage  in  air. 

tThis  calculation  can  be  simplified  by  using  an  abbreviated  table   (page  597)    giving  the  O2  figure  j 

corresponding  to  the  various  percentages  of  N  in  the  expired  air. 


METHOD   FOR   DETERMINING   RESPIRATORY    EXCHANGE   IN    MAN  597 

air  at  0°  and  760  mm.  Hg.  To  do  this  two  things  must  be  taken  into  account.  (1) 
Since  the  expired  air  is  saturated  with  water,  the  pressure  due  to  water  vapor  must 
be  subtracted  from  the  observed  barometric  pressure  to  obtain  the  true  pressure.  The 
vapor  tension  of  water  for  various  temperatures  is  given  in  Table  II  on  page  598. 
(2)  Since  the  barometer  tube  lengthens  or  contracts  with  heat  or  cold,  the  baro- 
metric readings  must  be  corrected.  The  corrections  for  ordinary  barometric  read- 
ings are  found  in  Table  III,  page  598.  The  figure  corresponding  to  the  temperatures 
is  subtracted  from  the  barometric  reading  in  order  to  obtain  correct  barometric  pres- 
sure. 

In  the  above  experiment,  the  correction  for  the  barometer  is  2.41  mm.  (see  Table  III, 
page  598),  and  that  for  vapor  tension  at  20°  C.  is  17.4  (see  Table  II,  page  598). 
Actual  Barometric  Pressure, — 747 — (17.4  +  2.4)  =  727.2  mm. 

The  coefficient  of  expansion  of  gases  is  taken  as  0.003665)  or  1/273;  therefore  the 
volume  at  0°  equals  the  volume  at  1°  divided  by  1  +  0.003665  t;  and  hence 

"\r 

Vo  = ,  when  Vo  —  Volume  at  0°  and  V  —  Volume  at  t°. 

1  +  0.003665  t    ' 

VT* 

The  volume  of  gas  varies  inversely  as  the  pressure,  Vo  =  ,  where  V  =  volume  at 

760 

P  pressure;  therefore  working  both  corrections  together,  we  have 


760  (1  +  0.003665  t) 
This  formula  applied  to  the  present  problem  reads: 

Vo  =  100X727.2 =89.14  liters. 

760  (1  +  0.003665x20) 

The  latter  calculation  can  be  considerably  simplified  by  using  standard  tables 
which  give  constants  for  corrections  of  gas  volumes.  These  are  easily  obtainable  and 
are  given  in  part  in  Table  IV. 

According  to  these  tables  for  20°  C.  and  727.21  mm.  Hg.  B.F.,  the  factor  is 
0.89124;  therefore  the  total  volume  of  air  breathed  in  15  min.  was: 

0.89124  x  100  =  89.124  liters,  at  0°C.  and  760  mm.  Hg. 
and  the  absorbed  O2, 

0.89124  x  4.57  =  40.7  liters  of  O2,  or  16.28  L.  per  hour. 

The  Caloric  Value  Calculated  from  the  Gas  Exchange  (Indirect  Calorimetry). — 
This  can  be  done  by  using  Table  V  but  it  is  more  accurate  to  know  the  nonprotein  R.Q. 
which  is  given  in  the  first  column  of  the  table.  This  latter  is  obtained  by  deducting 
from  the  total  CO2  eliminated,  the  CO2  derived  from  protein  (found  by  multiplying  the 
urinary  N  by  9.35)  and  by  deducting  from  the  total  O2  absorbed  the  O2  required  to 
oxidise  protein  (found  by  multiplying  urinary  N"  by  8.45).  Suppose,  for  example,  that 
14.4  gm.  N  is  excreted  in  the  24  hrs.  urine;  i.e.,  0.6  gm.  per  hr.  Then,  9.35x0.6  = 
5.610  gm.  CO2  or,  (since  1  gm.  CO2  =  0.5087  L)  2.85  L  must  be  subtracted  from  14.152  L 
giving  11.302  L  and  similarly  8.45  x  .6  =  5.070  gm.  O2  or  (since  1  gm.  O2  =  0.7  L) 
3.5490  must  be  subtracted  from  16.28  giving  12.73.  The  nonprotein  R.Q.  is  therefore 

11  302 

•    '        =.88.     Referring  to  Table  V  we  see  that  at  R.Q.  0.88  one  liter  of  O,  equals 

1^.730 

4.900  C.  in  1  hr.  4.9  x  16.28  —  79.77  C  were  expended.     As  a  matter  of  fact  for  most 
purposes  it  is  sufficiently  accurate  to  use  the  uncorrected  R.Q.  for  Table  V. 


598  METABOLISM 


TABLE  I 

THE  PERCENTAGE  OF  OXYGEN  WHICH  is  EQUIVALENT  TO  THE  NITROGEN  FOUND  IN  THE 

EXPIRED  AIR 

To  obtain  the  nitrogen  in  the  expired  air,  add  the  percentage  of  CO2  and  O2  found 
and  subtract  the  sum  from  100.  The  table  gives  the  percentage  for  O2  corresponding  to 
this  figure : 

%Na     78.7  78J3  78^9 79^0 79O  79^2 79^3  79^4 79J5      79^6      79/7 79.8 

%02     20.86  20.88  20.90  20.93  20.96  20.98  21.01  21.04    21.07    21.10    21.12    21.14 

79.9  80.0  80.1  80.2  80.3  80.4  80.5  80.6 

21.16  21.19  21.22  21.25  21.28  21.31  21.35  21.38 


TABLE  II 
TENSION  OF  AQUEOUS  VAPOR  IN  MILLIMETERS  OF  MERCURY 

To  obtain  the  dry  barometer  pressure,  subtract  the  mm.  Hg    corresponding  to  the 
temperature  of  the  air  from  the  barometer  pressure  at  the  time  of  the  experiment: 

Temp.       15°        16*         17°        18"        19°        20°        21°        22°        23°        24°         25°" 
Mm.          12.7       13.5       14.4       15.4       16.3       17.4        18.5       19.7       20.9       22.2       23.5 


TABLE  III 

TEMPERATURE  CORRECTIONS  TO  REDUCE  READINGS  OF  A  MERCURIAL  BAROMETER  WITH  A 

BRASS  SCALE  TO  0°C. 

Subtract  the  appropriate  quantity  as  found  in  table  from  the  height  of  the  barometer. 
The  table  is  for  a  barometer  with  a  brass  scale,  and  the  values  are  a  little  lower  (about 
.2  mm.)  than  for  the  glass  scale.  The  corrections  for  intermediate  temperatures  can  be 
approximated  by  interpolation. 


Temp. 

700 
mm. 

710 
mm. 

720 
mm. 

730 
mm. 

740 
mm. 

750 

mm. 

760 
mm. 

770 
mm. 

15° 
20° 
25° 

1.69 
2.26 
2.83 

1.72 

2.22 
2.87 

1.74 
2.32 
2.91 

1.77 
2.36 
2.95 

1.79 
2.39 
2.99 

1.81 
2.42 
3.03 

1.84 
2.45 
3.07 

1.86 
2.48 
3.11 

TABLE  IV 
TABLE  FOR  REDUCING  GASEOUS  VOLUMES  TO  NORMAL  TEMPERATURE  AND  PRESSURE 

The  observed  volume,  when  multiplied  by  the  factor  corresponding  to  the  temperature 
and  corrected  pressure,  will  give  the  volume  of  the  expired  air  reduced  to  0°  and  760  mm. 


Mm. 

15° 

16° 

17° 

18° 

19° 

20° 

21° 

22° 

23° 

24° 

25° 

720 
730 
740 
750 
760 
770 

.898 
.910 
.922 
.935 
.947 
.960 

.894 
.907 
.919 
.932 
.944 
.957 

.891 
.904 
.916 
.928 
.941 
.953 

.888 
.901 
.913 
.925 
.938 
.950 

.885 
.897 
.910 
.922 
.934 
.948 

.882 
.894 
.907 
.919 
.931 
.945 

.880 
.891 
.904 
.916 
.928 
.940 

.877 
.888 
.901 
.913 
.925 
.936 

.873 
.885 
.897 
.910 
.922 
.933 

.870 
.882 
.894 
.907 
.919 
.930 

.867 
.879 
.891 
.904 
.916 
.927 

METHOD   FOR  DETERMINING   RESPIRATORY   EXCHANGE   IN   MAN 


599 


TABLE  V 


R.  Q.           CALORIES  FOR  1  LITER  Oa           RELATIVE  CALORIES  CONSUMED  AS 

Number                  Carbohydrate                    Fat 
per  cent                     per  cent 

0.707 

4.686 

0 

100 

0.71 

4.690 

1.4 

98.6 

0.72 

4.702 

4.8 

95.2 

0.73 

4.714 

8.2 

91.8 

0.74 

4.727 

11.6 

88.4 

0.75 

4.739 

15.0 

85.0 

0.76 

4.752 

18.4 

81.6 

0.77 

4.764 

21.8 

78.2 

0.78 

4.776 

25.2 

74.8 

0.79 

4.789 

28.6 

71.4 

0.80 

4.801 

32.0 

68.0 

0.81 

4.813 

35.4 

64.6 

0.82 

4.825 

38.8 

61.2 

0.83 

4.838 

42.2 

57.8 

0.84 

4.850 

45.6 

54.4 

0.85 

4.863 

49.0 

51.0 

0.86 

4.875 

52.4 

47.6 

0.87 

4.887 

55.8 

44.2 

0.88 

4.900 

59.2 

40.8 

0.89 

4.912 

62.6 

37.4 

0.90 

4.924 

66.0 

34.0 

0.91 

4.936 

69.4 

30.6 

0.92 

4.948 

72.8 

27.2 

0.93 

4.960 

76.2 

23.8 

0.94 

4.973 

79.6 

20.4 

0.95 

4.985 

83.0 

17.0 

0.96 

4.997 

86.4 

13.6 

0.97 

5.010 

89.8 

10.2 

0.98 

5.022 

93.2 

6.8 

0.99 

5.034 

96.6 

3.4 

1.00 

5.047 

100.0 

0.0 

(From  Lusk.) 


CHAPTER  LXV 
STARVATION 

In  order  to  provide  a  standard  with  which  we  may  compare  other 
conditions,  we  shall  first  of  all  study  the  metabolism  during  starva- 
tion. A  valuable  chart  compiled  from  observations  made  in  the  Carne- 
gie Institution  of  Washington  on  a  man  who  fasted  for  thirty-one  days 
is  produced  in  Fig.  182. 

The  Excretion  of  Nitrogen. — When  an  animal  is  starved,  it  must 
live  on  its  own  tissues,  but  in  doing  so  it  saves  its  protein,  so  that  the 
excretion  of  nitrogen  falls  after  a  few  days  to  a  low  level,  the  energy 
requirements  being  meanwhile  supplied,  so  far  as  possible,  from  stored 
carbohydrate  and  fat.  Although  always  small  in  comparison  with  fat, 
the  stores  of  carbohydrate  vary  considerably  in  different  animals.  They 
are  much  larger  in  man  and  the  herbivora  than  in  the  carnivora.  Dur- 
ing the  first  few  days  of  starvation  it  is  common,  in  the  herbivora,  to  find 
that  the  excretion  of  nitrogen  is  actually  greater  than  it  was  before 
starvation,  because  the  custom  has  become  established  in  the  metabolism 
of  these  animals  of  using  carbohydrates  as  the  main  fuel  material,  so 
that  when  carbohydrates  are  withheld,  as  in  starvation,  proteins  are 
used  more  than  before  and  the  nitrogen  excretion  becomes  greater.  We 
may  say  that  the  herbivorous  animal  has  become  carnivorous.  The  same 
thing  may  occur  in  man  when  the  previous  diet  was  largely  carbohy- 
drate; thus,  almost  invariably  in  man  the  nitrogen  output  is  larger  on 
the  third  and  fourth  days  of  starvation  than  on  the  first  and  second. 

Another  factor  influencing  the  nitrogen  excretion  during  the  early 
days  of  the  fast  is  the  amount  of  previous  intake  of  nitrogen;  the  greater 
this  has  been,  the  greater  the  excretion.  By  the  seventh  day,  however,  a 
uniform  output  of  nitrogen  will  usually  be  reached  irrespective  of  the 
individual's  protein  intake.  During  the  greater  part  of  starvation,  most 
of  the  energy  required  to  maintain  life  is  derived  from  fat,  as  little  as 
possible  being  derived  from  protein.  This  type  of  metabolism  lasts  until 
all  the  available  resources  of  fat  have  become  exhausted,  when  a  more 
extensive  metabolism  of  protein  sets  in,  with  the  consequence  that  the 
nitrogen  excretion  rises.  This  is  really  the  harbinger  of  death — it  is  often 
called  the  premortal  rise  in  nitrogen  excretion.  It  indicates  that  all  the 
ordinary  fuel  of  the  animal  economy  has  been  used  up,  and  that  it  has 

600 


STARVATION 


601 


[NUTRITION  LABORATORY  OF  THE  CARNEGJE  INSTITUTION  OF  WASHINGTON.  BOSTON.  MASSACHUSETTS] 
METABOLISM  CHART  OF  A  MAN  FASTING  31  DAYS 

APRIL  14 -MAY  15.  1912 


OXYGEN  AND  CARBON 
DIOXIDE.  c.c. 


ALVEOLAR  CO,  TENSION,  mm.— a.      3<6° 
38.0  3.50 


DIOOO  PRESSURE.™. §f£ 


I    23456789   10  II  12  1314  15  16  17  18  192021  22  23  24  25  26  27  28  29  30  3f 


XYGENKR  KILO.  PER  MINUTE 


36.0  3.40 
34.0  3.30 
32.0  3.20 
30.0  3.10 
8.0  3.00 
2.90 

128  2.80 
124  2.70 
120  2.60 
I  16  2.50 
I  12  2.40 
108  I7"00 
104  1650 
100  1600 

96  1550 

36.8  1500 
36.4  1450 
36.0  1400 
2  1350 


V  -£*RBON  WOXI  E  PER  K  La  PER  MINUTE/ 


PHOSPHORUS  (P,0s).  CMS. 

Sihi 


3    4    5    6    7    8    9    1.0  I.I  12  13  14  15  1.6  17  18  I?  20  21  2.Z  23  24  25  26  2.7  2    29  30  3 


CARBON  IN  URINE 
B-OXYBUTYRIC  ACID. 


URICACID-N.GM. 


TOTAL  SULPHUR  (S),GM. 


AMMONIA-N.  CMS. 


Fig.  182. — Curve  constructed  from  data  obtained  from  a  man  who  fasted  for  thirty-one  days. 
The  days  of  the  fast  are  given  along  the  abscissae,  and  the  various  measurements  along  the  or- 
Oinates.  (From  F.  G.  Benedict.)  ' 


602  METABOLISM 

become  necessary  to  burn  the  very  tissues  themselves  in  order  to  obtain 
sufficient  energy  to  maintain  life.  Working  capital  being  all  exhausted, 
an  attempt  is  made  to  keep  things  going  for  a  little  longer  time  by  liq- 
uidation of  permanent  assets.  But  these  assets,  being  represented  largely 
by  protein,  are  of  little  real  value  in  yielding  the  desired  energy  because, 
as  we  have  seen,  only  4.1  calories  are  available  against  9.3,  obtainable 
from  fats. 

These  facts  explain  why  during  starvation  a  fat  man  excretes  daily 
less  nitrogen  than  a  lean  man,  and  why  the  fat  man  can  stand  the  starva- 
tion for  a  longer  time.  The  premortal  rise  is,  however,  not  prevented  by 
feeding  oil,  which  would  seem  to  indicate  that  death  may  be  due  not  so 
much  to  the  absence  of  fuel  as  to  serious  nutritional  disturbance  of  es- 
sential organs;  e.  g.,  there  may  be  no  available  material  to  supply  the 
glands  of  internal  secretion  with  the  building  stones  they  must  have 
(see  page  614). 

Not  only  is  there  this  general  saving  of  protein  during  starvation, 
but  there  is  also  a  discriminate  utilization  of  what  has  to  be  used  by  the 
different  organs,  according  to  their  relative  activities.  This  is  very 
clearly  shown  by  comparison  of  the  loss  of  weight  which  each  organ  un- 
dergoes during  starvation.  The  heart  and  brain,  which  must  be  active  if 
life  is  to  be  maintained,  lose  only  about  3  per  cent  of  their  original 
weight,  whereas  the  voluntary  muscles,  the  liver  and  the  spleen  lose 
31,  54  and  67  per  cent,  respectively.  No  doubt  some  of  this  loss  is  to 
be  accounted  for  as  due  to  the  disappearance  of  fat,  but  a  sufficient 
remainder  represents  protein  to  make  it  plain  that  there  must  have  been 
a  mobilization  of  this  substance  from  tissues  where  it  was  not  absolutely 
necessary,  such  as  the  liver  and  voluntary  muscles,  to  organs,  such  as  the 
heart,  in  which  energy  transformation  is  sine  qua  non  of  life.  The  vital 
organs  live  at  the  expense  of  those  whose  functions  are  accessory. 

The  energy  output  per  square  meter  of  body  surface  steadily  declines. 
In  the  man  examined  by  Benedict,  it  was  958  C.  per  square  meter  of 
surface  at  the  end  of  the  first  twenty-four  hours,  but  only  737  on  the 
thirty-first  day  of  the  starvation  period.  The  oxygen  intake  and  carbon- 
dioxide  output  correspondingly  diminish. 

The  behavior  of  the  nitrogenous  metabolites  in  the  urine  is  of  par- 
ticular interest,  the  following  facts  being  of  significance:  Urea  nitrogen 
relatively  falls  and  NH3  nitrogen  rises.  For  example,  on  the  last  day  of  feed- 
ing the  percentage  output  of  NH3  nitrogen  in  relation  to  total  nitrogen  was 
3.16 ;  on  the  eighth  day  of  the  fast  it  was  14.88  (Cathcart)  .2  Acidosis  is  the 
cause.  The  total  amount  of  creatinine  and  creatine  shows  only  a  slight 
fall,  but  creatinine  relatively  decreases  and  creatine  increases  (Cathcart). 
Since  creatine  is  a  substance  peculiar  to  muscle  tissue,  it  is  possible  by 


STARVATION  603 

comparing  the  creatine  and  creatinine  output  with  that  of  nitrogen  to 
determine  whether  all  of  the  nitrogen  liberated  by  the  breakdown  of 
muscle  has  been  excreted,  or  whether  some  has  been  retained  either  for 
resynthesis  in' the  muscle  itself  or  for  use  elsewhere.  As  a  matter  of  fact 
the  muscle  breakdown  as  calculated  from  the  creatine-creatinine  output 
is  greater  than  that  calculated  from  the  nitrogen,  indicating  that  synthesis 
of  the  noncreatine  remainder  must  be  occurring. 

That  transference  of  nitrogenous  substances  from  place  to  place  in  the 
body  in  starvation  is  proved  (1)  by  the  constant  presence  of  amino  ni- 
trogen in  the  blood  and  tissues  (Van  Slyke)  ;  and  (2)  by  the  effect  of 
copious  water  drinking.  The  latter  causes  a  decided  increase  in  the  out*- 
put  of  nitrogen,  because  of  the  excretion  of  some  of  the  nitrogenous 
substances.  It  is  probable,  however,  that  in  such  cases  there  is  also  a 
subsequent  increase  in  endogenous  protein  metabolism,  since  the  washed- 
out  free  nitrogen  would  have  to  be  replaced. 

Excretion  of  Purines. — Although  at  first  they  fall  somewhat,  the  total 
amount  increases  as  the  fast  progresses.  Perhaps  the  first  decline  is 
due  to  general  using  up  of  hypoxanthine  of  muscle  and  the  later  rise 
to  the  breakdown  of  nuclei  (page  671). 

Excretion  of  Sulphur. — It  is  important  to  compare  the  excretion  of 
sulphur  and  nitrogen.  In  the  early  days  of  starvation  a  ratio  of  17  N :  1  S 
has  been  found,  but  later  one  of  14.5: 1,  which  is  practically  the  same 
as  that  in  muscle  (i.e.,  14;  1),  indicating  that  late  in  fasting  the  main 
source  of  protein  supply  is  muscle. 

Several  of  the  changes  observed  during  starvation  can  be  attributed 
to  the  condition  of  acidosis  which  supervenes.  The  acids  are  derived 
from  incomplete  combustion  of  fat  (see  page  715),  and  are  represented 
by  /?-oxybutyric,  the  amount  being  sometimes  considerable  (10-15  grams 
a  day),  especially  in  obese  individuals.  The  large  ammonia  excretion 
(sometimes  2  grams  a  day)  is  evidently  for  the  purpose  of  neutralizing 
the  excess  of  acid.  Another  consequence  of  the  acidosis  is  the  decline 
in  the  alveolar  tension  of  C02  (page  379),  and  it  is  possible  that  some  of 
the  circulatory  changes  shown  in  the  chart  may  also  be  dependent  on 
it.  For  reducing  obesity  the  method  of  repeated  fasting  is  quite  safe 
provided  the  acidosis  is  carefully  watched  and  the  diet  which  is  given 
contains  accessory  food  factors  (page  618). 

Many  secondary  changes  also  occur  in  the  starving  organism.  Thus, 
the  mobilization  of  fat  is  often  responsible  for  a  pronounced  increase  in 
the  fat  content  of  the  blood  (see  page  698). 

The  amino  nitrogen  of  the  blood  is  not  perceptibly  reduced  by  starva- 
tion (page  613)  but  early  in  the  condition  the  blood  sugar  becomes  much 
lower  than  normal,  after  which  it  remains  steady.  This  is  significant 


604  METABOLISM 

when  we  remember  that  after  two  or  three  days  of  starvation  all  of  the 
available  glycogen  has  been  used  up.  It  indicates  that  carbohydrate  must 
be  essential  for  life,  and  that  it  is  produced  in  starvation  from  proteins 
(see  page  699).  The  glycogen  content  of  the  skeletal  muscles  becomes 
reduced  but  not  that  of  the  heart. 

Starvation  ends  in  death  in  an  adult  man  in  somewhat  over  four 
weeks  but  much  sooner  in  children,  because  of  their  more  active  metab- 
olism. At  the  time  of  death  the  body  weight  may  be  reduced  by  50  per 
cent.  The  body  temperature  does  not  change  until  within  a  few  days 
of  death,  when  it  begins  to  fall,  and  it  is  undoubtedly  true  that  if  means 
are  taken  to  prevent  cooling  of  the  animal  at  this  stage,  life  will  be 
prolonged. 

Death  from  starvation  must  be  due  either  to  a  general  failure  of  all 
the  cells  or  to  injury  of  certain  organs  that  are  essential  for  life.  Since 
the  loss  of  protein  from  the  body  as  a  whole  only  amounts  to  between  20 
and  50  per  cent  at  the  time  of  death  by  starvation,  it  is  unlikely  that  gen- 
eral failure  can  be  the  cause.  If  it  were  so,  death  would  always  occur 
when  some  fixed  loss  of  protein  had  occurred.  Certain  organs  evidently 
cease  to  perform  their  function,  either  because  they  are  deprived  of  raw 
material  for  the  elaboration  of  some  substance  (hormone)  necessary  for 
life,  or  because  they  themselves  wear  out  from  want  of  nourishment. 

NORMAL  METABOLISM 

Apart  from  the  practical  importance  of  knowing  something  about  the 
behavior  of  an-  animal  during  starvation,  such  knowledge  is  of  great 
value  in  furnishing  a  standard  with  which  to  compare  the  metabolism 
of  animals  under  normal  conditions.  Taking  again  the  nitrogen  balance 
as  indicating  the  extent  of  protein  wear  and  tear  in  the  body,  let  us 
consider  first  of  all  the  conditions  under  which  equilibrium  may  be  .re- 
gained. It  would  be  quite  natural  to  suppose  that,  if  an  amount  of  pro- 
tein containing  the  same  amount  of  nitrogen  as  is  excreted  during 
starvation  were  given  to  a  starving  animal,  the  intake  and  output  of 
nitrogen  would  balance.  We  are  led  to  make  this  assumption  because  we 
know  that  the  balance  sheet  of  a  business  concern  showing  an  excess  of 
expenditure  over  income  could  be  adjusted  in  this  way.  But  it  is  a  very 
different  matter  with  the  nitrogen  balance  sheet  of  the  body;  for,  if  we 
give  the  starving  animal  just  enough  protein  but  no  other  foodstuffs  to 
cover  the  nitrogen  loss,  we  shall  cause  the  excretion  to  rise  to  a  total 
which  is  practically  equal  to  the  starvation  amount  plus  all  that  we  have 
given  as  food ;  and  although  by  daily  giving  this  amount  of  protein  there 
may  be  a  slight  decline  in  the  excretion,  it  will  never  become  the  same  as 


STARVATION  605 

that  of  the  intake.  The  only  effect  of  such  feeding  will  be  to  prolong 
life  for  a  few  days. 

Nitrogenous  Equilibrium. — To  attain  equilibrium  we  must  give  an 
amount  of  protein  the  nitrogen  of  which  is  at  least  two  and  one-half 
times  that  excreted  during  the  starvation  level.  For  a  few  days  follow- 
ing the  establishment  of  this  pure  protein  diet,  the  nitrogen  excretion 
will  be  far  in  excess  of  the  intake,  but  it  will  gradually  decline  until  the 
two  practically  correspond.  Having  once  gained  an  equilibrium,  we  may 
raise  the  level  at  which  it  stands  by  gradually  increasing  the  protein  in- 
take. During  this  progressive  raising  of  the  ingested  protein,  it  will  be 
found,  at  least  in  the  carnivora  (cat  and  dog),  that  a  certain  amount  of 
nitrogen  is  retained  by  the  body  for  a  day  or  so  immediately  following 
each  increase  in  protein  intake.  The  excretion  of  nitrogen,  in  other 
words,  does  not  immediately  follow  the  dietetic  increase.  The  amount  of 
nitrogen  thus  retained  is  too  great  to  be  accounted  as  a  retention  of  dis- 
integration products  of  protein;  it  must  therefore  be  due  to  an  actual 
building  up  of  new  protein  tissue — that  is,  growth  of  muscles. 

Nitrogenous  equilibrium  on  a  protein  diet  alone  is  readily  attainable 
in  the  cat,  and  less  readily,  in  the  dog.  But  in  man  and  the  herbivorous 
animals,  it  is  impossible  to  give  a  sufficiency  of  protein  alone  to  maintain 
equilibrium;  there  will  always  be  an  excess  of  excretion  over  intake. 
Indeed  it  scarcely  requires  any  experiment  to  prove  this,  for  it  is  self- 
evident  when  we  consider  that  there  are  less  than  1000  (X  in  a  pound  of 
uncooked  lean  meat,  and  that  there  are  few  who  could  eat  over  three 
pounds  a  day,  an  amount,  however,  which  would  scarcely  furnish  all  of 
the  required  calories.  A  person  fed  exclusively  on  flesh  is  therefore 
being  partly  starved,  even  though  he  may  think  that  he  is  eating  abundantly 
>and  is  quite  comfortable  and  active.  This  fact  has  a  practical  application 
in  the  so-called  Banting  cure  for  obesity. 

Protein  Sparers. — Very  different  results  are  obtained  when  carbohy- 
drates or  fats  are  freely  given  with  the  protein  to  the  starving  animal. 
Nitrogen  equilibrium  can  then  be  regained  on  very  much  less  protein, 
so  that  we  speak  of  fats  and  carbohydrates  as  being  "protein  sparers." 
Carbohydrates  are  much  better  protein  sparers  than  fats;  indeed  they 
are  so  efficient  in  this  regard  that  it  is  now  commonly  believed  that  car- 
bohydrates are  essential  for  life,  and  that  when  the  food  contains  no 
trace  of  carbohydrates,  a  part  of  the  carbon  of  protein  has  to  be  con- 
verted into  carbohydrate.  This  important  truth  is  supported  by  evi- 
dence derived  from  other  types  of  investigation  (e.  g.,  the  behavior  of 
diabetic  patients,  in  whom  the  power  to  use  carbohydrates  is  greatly 
depressed).  The  marked  protein-sparing  action  of  carbohydrates  is  il- 
lustrated in  another  way — namely,  by  the  fact  that  we  can  greatly 


606  METABOLISM 

diminish  the  protein  breakdown  during  starvation  by  giving  carbo- 
hydrates. By  using  protein  sparers  we  can  indeed  reduce  the  daily  nitro- 
gen excretion  to  about  one-third  its  amount  in  complete  starvation.  Re- 
moval of  carbohydrate  from  the  diet  is  said  to  entail  a  failure  of  the 
muscles  to  use  again  in  their  metabolism  certain  of  the  products  (e.  g., 
creatine)  which  result  from  their  disintegration.  At  any  rate  it  has 
been  found  that  creatine  is  excreted  in  the  urine  under  these  conditions. 

As  to  the  nature  of  the  processes  occurring  in  the  body  during  protein 
sparing,  two  possibilities  have  to  be  borne  in  mind:  either  the  body  pro- 
tein is  catabolized  less  rapidly  or  the  protein  sparer  unites  with  certain 
of  the  breakdown  products  of  protein  to  form  new  protein.  Recent  work 
by  Davis,  Hall  and  WTiipple68  affords  strong  support  to  the  latter  view. 
These  workers  investigated  the  rate  of  repair  of  the  liver  and  the  curve 
of  urinary  nitrogen  excretion  in  dogs  after  causing  destruction  of  a  large 
part  of  the  liver  tissue  by  chloroform  administration.  In  animals  in 
which  about  one  half  of  each  lobule  had  been  destroyed,  only  about  50 
per  cent  was  found  to  be  repaired  in  nine  days,  and  the  urinary  nitrogen 
was  higher  than  the  normal  starvation  level  although  no  food  was  given ; 
to  other  animals  to  which  sugar  was  given  the  repair  of  the  liver  was 
complete  in  nine  days  and  the  curve  of  nitrogen  decidedly  below  that 
of  starvation.  These  observations  open  up  a  new  field  for  the  investiga- 
tion of  problems  of  the  growth  of  new  tissue  in  the  adult  animal  and  their 
prosecution  should  afford  aid  in  determining  the  influence  of  various 
dietetic  conditions  on  such  growth.  Davis  and  Whipple69  have  already 
published  some  important  observations  in  this  direction  and  among  other 
things  have  found  that  a  diet  of  bread  and  milk,  or  one  of  cooked  liver 
or  kidney,  causes  more  rapid  repair  than  one  of  cooked  skeletal  muscle. 
Fats  do  not  accelerate  the  repair  process. 

The  Irreducible  Protein  Minimum. — In  the  case  of  a  man  living  on  an 
average  diet,  although  the  daily  nitrogen  excretion  is  about  15  grams, 
it  can  be  lowered  to  about  6  grams  provided  that  in  place  of  the  protein 
that  has  been  removed  from  the  diet  enough  carbohydrate  is  given  to 
bring  the  total  calories  up  to  the  normal  daily  requirement.  If  an  excess 
of  carbohydrate  over  the  energy  requirements  is  given,  the  protein  may 
be  still  further  reduced  without  disturbing  the  equilibrium.  It  has  been 
found  that  it  is  not  the  amount  of  carbohydrate  alone  that  determines 
the  ease  with  which  the  irreducible  protein  minimum  can  be  reached ;  the 
kind  of  protein  itself  makes  a  very  great  difference.  This  has  been  very 
clearly  shown  by  one  investigator,  who  first  of  all  determined  his  nitro- 
gen excretion  while  living  exclusively  on  starch  and  sugar,  and  who  then 
proceeded  to  see  how  little  of  different  kinds  of  protein  he  had  to  take 
in  order  to  bring  himself  into  nitrogenous  equilibrium.  He. found  that 


STARVATION  ,  607 

he  had  to  take  the  following  amounts :  30  gm.  meat  protein,  31  gm.  milk 
protein,  34  gm.  rice  protein,  38  gm.  potato  protein,  54  gm.  bean  protein, 
76  gm.  bread  protein,  and  102  gm.  Indian-corn  protein.  The  organism 
is  evidently  able  to  satisfy  its  protein  demands  much  more  readily  with 
meat  than  with  vegetable  proteins. 

This  variability  in  the  food  value  of  different  proteins  depends  on  their 
ultimate  structure — that  is,  on  the  proportion  and  manner  of  linkage 
of  the  various  amino  acids  that  go  to  build  up  the  molecule.  In  no  two 
proteins  are  these  building  stones,  as  they  are  called,  present  in  exactly 
the  same  proportions,  some  proteins  having  a  preponderance  of  one  or 
more  and  an  absence  of  others,  just  as  in  a  row  of  houses  there  may  be 
no  two  that  are  exactly  alike,  although  for  all  of  them  the  same  build- 
ing materials  were  available.  Albumin  and  globulin  are  the  most  im- 
portant proteins  of  blood  and  tissues,  so  that  the  food  must  contain  the 
necessary  units  for  their  construction.  If  it  fails  in  this  regard,  even  to 
the  extent  of  lacking  only  one  of  the  units,  the  organism  will  either  be 
unable  to  construct  that  protein,  and  will  therefore  suffer  from  partial 
starvation,  or  it  will  have  to  construct  for  itself  this  missing  unit.  It 
is  therefore  apparent  that  the  most  valuable  proteins  will  be  those  that 
contain  an  array  of  units  that  can  be  reunited  to  form  all  the  varieties 
of  protein  entering  into  the  structure  of  the  body  proteins.  Naturally, 
the  protein  which  most  nearly  meets  the  requirements  is  meat  protein, 
so  that  we  are  not  surprised  to  find  that  less  of  this  than  of  any  other 
protein  has  to  be  taken  to  gain  nitrogenous  equilibrium. 

The  most  exact  information  regarding  the  "food  value "  of  different 
proteins  has  been  secured  by  observations  on  the  rate  of  growth  of  young 
animals.  This  method  yields  more  reliable  information  than  can  be 
secured  by  studies  on  the  nitrogenous  balance,  because  it  is  not  usually 
possible  to  keep  up  the  latter  observations  for  a  sufficient  period  of 
time,  or  to  secure  an  adequate  number  of  data.  During  growth  the 
building-up  processes  are  in  excess  of  the  breaking-down,  so  that  the 
effect  is  an  increase  in  bulk  of  the  tissues,  thus  permitting  us,  by  the  sim- 
ple expedient  of  observing  the  body  weight,  to  draw  conclusions  as  to 
the  influence  of  various  foodstuffs  on  tissue  construction. 


CHAPTER  LXVI 
NUTRITION  AND  GROWTH 

In  the  growth  of  animal  tissues  two  factors  are  concerned,  one  being 
the  property  of  the  cell  to  grow,  the  growth  factor;  and  the  other,  the 
availability  of  suitable  material  to  grow  upon,  the  food  factor.  Concern- 
ing the  growth  factor  little  is  known;  its  variability  in  different  species 
of  animal,  its  irregularity  despite  proper  adjustment  of  the  food  factors, 
its  abnormality  leading  to  tumor  formation,  etc.,  are  all  well-known  but 
apparently  inexplicable  facts  (Mendel8).  The  growth  factor  is  very  sen- 
sitive towards  the  activity  of  certain  of  the  ductless  glands  such  as  the 
anterior  lobe  of  the  pituitary  (page  808),  and  towards  substances  of 
unknown  chemical  nature  contained  in  various  foods.  These  are  called 
accessory  food  factors  or  vitamines  (page  618). 

THE  FOOD  FACTOR  OF  GROWTH 

Our  knowledge  is  constantly  increasing  concerning  the  food  factor  of 
growth,  and  many  facts  of  extreme  practical  importance  have  been  ac- 
cumulated in  recent  years.  In  seeking  for  the  relationship  of  food  to 
growth,  we  must  first  of  all  consider  whether  this  process  entails  a 
greater  expenditure  of  energy  than  is  necessary  for  mere  maintenance 
in  adult  life.  Important  results  bearing  on  this  question  have  been  se- 
cured by  observations  on  the  basal  metabolism  of  young  children.  In 
computing  the  energy  supply  of  fasting  adult  animals  of  different  sizes, 
it  will  be  remembered  that  the  smaller  the  animal,  the  greater  is  the 
energy  exchange  in  relationship  to  the  body  weight,  although  when 
computed  in  relationship  to  body  surface  tolerably  constant  values  are 
obtained.  When  the  calorie  output  per  square  meter  is  determined  in 
growing  children,  there  is,  as  we  have  already  seen,  clear  evidence  of 
greater  energy  expenditure  (see  page  577),  particularly  marked  in  boys 
just  before  puberty.  An  increased  energy  metabolism  has  also  been  de- 
scribed in  the  case  of  infants,  but  the  uncontrollable  muscular  activity, 
the  psychic  disturbances,  etc.,  may  explain  the  result.  Even  after  dis- 
counting these  factors,  however,  it  is  possible  that  there  may  be  a  cer- 
tain influence,  depending  probably  on  the  active  mass  of  growing  proto- 
plasmic tissue,  which  stimulates  the  energy  expenditure.  The  question 
is  not  yet  finally  settled. 

608 


NUTRITION    AND   GROWTH 


609 


The  Relationship  of  Proteins  to  Growth  and  Maintenance  of  Life. — 

Since  protein  constitutes  the  fundamental  chemical  basis  of  the  cell,  it 
is  natural  to  devote  attention  in  the  first  place  to  this  food  principle. 
In  the  pioneer  investigations,  studies  on  the  nitrogen  balance  in  young 
animals  yielded  results  from  which  it  was  concluded  that  the  conditions 
for  the  disintegration  of  protein  are  less  developed  in  young  animals 
than  in  adults,  so  that  the  growing  organs  rapidly  withdraw  circulating 
protein  and  build  it  into  tissue  protein. 

In  consideration  of  the  accumulation  of  data  extending  over  several 
decades,  Rubner  denied  these  conclusions,  and  showed  that  the  diet  of 
the  growing  infant  is  by  no  means  relatively  rich  in  protein.  He  con- 
cluded that  ' '  growth  is  not  proportional  to  the  quantity  of  protein  in  the 
diet. "  Important  though  this  pioneer  work  may  have  been  in  the  de- 
velopment of  our  present-day  conception,  the  viewpoint  of  the  men  who 
carried  it  out  was  very  much  narrowed  on  account  of  the  paucity  of 
knowledge  concerning  the  structure  of  the  protein  molecule.  No  allow- 
ance was  made  for  the  fact,  which  has  recently  been  firmly  established, 
that  the  protein  molecule  may  vary  extremely  in  regard  to  the  units 
of  which  it  is  composed,  and  that  the  growing  tissues  may  demand,  not 
so  much  an  abundance  of  protein  as  such,  but  rather  a  proper  supply  of 
all  the  building  stones  which  are  required  for  growth  (Mendel). 

QUANTITATIVE  COMPARISON  OF  AMINO  ACIDS  OBTAINED  BY  HYDROLYSIS  OF  PROTEINS* 
(Compiled  by  T.  B.  Osborne,  1914)  f 


CASEIN 

OVAL- 
BUMIN 

GLIADIN 

ZEIN 

EDESTIN 

LEGUMIN 

ox 

MUSCLE 

Glycocoll 

0.00 

0.00 

0.00 

0.00 

3.80 

0.38 

4.0 

Alanine 

1.50 

2.22 

2.00 

13.39 

3.60 

2.08 

8.1 

Valine 

7.20 

2.50 

3.34 

1.88 

6.20 

? 

2.0 

sLeucine 

9.35 

10.71 

6.62 

19.55 

14.50 

8.00 

14.3 

Proline 

6.70 

3.56 

13.22 

9.04 

4.10 

3.22 

8.0 

Phenylalanine 

3.20 

5.07 

2.35 

6.55 

3.09 

3.75 

4.5 

Glutaminic  acid 

15.55 

9.10 

43.66 

26.17 

18.74 

13.80 

10.6 

Aspartic  acid 

1.39 

2.20 

0.58 

1.71 

4.50 

5.30 

22.3 

Serine 

0.50 

? 

0.13 

1.02 

0.33 

0.53 

? 

^Tyrosine 

4.50 

1.77 

1.61 

3.55 

2.13 

3.55 

4.4 

XJystine 

? 

? 

0.45 

? 

1.00 

? 

? 

Histidine 

2.50 

1.71 

1.84 

0.82 

2.19 

2.42 

4.5 

Arginine 

3.81 

4.91 

2.84 

1.55 

14.17 

10.12 

11.5 

Lysine 

5.95 

3.76 

0.93 

0.00 

1.65 

4.29 

7.6 

Tryptophane,  about 

1.50 

present 

1.00 

0.00 

present 

present 

present 

Ammonia 

1.61 

1.34 

5.22 

3.64 

3.28 

1.99 

1.07 

65.49 

48.85 

85.68 

88.87 

82.28 

57.43 

102.87 

*These    analyses    are    combinations    of    what    appear    to    be    the    best    determinations    of    various 
chemists. 

fThe  figures  for  the  more  recent  analyses  of  gliadin  are  inserted. 

From  the  accompanying  table  giving  the  percentage  of  the  various 
ammo  acids,  etc.,  present  in  certain  proteins,  it  will  be  evident  that  there 


610 


METABOLISM 


are  very  marked  variations  in  the  units  of  which  different  proteins  are 
composed.  If  any  one  of  these  units  should  be  essential  for  growth  and 
the  organism  be  unable  to  manufacture  the  missing  unit  for  itself,  it 
is  clear  that  growth  could  not  proceed  however  much  protein  not  contain- 
ing the  necessary  unit  we  might  feed  to  the  animal.  It  is  an  application 
of  the  law  of  the  minimum,  and  is  analogous  with  the  failure  of  growth 
which  has  long  been  known  to  ensue  when  certain  inorganic  substances 
are  withheld  from  the  growing  animal.  A  diet  might  be  perfectly  bal- 
anced as  judged  by  comparison  of  the  nitrogen  intake  and  output,  and 
yet  if  it  should  fail  to  contain  even  one  of  the  essential  units  and  the 
organism  should  be  incapable  of  supplying  this  unit,  then  would  the 
diet  be  inadequate  for  growth. 

These  important  facts  are  the  outcome  of  modern  work,   and  they 


Days 


Each  divi$ion=&0days. 


Fig.  183. — Curves  of  growth  of  rats  on  basal  rations  plus  the  various  proteins  indicated.  The 
normal  curve  may  be  taken  as  that  with  casein  (I).  (Adapted  from  Lafayette  B.  Mendel  and 
T.  B.  Osborne.) 

have  been  established  by  observations  on  the  growth  of  young  animals 
fed  with  a  "  basal  ration "  to  which  were  added  mixtures  of  amino  acids 
or  various  proteins  which  differ  considerably  from  one  another  in  the 
nature  of  the  units  entering  into  their  make-up.  In  such  experiments 
the  periods  during  which  growth  is  observed  must  be  prolonged,  since 
a  transient  increase  in  weight  might  depend  merely  on  repair  processes 
occurring  in  tissues  which  had  previously  for  some  reason  been  brought 
below  par. 

Among  the  most  important  observations  have  been  those  of  F.  Gow- 
land  Hopkins,  Lafayette  B.  Mendel  and  T.  B.  Osborne8  and  of  McCollum9 
and  his  collaborators.  The  animals  chosen  for  Mendel  and  Osborne 's 
experiments  were  young  white  rats.  Large  batches  of  these  animals 


NUTRITION    AND   GROWTH 


611 


were  fed  on  a  basal  ration  consisting  of  protein-free  milk  (containing 
the  inorganic  salts,  the  sugars,  traces  of  protein,  and  unknown  substances 
having  an  important  influence  on  growth — vitamines),  to  which  were 
added  more  carbohydrate,  purified  fat,  and  the  protein  whose  influence 
on  growth  it  was  desired  to  study.  The  same  diet  was  fed  at  regular  in- 
tervals to  a  given  batch  of  rats,  and  the  weight  of  each  rat  was  period- 
ically taken,  the  observation  being  prolonged  until  the  animals  grew  to 
maturity  and  produced  young,  and  these  again  grew  to  maturity,  repro- 
duced, and  so  on.  By  plotting  the  results  in  curves,  with  the  time  peri- 
ods along  the  abscissae  and  the  average  weight  of  the  rats  of  each  batch 
along  the  ordinates,  the  extent  of  the  influence  of  a  given  diet  on  the 
curve  of  growth  was  obtained.  A  normal  curve  of  growth  is  shown  in 


Days 


Each  division  -  80  days 


Days 


Each  division -20  days 


Fig.  184. — Curves  of  growth  of  rats  on  basal  rations  plus  the  proteins  indicated.  In  curve 
III  the  effect  of  the  addition  of  zein  to  an  inadequate  allowance  of  the  perfect  protein,  lactalbumin, 
is  shown;  and  in  IV  the  effect  of  the  addition  of  cystine  to  a  deficient  casein  allowance.  (From 
Lafayette  B.  Mendel  and  T.  B.  Osborne.)  . 

No.  1  of  Fig.  183.  It  was  obtained  from  results  secured  by  adding  liberal 
amounts  of  casein  to  the  basal  diet.  Similar  curves  were  obtained  with 
lactalbumin  of  milk  and  ovalbumin  and  ovovitellin  of  egg.  Perhaps  the 
most  interesting  substances  capable  of  producing  the  normal  curve  of 
growth  are  certain  of  the  proteins  that  T.  B.  Osborne  has  succeeded  in 
separating  in  crystalline  form  from  vegetable  foodstuffs.  These  are 
edestin  (hempseed),  globulin  (squash  seed),  excelsin  (Brazil  nut),  glu- 
telin  (maize),  globulin  (cottonseed),  glutein  (wheat),  glycinin  (soy  bean), 
cannabin  (hempseed). 

That  growth  proceeds  normally  with  any  one  of  these  proteins  when  it 
is  fed  abundantly  does  not,  however,  necessarily  indicate  that  each  con- 


612  METABOLISM 

tains  in  adequate  proportion  all  of  the  necessary  units  to  meet  the  pro- 
tein demands  of  growing  tissues.  In  the  case  of  casein,  for  example, 
one  of  the  units,  namely,  glycocoll,  which  is  the  simplest  of  all  the 
amino  acids,  is  entirely  missing,  and  another,  cystine,  which  is  a  sul- 
phur-containing amino  acid,  is  present  only  in  small  amount.  The  ab- 
sence of  glycocoll,  however,  is  not  of  importance,  because  the  organism 
can  manufacture  it  for  itself  (see  page  663).  In  the  case  of  cystine, 
which  the  tissues  can  not  manufacture  themselves,  the  deficiency  has  to 
be  made  up  for  by  feeding  an  excess  of  casein  so  as  to  cover  the  needs 
of  the  tissues  for  this  amino  acid.  By  so  doing  a  superabundance  of 
most  of  the  other  units  will  be  ingested,  and  this  superabundance  will 
entail  the  destruction  and  excretion  of  the  useless  amino  acids,  a  process, 
however,  which  is  conducted  in  such  a  way  as  to  permit  of  the  utilization, 
by  the  organism,  of  a  part  of  the  energy  which  the  cast-off  amino  acids 
contain  (see  page  699).  It  is,  therefore,  not  entirely  a  wasteful  process. 

When  the  supply  of  casein  is  limited,  on  the  other  hand,  the  curve 
of  growth  becomes  subnormal,  because  an  insufficient  supply  of  cystine 
is  thereby  offered  (Fig.  184).  Similar  results  have  been  obtained  in  the 
case  of  edestin,  a  protein  from  hempseed.  This  contains  an  insufficiency 
of  the  diamino  acid,  lysine.  Fed  in  abundance,  edestin  gave  a  normal 
curve  of  growth,  but  when  fed  in  insufficient  amount  the  curve  failed  to 
ascend  properly  (which,  however,  it  could  be  made  to  do  by  adding  some 
lysine  to  the  edestin). 

There  is  a  large  group  of  proteins  which  fail  to  permit  of  any  growth 
no  matter  in  what  amounts  they  may  be  added  to  the  basal  ration.  These 
include:  legumelin  (soy  bean),  vignin  (vetch),  gliadin  (wheat  or  rye), 
legumin  (pea),  legumin  (vetch),  hordein  (barley),  conglutin  (lupine), 
gelatine  (horn),  zein  (maize),  phaseolin  (kidney  bean).  The  adequacy 
to  maintain  growth  of  any  of  these  pure  proteins  varies  according  to 
the  deficiency  in  their  amino  acids.  In  the  case  of  gliadin  of  wheat  or 
rye,  glycocoll  is  -lacking,  and  lysine  is  present  only  in  small  amount  (see 
table).  The  absence  of  glycocoll  can  not,  however,  as  we  have  already 
seen  in  the  case  of  casein,  explain  the  inadequacy  of  gliadin  as  a  foodstuff 
for  growth  (Curve  II  in  Fig.  183) .  It  must  be  the  lysine  that  is  at  fault.  A 
still  more  deficient  protein  is  the  zein  of  maize.  With  this  as  the  only 
protein  added  to  the  basal  diet,  the  curve  of  growth  actually  descends 
(Curve  III  of  Fig.  183),  thus  indicating  that  the  animal  is  starving  and 
must  soon  succumb.  The  missing  units  in  this  protein  are  glycocoll, 
lysine  and  tryptophane  (see  table  on  page  609),  and  it  is  very  signifi- 
cant that  if  the  latter  two  amino  acids  are  supplied  along  with  zein,  an 
almost  normal  curve  of  growth  will  result.  Some  improvement  can 
even  be  brought  about  by  giving  tryptophane  alone ;  that  is  to  say,  the 


NUTRITION   AND   GROWTH  613 

curve  assumes  a  horizontal  line  instead  of  descending,  indicating  that, 
although  inadequate  for  growth,  the  diet  is  now  sufficient  for  the  main- 
tenance of  life. 

An  important  fact  demonstrated  by  these  experiments,  is  that  cer- 


Fig.  185. — Photographs  of  rats  of  same  brood  on  perfect  diet  (uppermost  picture) ;  on  a  main- 
tenance diet  but  inadequate  for  growth  (middle  picture) ;  and  on  a  diet  that  was  inadequate  both 
for  maintenance  and  growth.  (From  Mendel  and  Osborne.) 

tain  diets  are  adequate  for  the  maintenance  of  life  although  they  are 
inadequate  for  growth.  In  conformity  with  this  conclusion,  it  was  found 
when  young  white  rats  were  fed  with  gliadin  alone  for  periods  of  time  ex- 
ceeding those  in  which  they  should  have  become  full  grown,  that 
they  remained  in  an  ungrown  stunted  condition.  The  capacity  to  grow 


614  METABOLISM 

had  not,  however,  been  lost,  for  when  the  gliadin  was  replaced  by  milk, 
the  animals  resumed  growth  at  a  very  great  rate.  The  capacity  to  grow 
had  only  been  inhibited  by  the  inadequate  diet,  and  there  was  nothing 
really  abnormal  about  the  stunted  animals.  For  example,  the  reproduc- 
tive function  developed  normally,  as  was  shown  in  the  case  of  a  young 
female  rat  which,  after  being  fed  with  gliadin  as  the  sole  protein  sup- 
ply for  154  days,  was  mated  and  produced  four  young.  Although  the 
mother  was  still  maintained  on  the  gliadin  diet,  the  young  rats  pre- 
sented normal  growth,  for  they  were  living  on  the  milk  supplied  by  the 
mother,  and  this  milk,  because  it  contained  either  casein  or  some  other 
necessary  accessory  factor  (vide  infra),  was  an  adequate  food. 

After  removal  from  the  mother,  three  of  these  rats  were  fed  on  an  arti- 
ficial diet  of  casein,  edestin  and  the  basal  ration,  and  continued  the  nor- 
mal course  of  growth,  but  when  one  of  them  was  placed  on  the  gliadin 
food  mixture  it  immediately  failed  to  grow  properly.  It  would  appear 
from  these  experiments  that,  of  the  two  amino  acids  that  are  missing  or 
deficient  in  gliadin — namely,  glycocoll  and  lysine — it  must  be  the  lysine 
that  is  essential  for  growth.  This  very  important  conclusion  was  fully 
corroborated  by  finding  that,  in  young  rats  stunted  by  previous  gliadin 
feeding,  growth  immediately  started  when  lysine  was  added  to  the  diet 
and  ceased  again  when  the  lysine  was  removed,  and  so  on,  the  experi- 
ments being  often  repeated  in  various  modifications.  Mendel  and  Os- 
borne  call  attention  to  the  relatively  high  percentage  of  lysine  in  all 
those  proteins  that  are  concerned  in  nature  with  the  growth  of  young 
animals;  thus,  it  is  present  in  large  amounts  in  casein,  lactalbumin  and 
egg  vitellin. 

It  is  particularly  in  protein  of  vegetable  origin  that  indispensable  units 
are  likely  to  be  missing,  the  best  known  of  these  units  being  the  aromatic 
amino  acids,  tyrosiiie  and  tryptophane;  the  diamino  acid,  lysine;  and 
the  sulphur-containing  acid,  cystine.  Some  animal  proteins,  such  as 
gelatine,  also  fail  to  contain  aromatic  groups,  and  are  therefore  utterly 
inadequate  as  foods. 

That  the  absence  of  one  or  two  units  should  render  a  protein  in- 
capable of  maintaining  life  suggests  that  a  specific  role  may  be  taken 
by  certain  amino  acids  in  the  maintenance  of  nutritional  rhythm;  thus, 
they  may  be  necessary  for  the  elaboration  of  some  hormone  or  other  in- 
ternal secretion  essential  to  life,  such  as  epinephrine,  the  active  principle 
of  the  suprarenal  gland.  This  is  an  aromatic  substance  not  far  removed 
in  its  chemical  structure  from  tyrosine  (see  page  773).  It  is  therefore 
natural  to  suppose  that  the  absence  of  the  tryptophane  unit  in  zein  is  the 
reason  that  this  protein  is  incapable  of  maintaining  the  initial  body  weight. 


NUTRITION   AND   GROWTH  615 

In  attacking  the  problem  from  this  viewpoint,  Hopkins  and  Willcock10 
made  observations  on  the  survival  period  of  young  mice;  that  is,  the 
period  during  which  the  animals  survived  when  fed  on  a  basal  diet 
mixed  either  with  zein  alone  or  with  zein  plus  small  quantities  of  tryp- 
tophane.  It  was  found  that,  with  zein  alone,  the  mice  were  unable  to 
maintain  growth;  they  lost  in  weight  and  died  in  from  about  a  week  to 
about  a  month.  Other  mice  fed  on  the  same  amount  of  basal  diet  and 
zein,  but  to  which  was  also  added  some  tryptophane,  although  they  did 
not  grow,  were  capable  of  maintaining  their  body  weight  and  lived  in 
some  instances  for  nearly  a  month  and  a  half.  There  were  other  indica- 
tions of  the  difference  in  the  efficiency  of  the  two  diets.  The  mice  fed 
on  the  zein  alone  were  very  inactive,  and  remained  for  a  considerable 
period  of  the  time  in  a  condition  of  torpor.  The  hair  was  ruffled,  the 
eyes  w^ere  half  closed,  and  the  ears,  feet  and  tail  were  cold.  The  ani- 
mals, however,  gave  evidence  of  having  a  good  appetite.  On  the  other 
hand,  the  mice  to  which  tryptophane  was  also  given  manifested  a  strik- 
ingly different  behavior,  being  active  and  more  or  less  normal  until 
just  before  death.  That  both  groups  of  animals  failed  to  live  more  than 
forty-four  or  forty-eight  days  is  probably  to  be  accounted  for  by  the 
absence  in  the  zein  of  the  other  unit,  lysine.  Had  this  been  added  along 
with  the  tryptophane  it  is  probable,  in  the  light  of  Mendel  and  Osborne's 
observations,  that  the  animals  would  have  survived  much  longer. 

To  supply  the  missing  unit,  besides  using  the  pure  amino  acid,  we 
may  employ  other  proteins  which  contain  the  required  amino  acid  (Curve 
III  of  Fig.  184).  That  mixtures  of  protein  foodstuffs  are  desirable  has  long 
been  apparent  to  those  who  have  studied  practical  dietetics.  We  must  com- 
bine the  unsuitable  protein  with  others  which,  although  in  themselves 
perhaps  also  unsuitable,  yet  furnish  us  with  a  mixture  which  contains  all 
the  essential  units  both  for  maintenance  and  growth.  As  Mendel  points 
out,  these  considerations  suggest  that  we  may  be  able  to  utilize  certain 
of  the  low  priced  protein  by-products  of  the  cereal,  meat  and  milk  in- 
dustries. The  test  of  the  adequacy  of  the  corrected  diet  must,  however, 
be  determined  by  experiments  of  the  type  which  we  have  just  described. 
It  is  probably  in  stock-raising  rather  than  in  connection  with  human  nu- 
trition that  these  facts  will  prove  of  practical  value ;  for,  not  only  is  the  diet 
of  man  more  varied,  but  it  contains  animal  proteins  in  which  the  deficien- 
cies are  not  so  common. 

Most  important  work  of  this  character  is  being  conducted  by  McCol- 
lum  and  his  collaborators.12  It  would  take  us  beyond  the  confines  of 
this  book  to  discuss  the  results  in  detail,  but  it  may  be  mentioned  that 
they  have  shown  that,  since  the  adequacy  of  the  diet  depends  on  a 
multiplicity  of  factors  besides  the  ammo-acid  make-up  of  proteins, — 
some  of  which  we  shall  discuss  immediately, — very  extensive  observa- 


616  METABOLISM 

tions  with  various  food  mixtures  must  be  conducted  over  long  periods 
of  time.  The  nutritive  values  of  the  common  cereals  added  to  a  stand- 
ard diet  that  had  brought  the  animals  (rats)  to  the  threshold  of  death, 
were  found  to  be  as  follows:  With  cornmeal  there  was  immediate  recov- 
ery and  rapid  growth,  both  of  which  were  also  secured  in  considerable 
degree  by  wheat  embryo  and  entire  wheat  kernel ;  with  rye  and  oats,  on 
the  other  hand,  there  was  little  if  any  improvement. 

Much  work  is,  of  course,  yet  to  be  done  before  we  can  determine  the 
exact  role  which  each  unit  plays  in  the  physiological  development  of 
young  animals.  To  sum  up  what  we  already  know,  it  may  be  said  that 
glycocoll  is  not  essential,  since  it  can  be  manufactured  by  the  animal 
itself;  that  tryptophane  is  essential  for  maintenance,  probably  because 
it  is  required  for  the  production  of  certain  essential  hormones,  for  the 
make-up  of  which  in  its  absence  other  tissues  must  become  disintegrated, 
leading  therefore  to  a  diminution  in  body  weight;  and  that  lysine  ap- 
pears to  be  essential  for  growth.  Tissues  can  be  maintained  without 
lysine,  but  they  can  not  grow.  That  the  young  rats  in  the  experiments 
of  Mendel  grew  normally  while  living  on  milk  supplied  by  the  stunted 
mother  indicates  that  the  requisite  lysine  must  have  been  produced  in 
the  mother's  body. 

In  the  application  of  the  foregoing  principles  to  human  dietetics,  it 
is  undoubtedly  safe  to  follow  Bayliss's  advice  to  take  care  of  the  calo- 
|ries  and  allow  the  proteins  to  take  care  of  themselves.11  For  example, 
in  the  case  of  milk  the  deficiency  of  cystine  in  its  chief  protein,  casein, 
is  corrected  by  the  presence  of  lactalbumin,  which,  though  present  in 
only  small  amounts,  contains  sufficient  quantities  of  this  amino  acid  to 
meet  the  demands  of  the  growing  tissue. 

These  observations  on  maintenance  and  growth  suggest  very  interest- 
ing applications  in  connection  with  the  growth  of  tumors.  Is  it  possible 
that  we  might  retard  the  growth  of  tumors  by  a  diet  that  was  insufficient 
for  growth  while  sufficient  for  maintenance.  In  an  experiment  devised 
to  test  this  proposition  mice  were  fed  on  a  diet  of  starch,  lard,  lactose 
and  gluten  on  which  they  could  merely  maintain  existence  but  failed 
to  grow.  Some  of  these  rats  were  inoculated  with  a  rapidly  growing 
tumor  at  the  same  time  as  another  batch  of  mice  kept  on  normal  diet,  and 
it  was  found  that  the  tumor  grew  much  more  slowly  in  the  stunted  mice 
than  in  the  others.  One  mouse,  for  example,  on  the  restricted  diet  had 
a  scarcely  visible  tumor  52  days  after  the  inoculation.  When  this  mouse, 
however,  was  placed  on  a  normal  diet  of  bread,  milk,  etc.,  the  tumor 
immediately  began  to  grow  at  a  very  great  rate.13  Too  much  importance 
should  not  be  placed  on  this  experiment. 

We  shall  now  pass  on  to  consider  some  of  the  factors  besides  the  pro- 
tein content  which  have  an  important  bearing  on  dietetic  efficiency. 


CHAPTER  LXVII 
NUTRITION  AND  GROWTH  (Cont'd) 

THE  RELATIONSHIP  OF  OTHER  FACTORS  THAN  PROTEINS 

The  Relationship  of  Carbohydrates, — As  we  have  seen  elsewhere,  car- 
bohydrates are  almost  certainly  essential  for  normal  metabolism.  If  they 
are  not  given  with  the  food,  they  must  be  manufactured  out  of  protein  by 
the  organism  itself.  It  is  not  surprising,  therefore,  that  their  absence 
from  the  diet  of  growing  animals  should  lead  to  abnormality  in  the 
rate  of  growth.  Pediatrists  have  not  infrequently  insisted  that  one 
form  of  carbohydrate  is  more  advantageous  for  growth  than  another. 
This  no  doubt  in  the  main  is  true,  but  the  whole  question  of  adequacy 
probably  depends  on  the  digestibility  of  the  carbohydrate  and  not  upon 
its  essential  chemical  nature.  It  is  likely  that  the  only  carbohydrate 
required  by  the  tissues  is  glucose.  The  readiness  with  which  the  car- 
bohydrate of  the  food  becomes  converted  into  this  monosaccharide  is 
probably  the  only  determinant  of  its  efficiency  as  food  material. 

The  Relationship  of  Fats. — Although  fats  are  an  invariable  constit- 
uent of  practically  every  diet,  it  is  yet  a  debatable  question  as  to 
whether  they  are  essential  to  the  maintenance  of  a  healthy  normal 
organism.  Difficulties  standing  in  the  way  of  a  solution  of  this  problem 
are  that  it  is  not  only  technically  very  difficult  to  remove  fat  entirely 
from  the  common  foodstuffs,  but  also  that  the  simple  fats  are  usually 
associated  with  substances  having  similar  solubilities  and  physical 
properties:  namely,  the  lipoids,  phosphatides,  cholesterol,  pigments,  etc. 
Since  these  substances  are  present  in  practically  every  cell,  it  is  almost 
certain  that  they  can  be  manufactured  by  living  protoplasm.  Indeed, 
experimental  evidence  is  not  wanting  to  show  that  this  is  actually  the 
case.  Although  the  cell  can  manufacture  lipoids,  a  young  animal  can 
apparently  not  grow  when  these  substances,  as  well  as  simple  fat,  are 
entirely  absent  from  the  diet.  This  has  been  shown  by  feeding  young 
mice  on  a  diet  from  which  all  traces  of  fat  and  lipoids  had  been  removed 
by  extraction  with  alcohol  and  ether  (Stepp)14.  On  such  a  diet  the  mice 
lived  only  a  few  weeks.  They  could  be  kept  alive  much  longer  when 
some  of  the  alcohol-ether  extract  was  mixed  with  the  diet,  but  not  so 
when  neutral  fat  instead  of  the  alcohol-ether  extract  was  added.  The 

617 


618  METABOLISM 

addition  of  the  ash  of  the  lipoid  extract  failed  to  maintain  the  mice,  so 
that  the  lacking  substance  could  not  be  inorganic  in  nature. 

As  we  shall  see  immediately,  these  results  are  dependent  upon  the 
presence  in  fats  of  so-called  accessory  food  factors  or  vitamines. 

The  Relationship  of  Inorganic  Salts. — Inorganic  salts  are  also  an  es- 
sential ingredient  of  the  diet.  McCollum  found  that  young  animals  soon 
ceased  to  grow  when  fed  on  a  diet  of  corn  and  purified  casein,  but  that 
rapid  growth  returned  when  a  suitable  salt  mixture  was  added.  Oats, 
wheat,  and  beans  have  also  been  shown  to  require  some  adjustment  of  their 
ash  content  to  make  them  adequate  for  growth.  Most  of  the  animal  foods 
contain  in  themselves  sufficient  inorganic  material,  as  is  evidenced 
among  other  things  by  the  adequacy  of  milk  alone  as  diet  for  growing 
animals  and  the  abhorrence  of  salt  that  is  shown  by  strictly  carnivorous 
animals.  In  the  usual  mixed  diet  of  man  there  is  almost  always  enough 
inorganic  material,  the  salt  which  he  adds  being  largely  for  seasoning 
purposes.  When  a  preponderance  of  vegetable  food  is  taken,  however, 
the  salt  comes  to  have  a  real  dietetic  value. 

ACCESSORY  FOOD  FACTORS,  VITAMINS 

Even  when  the  requirements  of  the  animal  body  for  calories  and 
protein  building  stones  are  fully  met,  the  diet  will  fail  to  maintain 
health  unless  it  also  contains  substances  of  an  unknown  chemical  nature 
called  "accessory  food  factors"  or  "vitamins."  These  are  entirely  of 
plant  origin,  and  require  to  be  taken  only  in  very  small  quantities  to 
display  their  beneficial  action.  They  do  not  become  rapidly  destroyed 
in  metabolism,  but  may  remain  attached  to  the  tissues  sufficiently  long 
so  that  carnivorous  animals  obtain  them  indirectly.  Great  advancement 
in  our  knowledge  of  vitamins  had  been  made  in  recent  years,  particu- 
larly through  the  work  of  F.  Gowland  Hopkins  and  Harriette  Chick,70 
Osborne  and  Mendel,71  Funk,15  McCollum,12  and  McCarrison.75 

Serious  and  prolonged  absence  of  certain  vitamins  from  the  dietary 
may  hinder  the  growth  of  young  animals  or  may  be  the  cause  of  various 
serious  diseases  in  adults. 

The  human  diseases  which  are  known  definitely  to  be  due  to  the  absence 
of  one  or  other  of  the  vitamins  are  beriberi,  scurvy  and  rickets,  and 
accordingly  three  vitamins  are  distinguished: 

1.  Antiberiberi  or  antineuritic  vitamin  (also  called  water  soluble  "B" 
growth  factor). 

2.  Antirachitic  vitamin  (also  called  fat-soluble  A  growth  factor). 

3.  Antiscorbutic  vitamin. 

It  will  be  observed  that  the  vitamins  also  differ  from  one  another  in 
their  solubilities. 


NUTRITION   AND   GROWTH  619 

Investigation  of  the  distribution  of  the  vitamins  among  the  various 
foodstuffs,  and  their  degree  of  stability  towards  heating,  etc.,  has  been 
very  materially  facilitated  by  the  fact  that  certain  of  the  lower  animals 
suffer  diseases  like  those  seen  in  man  when  vitamins  are  absent  from 
the  diet.  This  renders  it  possible  to  prosecute  the  investigations  in- 
tensively and  under  scientifically  controlled  conditions,  thus  affording 
knowledge  which  enables  us  to  alleviate  human  suffering. 

The  Antiberiberi  or  Antineuritic  Vitamin. — Beriberi  is  a  disease  char- 
acterized by  wasting,  anesthesia  and  paralysis,  and  sometimes  by  ex- 
cessive edema.  Pathologically,  it  is  a  form  of  severe  neuritis.  It  is 
common  in  rice-eating  communities,  and  the  first  clue  to  its  chief  cause 
was  afforded  by  the  observation  that  it  does  not  occur  among  people 
who  take  unmilled  rice,  and  that  it  disappears  in  those  who  take  "pol- 
ished" rice  when  the  millings  or  a  watery  extract  of  them  (pericarp  and 
germ)  are  added  to  the  diet.  It  was  observed  by  Eijkman  that  the  poul- 
try of  a  prison  where  beriberi  was  prevalent  exhibited  symptoms  very 
like  those  of  the  human  disease,  and  further  investigation  showed  ex- 
tensive nerve  degeneration  to  exist  in  the  affected  animals.  Pigeons 
fed  on  polished  rice  develop  exactly  the  same  symptoms  so  that  experi- 
mental investigation  soon  rendered  it  possible  to  determine  with  accu- 
racy which  foodstuffs  prevent  beriberi.  Meanwhile  McCollum  and  Davis 
discovered  that  the  absence  of  the  same  water-soluble  vitamin  interfered 
seriously  with  the  growth  of  young  animals.  This  is  shown  in  Curve  II  of 
Pig.  186,  from  the  observations  of  Hopkins  and  Chick,  and  is  con- 
structed on  the  same  principles  as  those  of  Fig.  184.  It  will  be  observed 
that  the  withdrawal  of  the  vitamin  caused  an  immediate  cessation  of 
growth  followed  by  a  period  during  which  the  body  weight  remained 
more  or  less  constant,  but  ultimately  declined.  The  fact  discovered  by 
McCarrison75  that  atrophy  of  the  gastrointestinal  tract  also  results  from 
deficiency  in  this  vitamin,  may  be  responsible  in  part  at  least  for  the 
failure  of  growth.  During  this  stage  muscular  incoordination  is  a 
prominent  symptom,  and  death  ultimately  occurs.  The  curves  show 
that  this  vitamin  must  soon  disappear  from  the  organism  when  it  is  with- 
drawn from  the  food  and  that  the  animal  cannot  synthetize  it. 

It  will  be  noted  in  the  table  on  page  623  that  vitamin  B  is  present 
in  abundance  in  the  seeds  of  plants  and  the  eggs  of  animals.  It  is 
very  plentiful  in  yeast  and  in  yeast  extracts,  which  may  therefore 
be  added  to  the  diet  when  there  is  risk  of  its  deficiency.  It  is  ab- 
sent from  bread  made  with  white  wheat  flour,  but  beriberi  is  rare  in 
people  living  on  this  food,  since  other  foodstuffs  containing  the  vitamin 
are  usually  also  taken.  Beriberi  is  unknown  where  rye  bread  is  the 
staple  food. 

The  Antirachitic  Vitamin  (Fat-Soluble  A  Factor).— The  first  inkling 


620 


METABOLISM 


of  the  existence  of  this  factor  we  owe  to  Stepp  who  found  that  mice 
could  not  live  for  long  on  animal  foods  from  which  all  fatty  substances 
had  been  thoroughly  extracted  by  alcohol  and  ether.  If  the  extract  was 
restored  to  the  extracted  food,  this  again  became  adequate.  Hopkins 
then  showed  in  carefully  controlled  work  that  animals  (rats)  not  only 
failed  to  grow,  but  declined  and  died  when  they  were  fed  on  artificial 
diet  composed  of  the  purified  constituents  of  milk,  although  they  might 
eat  voraciously.  The  addition  of  a  few  drops  of  milk,  insufficient  to 
raise  the  energy  or  protein  value  appreciably,  invariably  caused  normal 


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«  1?,^'  —  Curves  of  growth  of  rats  as  influenced  by  the  accessory  food  factors.     I.  The  effect 
/fat-s?lubl.e>   factor'     Note  that  the  curve  d°es  not  immediately  descend  after  removal  of 

...  -_  —    *B"  (water-soluble)   factor.     Note  that  growth  ceases 

„  **  1S  withdrawn.     III.  The  time  during  which  animals  survive  after  removal  of  the 

A  tactor  at  different  ages,  the  uppermost  curve  being  that  obtained  for  rats  that  were  nearly 
mature  before  the  factor  was  removed  from  the  diet  and  the  lower  ones  for  less  mature  animals. 
it  u  i  C(?.ntmuous  c«rve  is  for  young  fed  by  mothers  receiving  "A"  factor  int  their  diets; 
the  broken-line  curve  is  for  young  fed  by  mothers  receiving  none  of  this  factor.  (From  Hopkins 
and  Chick.) 

growth  to  return.  Osborne  and  Mendel  also  found  that  although  the 
rats  in  their  experiments  already  referred  to  on  page  609  grew  for  about 
two  months  upon  a  diet  containing  protein,  protein-free  milk,  starch  and 
lard,  they  ultimately  declined,  but  that  this  could  be  avoided  by  substi- 
tuting butter  for  the  lard,  and  that  the  active  substance  was  concen- 
trated in  the  butter-fat  portion  of  the  butter.  Later  work  by  various 
investigators  showed  that  most  animal  fats,  but  not  those  of  plants, 
contain  this  essential,  and  it  was  hence  called  fat-soluble  A  factor  or 


NUTRITION   AND   GROWTH  621 

vitamin.  Lard  does  not  contain  it,  so  that  young  animals  fed  with  this 
as  the  only  fat  of  an  otherwise  perfect  diet  fail  to  grow  as  shown  in 
Curve  I,  Fig.  186.  An  important  difference  will  be  observed  in  this 
curve  from  that  of  II  in  which  the  factor  B  (antiberiberi  vitamin)  is 
alone  deficient,  namely,  that  a  small  amount  of  growth  continues  for  a 
time  after  the  removal  of  the  proper  diet.  This  indicates  that  there  must 
be  some  reserve  of  the  fat-soluble  vitamin  in  the  body,  and  it  is  only 
after  this  is  exhausted  that  growth  entirely  ceases  and  decline  then  sets 
in.  Further  evidence  of  tissue  storage  of  this  vitamin  is  afforded  in 
Curve  IV  in  which  the  upper  curve  represents  the  normal  growth  of 
young  rats,  the  lower,  of  those  nursed  by  a  mother  receiving  a  diet  that 
was  deficient  in  the  vitamin. 

When  the  reserves  of  the  fat-soluble  vitamin  are  exhausted,  not  only 
do  the  young  animals  fail  to  grow,  but  they  become  highly  susceptible  to 
bacterial  disease,  one  symptom  of  which  is  a  very  characteristic  eye  in- 
fection (xerophthalmia)  which  begins  with  a  swelling  of  the  lids,  and 
later  develops  into  a  purulent  conjunctivitis,  often  leading  to  blindness. 
Administration  of  some  fat-soluble  vitamin  in  the  diet  dispels  the  eye 
symptoms  usually  within  a  few  days.  When  the  dietary  of  adult  ani- 
mals contains  none  of  this  vitamin,  the  eye  symptoms  also  develop, 
the  general  condition  greatly  deteriorates  and  the  animals  become  ex- 
tremely susceptible  to  bacterial  infections,  particularly  those  affecting 
the  lungs,  and  from  which  they  readily  succumb.  Adults  are,  however, 
much  less  susceptible  to  the  absence  of  the  fat-soluble  vitamin  than 
growing  animals.  This  may  be  because  of  great  storage  capacity  for  it 
and  is  shown  in  Curve  III  of  Fig.  186. 

At  the  same  time  it  is  worthy  of  note  that  there  is  reason  to  believe 
that  the  condition  known  as  war  edema  is  due  to  a  deficiency  of  this 
vitamin.  It  may  be  stated  here  that  when  both  the  A  and  B  factors 
are  absent  from  the  diet  young  animals  immediately  cease  to  grow  and 
develop  the  nervous  symptoms  due  to  the  absence  of  the  B  factor,  from 
which  they  usually  succumb  before  the  symptoms  due  to  the  absence  of 
the  A  factor  have  had  time  to  develop. 

It  is  believed  that  it  is  with  the  metabolism  within  the  cells  rather 
than  with  that  of  fat  itself  that  the  fat-soluble  vitamin  is  concerned. 

A  most  important  relationship  probably  exists  between  this  vitamin 
and  the  occurrence  of  rickets.  Thus  when  the  puppies  of  large  dogs  are 
fed  with  separated  milk,  bread,  linseed  oil,  yeast  and  orange  juice,  they 
grow  at  a  normal  rate,  but  in  about  six  weeks  develop  undoubted  symp- 
toms of  rickets  (bones  defectively  calcified  so  that  the  long  bones  bend, 
swelling  at  the  epiphyses,  a  rosary  at  the  costochondral  junctions,  the 
ligaments  loose,  general  lethargy  and  loss  of  muscular  tone).  In  this 
diet  both  the  water-soluble  and  the  antiscorbutic  factors  are  present  in 


622  METABOLISM 

abundance  (the  yeast  and  the  orange  juice),  but  the  fat-soluble  factor 
is  very  low.  Judged  by  its  effect  upon  the  growth  curve  of  rats  this  factor 
would  appear  to  be  absent  from  linseed  oil.  The  latter,  however,  does  con- 
tain a  trace  which  is  sufficient  to  allow  of  an  abnormal  form  of  growth 
in  puppies.  When  animal  fats,  such  as  cod-liver  oil  or  butter,  are  sub- 
stituted for  the  linseed  oil  in  the  above,  or  a  similar  diet,  rickets  does 
not  occur. 

It  will  be  seen  in  reference  to  the  table  on  page  623  that  there  are 
two  main  sources  for  the  fat-soluble  vitamin,  (1)  certain  animal  fats, 
and  (2)  green  leaves.  It  is  particularly  abundant  in  cream,  butter,  beef 
fat,  fish  oils  (particularly  cod-liver  oil  and  whale  oil)  and  egg  yolk.  It 
is  absent  or  present  only  in  traces  in  most  vegetable  oils,  such  as  lin- 
seed, olive,  cotton-seed,  but  in  some  of  them  such  as  peanut  oil  it  is 
present  in  larger  amounts. 

Its  presence  in  green  leaves  stands  out  in  contrast  to  its  absence  from 
root  vegetables.  It  is  also  present  in  certain  cereals  and  pulses. 

The  Antiscorbutic  Vitamine. — That  scurvy  is  definitely  due  to  the 
absence  from  the  dietary  of  some  vitamin  has  been  known  in  a  general 
way  for  a  long  time.  It  used  to  be  very  common  among  the  crews  in 
the  days  of  sailing  ships,  and  nautical  history  records  many  interesting 
observations,  by  captains  and  ship's  surgeons,  showing  that  it  could  be 
prevented  by  adding  certain  fruits  or  the  juices  of  fruits  or  vegetables 
to  the  daily  ration.  Indeed  lime  juice  became  a  regular  part  of  the 
mariner's  ration.  Great  progress  was  made  in  the  investigation  of 
the  precise  distribution  and  behavior  of  the  antiscorbutic  vitamin  by 
the  discovery  that  guinea  pigs  develop  the  disease  when  all  green  stuff 
is  removed  from  the  diet  and  the  animals  are  fed  on  grains  and  water 
or  autoclaved  milk.  The  symptoms  appear  in  about  20  days,  up  to  which 
time  if  young  animals  are  used,  the  growth  curve  continues.  The  symp- 
toms and  the  postmortem  findings  are  similar  to  those  seen  in  man,  (ten- 
derness and  swelling  in  the  joints,  swelling  of  the  gums,  loosening  of 
the  teeth,  tendency  to  hemorrhages  and  fractures  of  the  bones).  The 
curve  of  growth  declines,  and  the  animal  dies  usually  between  the  30th 
and  40th  days.  Important  work  is  being  done  in  the  Lister  Institute  in 
London  to  determine  the  minimal  amounts  of  various  foodstuffs  that 
are  required  in  the  scurvy  diet  to  prevent  the  occurrence  of  the  disease. 

Regarding  distribution  it  may  be  said  that  this  vitamin  is  found  in 
nature  in  all  tissues  which  are  actively  undergoing  metabolic  change. 
It  is  abundant  in  growing  green  leaves,  in  fruits  and  in  germinating 
seeds.  But  it  is  absent,  or  present  only  in  traces,  in  dormant  seeds,  or 
in  plant  tissues  that  have  been  dried.  It  is  also  present,  though  less 
abundant  in  fresh  animal  tissues  and  in  milk.  Although  potatoes  do 
not  contain  much  of  this  vitamin,  a  diet  composed  mainly  of  them  is 


NUTRITION   AND   GROWTH  623 

seldom  scorbutic  because  of  the  large  quantities  that  are  usually  con- 
sumed. Canned  vegetables  and  meats  only  contain  traces  of  it  because 
it  is  destroyed  in  the  heating  process.  Canned  fruits,  however,  contain 
more  of  it  because  it  is  preserved  by  the  acid. 

The  practical  application  of  the  results  of  these  observations  to  the 
nutrition  of  man,  and  particularly  to  the  dietetic  treatment  of  disease, 
is  undoubtedly  very  great.  This  is  especially  so  in  infants  and  growing 
children,  in  whom  the  correction  of  some  slight  inadequacy  in  the  diet 
may  have  the  most  pronounced  results,  not  only  on  growth  and  nourish- 
ment, but  also  on  the  power  of  resistance  against  disease  and  infection. 
The  beneficial  influence  of  cod-liver  oil,  for  example,  may  depend  on  some 
fat-soluble  accessory  food  factors,  while  the  miraculous  benefit  which 
scorbutic  children  derive  from  the  addition  of  the  juice  of  limes,  lemons, 
etc.,  to  the  food  is  undoubtedly  due  to  such  influences.  The  accumu- 
lating mass  of  evidence  as  to  the  faulty  nutrition  in  animals  fed  on 
certain  kinds  of  food  that  fail  to  contain  food  factors  emphasizes  the 
necessity  in  the  dietetic  treatment  of  such  diseases  as  diabetes,  nephritis, 
etc.,  of  seeing  to  it  that  the  diet  is  sound,  not  only  in  calories,  protein 
content,  and  palatability,  but  also  with  regard  to  the  presence  of  these 
factors. 

In  the  accompanying  table  the  relative  amounts  of  the  various  vita- 
mines  in  different  foodstuffs  is  indicated  by  the  use  of  plus  signs. 

THE  DISTRIBUTION  OF  THE  THREE  ACCESSORY  FACTORS  IN  THE  COMMONER  FOODSTUFFS 

WATER-SOLUBLE   B 

CLASSES  OF  FOODSTUFFS  FAT-SOLUBLE  A  OR      OR  ANTINEURITIC    ANTISCORBUTIC 

ANTIRACHITIC  (ANTIBERIBERl)  FACTOR 

FACTOR  FACTOR 

Fats  and  oils. 

Butter  +  +  +                                 0 

Cream  +  +                                   0 

Cod-liver  oil  +  +  +                                 0 

Mutton  or  beef  fat  or  suet  +  + 

P'ea-nut  or  arachis  oil  + 

Lard  0 

Olive  or  cottonseed  oil  0 

Linseed  oil  0 
Fish  oil,  whale  oil,  herring 

oil,  etc.  +  + 
Hardened     fats,     animal     or 

vegetable  origin  0 
Margarine     from     vegetable 

fats  or  lard  0 

Nut  butters  + 
Meat,  fish,  etc. 

Lean    meat     (beef,    mutton, 

etc.)  +                                    +                                 + 

Liver  ++                                 +  +                                + 

Kidney  and  Heart  +  -f                                    + 

Brain  and  sweetbreads  +                                  +  + 

Fish,  white  0                     very  slight,  if  any 


624 


METABOLISM 


THE  DISTRIBUTION  OF  THE  THREE  ACCESSORY  FACTORS  IN  THE  COMMONER  FOODSTUFFS 

(CONT'D.) 


CLASSES   OP   FOODSTUFFS 


FAT-SOLUBLE   A  WATER-SOLUBLE     B 

OR  OR    ANTINEURITIC      ANTISCORBUTIC 

ANTIRACHITIC  (ANTIBERIBERl)                 FACTOR 

FACTOR  FACTOR 


Fish,    fat     (salmon,    herring, 

etc.) 

Fish,  roe 
Tinned  meats 
Milk,   cheese,    etc. 

Milk,  cow's  whole,  raw 
Milk,  skim,  raw 
Milk,  dried  whole 
Milk  boiled  whole 
Milk  condensed,  sweetened 
Cheese,  whole  milk 
Cheese,  skim 
Eggs 

Fresh  or  dried 
Cereals,  pulses,  etc. 

Wheat,     maize,     rice,     whole 

grain 

Wheat,  germ 
Wheat,  maise,  bran 
White    wheaten    flour,    pure 

corn-flour,     polished     rice, 

etc. 

Custard    powders,    egg    sub- 
stitutes     prepared       from 

cereal  products 
Dried  peas,  lentils,  etc. 
Soy  beans,  haricot  beans 
Germinated  pulses  or  cereals 
Vegetables  and  fruits 
Cabbage,  fresh 
Cabbage,  fresh  cooked 
Swede,  raw  expressed  juice 
Lettuce,    Spinach    (dried) 
Carrots,  fresh  raw 
Potatoes,  cooked 
Beans,  fresh,  scarlet  runners, 

raw 

Onions,  cooked 
Lemon   juice,   fresh 
Lemon  juice,  preserved 
Lime  juice,  fresh 
Lime  juice,  preserved 
Orange  juice,  fresh 
Raspberries 
Apples 
Bananas 

Tomatoes  (canned) 
Nuts 

Miscellaneous. 
Yeast,  dried 

Yeast,  extract  and  autolysed 
Meat  extract 
Malt  extract 

Beer 


very  slight,  if  any 
very  slight 


0 

less   than  +  + 
undetermined 


less  than  -I- 
less  than  + 
less  than  + 


to 


4-   (at  least) 


very  slight 


-f  + 


0 

+  'in  some 
specimens 

0 


very  slight 

+  T 


I 


CHAPTER  LXVIII 
DIETETICS 

THE  CALORIE  REQUIREMENT 

In  the  application  of  the  important  facts  that  have  been  reviewed  in 
the  preceding  chapters  to  the  science  of  dietetics,  the  question  arises  as 
to  how  we  may  determine  with  scientific  accuracy  just  exactly  how  much 
food  should  le  taken  under  varying  conditions  of  bodily  activity.  In  a 
general  way,  we  know  that  the  amount  of  food  that  we  require  to  take 
is  proportional  to  the  nature  and  amount  of  bodily  exercise  that  is 
being  performed  at  the  time ;  and  that,  if  the  food  supply  is  inadequate, 
the  work  before  long  will  fall  off  not  only  in  quantity  but  in  quality  as 
well.  "Horses  (also  men)  work  best  when  they  are  well  fed,  and  feed 
best  when  they  are  well  worked, "  is  an  old  adage  and  one  the  truth  of 
which  can  not  be  overestimated  in  the  consideration  of  all  questions  of 
dietary  requirements.  An  ill-fed  beggar  will  rather  suffer  from  the 
pain  and  misery  of  starvation  than  attempt  to  perform  a  piece  of  work 
that  the  well-meaning  housewife  bargains  should  be  done  before  she 
gives  him  a  meal.  The  spirit  may  be  willing  but  the  flesh  is  weak.  If  he 
could  be  trusted,  he  should  be  fed  first  and  worked  afterwards.  Besides 
the  amount  of  work,  two  other  factors  are  well  known  to  influence  the 
demand  for  food — namely,  growth  and  climate.  A  young,  growing  boy 
will  often  demand  as  much  if  not  more  food  than  would  appear  to  be 
his  proper  share,  from  a  comparison  of  his  body  weight  with  that  of 
his  seniors;  and,  other  things  being  equal,  it  is  well  known  that  we  are 
inclined  to  eat  much  more  heartily  of  food  during  the  cold  days  of 
winter  than  during  the  sultry  days  of  July  and  August. 

That  we  know  these  facts  in  a  general  way,  indicates  that  the  first 
step  to  take  in  the  exact  determination  of  dietetic  requirements  is  to 
find  out  how  much  energy  the  body  expends  under  varying  conditions 
of  activity.  This,  as  we  have  seen,  may  be  done  by  having  the  person 
live  for  some  time  in  a  respiration  calorimeter,  so  that  we  may  measure 
the  calorie  output.  To  the  conclusions  drawn  from  results  of  observa- 
tions made  under  such  artificial  and  unusual  conditions  of  living,  the 
objection  might,  however,  quite  justly  be  raised  that  they  need  not 
apply  to  persons  going  about  their  ordinary  routine  of  life.  To  meet 

625 


626  METABOLISM 

this  objection  another  method,  which  we  may  call  the  statistical,  is  avail- 
able. It  consists  in  taking  the  average  diet  of  a  large  number  of  indi- 
viduals and  comparing  the  calorie  value  with  the  average  amount  and 
type  of  work  that  they  are  meanwhile  called  upon  to  perform,  and  can 
best  be  used  where  the  diet  is  accurately  known,  as  in  public  institu- 
tions, the  army,  the  navy,  etc.  The  total  food  supplied  is  then  divided 
by  the  number  of  individuals,  this  giving  the  per  capita  consumption. 
Obviously  some  get  more  than  others,  but  when  a  sufficient  number  of 
individuals  is  included,  such  errors  become  eliminated  by  the  law  of 
averages. 

The  reliability  of  this  method  is  testified  to  by  the  remarkable  corre- 
spondence in  the  calorie  value  of  the  food  consumed  by  farmers  in  widely 
different  communities: 

Calories 

Farmers  in   Connecticut 3,410 

"       "    Vermont    3,635 

"       "    New  York 3,785 

"       "    Italy 3,565 

"       "    Finland    3,474 


Average 3,551* 

*Lusk:     The  Fundamental  Basis  of  Nutrition. 

The  average  inhabitant  of  various  cities: 

London    2,665 

Paris    2,903 

Munich    3,014 

Konigsberg 2,394** 

**Rubner. 

Individuals  in  different  callings: 

Farmers'   families    (U.S.A.) 3.560 

Mechanics'  families  (U.S.A.) 3,605 

Professional  men's  families  (U.S.A.) 3,530 

Army  (U.S.A.)    3,851 

Navy   (U.S.A.)    4,998t 

tAtwater. 

In  general,  it  is  usually  computed  that  a  man 
--^weighing  70  kg.  requires  in  calories: 

^,500  for  a  sedentary  life, 
8,000  for  light  muscular  work, 
3,500  for  medium  muscular  work, 
4,000  and  upwards  for  very  hard  toil.J 
JMcKillop. 

These  figures  apply  to  the  average  man,  but  in  calculating  the  calorie 
requirements  of  a  family  or  a  community  we  must  make  allowance  for 
the  lesser  requirements  of  women  and  children.  Several  dietitians  have 
compiled  tables  showing  how  many  calories  are  expended  according  to 
age  and  sex,  and  from  the  figures  have  calculated  a  generalized  mean, 
which  shows  in  comparison  with  men  the  percentage  that  should  be  al- 
lowed for  women  and  children.  The  mean  values  are  as  follows : 


DIETETICS  627 

Man    100  _ 

Woman   S3 

Boy  over  16 92 

Boy  14-16 81 

Girl  14-16    74 

Child  10-13    64 

Child  6-9    49 

Child  2-5   36 

Child  under  2 . .  23 

In  calculating  the  calorie  requirement  of  the  population  as  a  whole, 
the  necessity  of  making  allowance  for  the  varying  needs  of  men,  women, 
and  children  would  obviously  make  the  calculations  far  too  complicated 
for  practical  purposes.  It  is  necessary  to  have  a  factor  by  which  we 
may  multiply  the  total  population  in  order  to  determine  its  ' '  man  value. ' ' 
This  factor  is  based  on  the  relative  proportion  of  men  to  women  and 
children,  and  it  amounts  very  nearly  to  0.75,  i.  e.,  three-quarters  of  the 
total  population  gives  "the  man  value."  Knowing  the  total  population, 
say,  of  a  city,  we  must  therefore  multiply  this  by  0.75  in  order  to  ascer- 
tain for  how  many  men  doing  moderate  muscular  work  (3000  C.)  food 
has  to  be  provided. 

THE  PROTEIN  REQUIREMENT 

The  facts  considered  in  the  previous  two  chapters  lead  to  the  question: 
To  what  extent  may  the  proportion  of  protein  in  the  diet  be  reduced 
with  safety?  It  is  evident  that  there  must  be  a  minimum  below  which 
every  one  of  the  necessary  building  materials  of  protein  could  not  be 
supplied  in  adequate  amount  to  reconstruct  the  worn-out  tissue  protein. 

The  extent  to  which  the  protein  content  of  the  diet  of  man  can  be 
lowered  with  safety  depends  on  several  factors,  of  which  the  most  im- 
>ortant  are:  first,  the  nature  of  the  protein;  second,  the  number  of  non- 
protein  calories ;  and  third,  the  extent  of  tissue  activity.  Where  so  many 
factors  must  be  taken  into  consideration,  the  only  method  by  which  the 
actual  minimum  can  be  determined  consists  in  what  may  be  called  "cut 
and  try  experiments."  Of  the  many  investigations  of  such  a  nature, 
probably  the  best  one  for  us  to  consider,  is  that  recently  published  from 
the  Nutrition  Laboratory  of  Copenhagen.  The  subject,  an  intelligent 
laboratory  servant,  lived  a  perfectly  normal  and  active  life  for  a  period 
of  five  months  on  a  diet  of  potatoes  cooked  with  margarine  and  a  little 
onion,  and  containing  4000  C.,  with  a  total  protein  content  of  29  grams. 
During  another  period  he  did  outdoor  work  as  a  mason  and  laborer,  and 
took  5000  C.  daily,  and  35  grams  of  protein. 

It  is  important  to  contrast  these  results  with  the  following  based  on 
municipal  statistics  of  gross  consumption. 


628  METABOLISM 

MUNICIPAL  FOOD  STATISTICS 


PROTEIN 

FAT 

CARBOHYDRATES 

CALORIES 

Konigsberg 
Munich 
Paris 
London 

gm. 
84 
96 
98 

98 

gm. 
31 
65 
64 
60 

gm. 
414 
492 
465 
416 

2394 
3014 
2903 
2665 

1  It  is  certain  that  man  can  lead  a  normal  existence  and  remain  in  good 
uiealth  on  very  much  less  protein  than  the  100  grams  which  statistical 
studies  show  to  be  the  amount  he  actually  takes.  This  discrepancy  be- 
tween the  amount  which  experiment  demonstrates  to  be  adequate  and 
that  which  habit  and  custom  demand,  raises  the  question  as  to  whether, 
after  all,  our  instincts  may  not  have  erred  and  so  made  us  unnecessarily 
extravagant  in  our  protein  intake.  It  has  been  suggested  that  such  pro- 
tein extravagance  will  in  various  ways  have  a  deleterious  effect  on  the 
organism;  thus,  that  the  excretory  organs,  such  as  the  kidneys,  will  be 
overtaxed  in  eliminating  the  unused  amino  acids,  that  the  constant  pres- 
ence of  these  bodies  in  excess  in  the  blood  will  cause  degeneration  and 
sluggish  metabolism,  and  that  the  excess  protein  in  the  intestine  will 
lead  to  the  production  of  poisonous  decomposition  products,  the  subse- 
quent absorption  of  which  into  the  blood  will  cause  toxemic  symptoms. 

Important  support  to  such  views  appeared  to  be  supplied  some  dozen 
years  ago  by  Chittenden,  who  was  able  to  show  that  he  himself  and  many 
other  persons  doing  different  kinds  of  work  could  be  supported  on  daily 
amounts  of  protein  that  were  not  more  than  from  one-third  to  one-half 
of  the  amount  usually  taken.  Not  only  so,  but  it  was  averred  that  dis- 
tinct improvement  was  experienced  in  the  general  sense  of  well-being 
and  of  mental  efficiency  as  a  result  of  the  lesser  protein  consumption. 

Taking  these  results  as  a  whole,  it  is  quite  clear  that  man  can  get 
along  under  ordinary  conditions  with  much  less  protein  than  he  usually 
takes;  but  that  really  proves  nothing,  for  the  question  is  not  can  he,  but 
should  he,  so  deprive  himself?  Are  instinct  and  custom  wrong  and  is 
Chittenden  right  ?  That  is  the  question.  To  answer  it  many  studies  have 
been  made  of  the  condition  of  peoples  who  for  economic  or  other  rea- 
sons are  compelled  to  live  on  less  protein  than  the  average.  Are  these 
people  healthier,  less  prone  to  infections  and  degenerative  diseases,  and 
more  efficient  mentally  than  others?  In  such  studies  great  care  must  be 
exercised  to  see  that  conditions  other  than  diet,  such  as  climate,  exercise, 
etc.,  are  properly  allowed  for.  It  would  not  be  fair,  for  example,  to 
compare  the  mental  and  bodily  condition  of  peoples  living  in  the  tropics 
and  who  take  comparatively  little  protein,  with  those  living  in  temperate 
zones,  who  consume  much  more.  After  discounting  all  of  these  other 


DIETETICS  629 

f,  factors,  it  has  been  quite  clearly  shown  that,  when  the  protein  allowance 
,  is  materially  reduced,  the  people  as  a  whole  are  less  robust,  mentally  in- 
ferior, and,  instead  of  being  less  prone  to  the  very  diseases  which  are 
[usually  supposed  to  be  due  to  overloading  of  the  organism  with  useless 
excretory  products,  are  more  liable  to  suffer  from  them. 

That  a  decided  reduction  in  protein  weakens  the  defense  of  the  organ- 
ism against  infection  is  probably  due  to  the  fact  that  the  fluids  of  the 
body  normally  contain  a  great  variety  of  so-called  antibodies — that  is, 
of  highly  complex  substances  that  are  largely  protein  in  nature.  When 
bacteria,  or  the  poisons  produced  by  them,  enter  the  body,  they  are  met 
by  one  or  more  of  these  defense  substances  and  destroyed  or  neutralized. 
Now  it  is  clear  that  there  should  always  be  a  surplus  of  protein-building 
materials  from  which  the  antibodies  may  be  constructed.  Such  an  excess 
will  constitute  a  "factor  of  safety"  against  disease.  And  there  are  fac- 
tors of  safety  of  another  nature  to  be  provided  for.  For  example  there 
must  always  be  an  adequate  supply  of  tryptophane,  of  lysine,  and  of 
cystine,  not  only  to  meet  the  bare  necessities  of  the  protein  constructive 
processes  that  go  on  under  normal  conditions,  but  also  to  make  good  the 
larger  amount  of  protein  wear  and  tear  that  greater  degrees  of  tissue 
activity  will  entail.  Although  moderate  muscular  exercise  does  not  ap- 
pear to  cause  any  immediate  consumption  of  protein  (carbohydrate  and, 
later,  fat  being  the  fuel  material  that  is  used),  yet  it  does  throw  a  greater 
strain  on  the  tissues  thus  causing  a  greater  wear  and  tear  of  the  ma- 
chinery, and  hence  a  demand  for  more  protein-building  material.  There 
are  also  certain  of  the  internal  secretions  of  the  body,  such  as  epineph- 
rine  (adrenaline),  that  are  essential  for  life,  and  as  crude  materials 
for  the  manufacture  of  which  certain  amino  acids  are  essential.  Tyro- 
sine  is  one  of  these,  and  since  proteins,  as  we  have  seen,  differ  from  one 
another  quite  considerably  in  the  amount  of  this  amino  acid  which  they 
contain,  it  is  advisable  to  provide  an  excess,  so  that  an  adequate  supply 
of  tyrosine  may  always  be  available. 

The  answer  to  one  of  the  most  important  practical  questions  in  die- 
tetics— namely,  "What  proportion  of  protein  should  the  diet  contain? " 
depends  on  these  scientific  principles.  The  source  of  the  protein  is  the 
important  thing.  With  animal  protein  there  is  no  doubt  that  we  could 
get  along  with  perfect  safety  by  taking  daily  not  more  than  50  or  60 
grams,  which  is  about  half  of  what  we  actually  consume.  If  the  protein 
is  of  vegetable  origin  and  part  of  it  of  the  first  quality,  as,  jjvheat  and 
Indian  corn  preparations,  more  should  be  taken  so  as  to  allow  for  the 
deficiency  of  certain  amino  acids.  When  vegetable  proteins  of  the  sec- 
ond quality,  such  as  those  of  peas,  beans,  lentils,  etc.,  are  alone  available, 
much  larger  amounts  are  necessary.  Such  proteins  are  inadequate  in  the 


C>30  METABOLISM 

case  of  growing  children  at  least,  and  even  in  adults  it  is  undoubtedly 
advisable  that  other  proteins  should  supplement  them. 

To  insure  safety,  therefore,  it  is  almost  imperative  that  the  diet  should 
contain  proteins  of  various  sources.  If  for  economic  reasons  the  main 
source  must  be  proteins  of  vegetable  origin,  then  some  animal  protein,  such 
as  is  contained  in  milk  or  meat  or  eggs,  should  be  added  to  at  least  one  of 
the  daily  meals.  When^peas' and  beans  are  mainly  depended  on  for  the 
protein  supply,  they  should  be  taken  either  with  milk  or  one  of  its  prep- 
arations, or  with  a  thick  gravy  or  sauce  made  from  meat  and  containing 
the  finely  minced  meat.  This  must  not  be  strained  off,  for  if  it  is,  the 
sauce  will  contain  only  the  meat  extractives  but  not  any  of  the  protein, 
which  is  coagulated  by  the  boiling  water.  Meat  extract,  in  other  words, 
contains  no  proteins;  it  is  not  a  food  but  merely  a  condiment  of  no  greater 
dietetic  value  than  tea  or  coffee. 

ACCESSORY  FOOD  FACTORS 

The  practical  point  to  be  remembered  is  that  three  accessory  fac- 
tors or  vitamins  are  known.  There  is  little  danger  of  the  diet  being 
inadequate  with  regard  to  food  factors  if  it  contains  some  fruits  or 
green  vegetables  or  unheated  fresh  milk.  Certain  of  the  food  factors 
are  destroyed  by  prolonged  cooking.  It  is  during  times  of  food  scarcity 
that  the  restricted  diet  may  require  to  be  scrutinized  to  see  that  it  con- 
tains the  essential  vitamins.  The  reader  is  referred  to  page  618,  where 
this  subject  is  more  fully  dealt  with. 

DIGESTIBILITY  AND  PALATABILITY 

We  have  seen  that  practical  dietetics  depends  on  several  factors,  the 
exact  relative  importance  of  which  cannot  perhaps  be  gauged  in  every 
case,  but  preparation  of  the  food  so  as  to  make  it  appetizing  must  un- 
doubtedly rank  high.  The  importance  of  good  cooking  will  now  be  ap- 
parent. It  is  the  act  of  making  food  appetizing  and  therefore  digestible. 
It  is  really  the  first  stage  in  digestion,  the  stage  that  we  can  control,  and  one 
therefore  to  which  much  attention  must  be  given,  especially  when  it  becomes 
necessary  to  make  attractive,  articles  of  diet  that  are  ordinarily  considered 
common  and  cheap.  Most  people  can  cook  a  lamb  chop  so  as  to  make  it 
reasonably  appetizing,  but  few  can  take  the  cheaper  cuts  of  meat  and  con- 
vert them  into  cooked  dishes  that  are  as  popular  and  attractive.  And  there 
are  still  fewer  who  can  take  the  left-overs  and  trimmings  and  convert  them 
in  the  same  way.  This  is  the  real  art  of  cooking,  and  too  much  encourage- 
ment cannot  be  given  to  the  effort  which  our  cooking  experts  are  making 


DIETETICS  631 

to  show  people  how  these  things  can  be  done.  The  waste  of  good  food  in 
a  large  city  is  truly  appalling. 

Cooking  has  other  advantages  than  making  the  food  appetizing.  The 
jheat  loosens  the  muscle  fibers  of  the  meat  so  that  it  is  more  readily 
masticated;  it  destroys  microorganisms  and  parasites  in  the  meat;  it  de- 
stroys antibodies  which,  might  interfere  with  the  action  of  the  digestive 
ferments.  Thus,  untreated  raw  white  of  egg  is  not  digested  in  the  stom- 
ach because  it  contains  one  of  the  antibodies  which  prevent  the  pepsin 
from  acting  on  it;  but  boiled  egg  white,  if  properly  chewed,  can  be  di- 
gested, and  whipping  the  egg  white  into  a  foam  partly  destroys  the  in- 
hibiting substance. 

Before  concluding,  something  should  be  said  about  the  laxative  quali- 
ties of  food,  for  it  is  often  in  this  particular  alone  that  one  food  is  more 
satisfactory  than  another.  A  diet  of  meat,  milk,  eggs,  and  white  bread  is 
apt  to  be  unphysiological  because  there  is  nothing  in  it  to  act  as  what  has 
been  called  intestinal  ballast;  that  is,  a  material  which  will  keep  the 
intestines  sufficiently  filled  to  stimulate  their  muscular  movements.  This 
ballast  is  best  furnished  in  the  shape  of  cellulose,  the  most  important 
constituent  of  green  food.  Peas,  beans,  cabbage,  salad,  and  many  fruits, 
'j  especially  apples,  should  always  occupy  a  place  in  the  daily  menu.  An- 
i  other  food  which  is  valuable  because  it  yields  this  ballast  is  the  outer 
grain  of  wheat,  oats,  etc.  So  much  must  not  be  taken  as  to  produce  a 
constant  intestinal  irritation,  and  each  person  must  determine  for  him- 
self where  this  limit  lies.  The  difference  among  various  breads  depends 
partly  on  the  degree  to  which  they  supply  ballast.  It  must  not  be  lost 
sight  of  that  many  of  these  foods  of  plant  origin  are  most  important  be- 
cause of  the  valuable  vitamines  they  contain. 

The  all-important  subject  of  food  economies  can  receive  no  attention 
here,  except  to  point  out  that  it  is  one  which  must  be  most  carefully  con- 
sidered in  the  solution  of  all  problems  of  dietetics.  An  admirable  ac- 
count of  the  subject  will  be  found  in  Graham  Lusk's  "Science  of  Nutri- 
tion" (third  edition)  and  .in  McKillop's  "Food  Values."16 


CHAPTER  LXIX 
THE  METABOLISM  OF  PROTEIN 

Introductory. — The  older  physiologists  believed  that  the  protein  taken 
with  the  food  was  brought  into  a  soluble  condition  by  the  digestive  en- 
zymes, and  that  it  was  then  absorbed  into  the  blood  and  directly  incor- 
porated with  the  tissues.  The  discovery  of  the  enzymes  trypsin  and 
erepsin  and  of  free  amino  acids  in  the  gastrointestinal  contents  clearly 
showed  that  this  simple  theory  of  Liebig  could  not  be  correct.  It  was, 
furthermore,  found  that  when  an  excess  of  proteins  such  as  egg  albumin 
gains  entry  to  the  blood,  part  of  the  protein  appears  in  an  unchanged 
condition  in  the  urine ;  and  that  enzymes  capable  of  digesting  this  pro- 
tein, but  not  other  varieties,  make  their  appearance  in  the  blood. 

After  the  injection  of  foreign  proteins  into  the  blood,  symptoms  of 
varying  severity  often  develop,  from  the  almost  instantaneous  death 
produced  by  snake  venom  to  the  slowly  developing  anaphylactic  reac- 
tions which  follow  the  injection  into  the  blood  of  many  proteins  chemi- 
cally indistinguishable  from  those  of  the  blood  serum  itself.  When  pro- 
tein is  taken  in  the  usual  amounts  by  mouth,  these  poisonous  reactions 
do  not  supervene, — even  snake  venom  is  harmless  when  swallowed, — nor 
is  it  possible  during  digestion  of  a  protein  meal  to  detect  food  protein  in 
the  blood  by  means  of  the  precipitin  reaction.  Finally  it  was  discovered 
that  the  very  slow  intravenous  injection  of  completely  digested  flesh  did 
not  produce  on  the  part  of  the  body  any  of  the  reactions  that  injected 
protein  Itself  produces,  indicating  that  perfect  assimilation  had  occurred. 
From  these  and  similar  observations  it  soon  became  clear  that  protein 

61  not  be  absorbed  as  such  from  the  alimentary  canal,  but  must  first  of 
be  completely  'broken  down  into  the  amino  acids,  which  are  then  rebuilt 
o  the  protein  of  the  organism.    The  direct  evidence  for  this  important 
change  in  belief  concerning  protein  metabolism  has  been  gained  by  the 
discoveries  that:     (1)  nitrogen  equilibrium  can  be  maintained  in  animals 
fed  with  completely  digested  protein  mixtures;  and  (2)  amino  acids  can 
be  isolated  from  the  blood. 

The  experiments  of  the  first  group  consist,  in  principle,  in  breaking  down  protein 
until  there  is  no  longer  the  characteristic  biuret  test  and  then  feeding  this  digestion 
mixture  to  animals  and  observing  them  from  day  to  day,  using  as  criteria  of  their 
nutritional  condition  the  body  weight  and  the  nitrogen  equilibrium.  (Page  605.)  It 
has  been  shown  that  success  in  maintaining  nutritional  efficiency  depends  partly  on  the 

632 


THE    METABOLISM    OF   PROTEIN  633 

nature  of  the  process  used  for  digesting  the  protein,  and  partly  on  the  presence  or  ab- 
sence of  carbohydrate  in  the  digestion  mixture.  It  was  found  that  the  products  of 
hydrolysis  by  acid  failed  to  maintain  equilibrium,  and  it  was  believed  that  this  was 
owing  to  the  fact  that  the  acid  had  more  completely  disrupted  the  protein  molecule,  and 
had  left  no  polypeptides,  which,  it  was  imagined,  remained  intact  during  enzyme  action 
and  were  essential  for  proper  protein  metabolism.  This  view  has  now  been  consider- 
ably altered,  since  it  has  been  shown  that  the  acid  actually  destroys  certain  amino 
acids  which  the  enzyme  leaves/  intact.  The  amino  acid  particularly  concerned  is 
tryptophane.  Thus,  when  different  groups  of  animals  were  fed  with  diets,  consisting  of 
(1)  fully  digested  casein,  (2)  fully  digested  casein  from  which  the  tryptophane 
had  been  removed,  it  was  found  that  nitrogen  equilibrium  could  not  be  maintained  on 
the  second  diet,  whereas  it  was  maintained  on  the  first.  When  the  protein  was  only 
partly  digested  by  acid — that  is,  not  digested  enough  so  as  to  break  up  all  the  trypto- 
phane— or  when  tryptophane  was  added  to  the  second  diet,  nitrogen  equilibrium  could 
be  satisfactorily  maintained. 

These  results  obtained  in  different  classes  of  animals  have  also  been  confirmed  for 
the  hum'an  subject.  For  example,  nitrogen  retention  has  been  observed  in  a  case  of 
a  boy  suffering  from  a  stricture  of  the  esophagus,  when  he  was  fed  by  rectum  for 
fifteen  days  with  digestion  products  resulting  from  the  action  of  trypsin  and  erepsin 
on  flesh. 

Concerning  the  second  type  of  evidence,  many  investigators  attempted  to  separate 
the  amino  acids  themselves  from  the  blood,  particularly  during  the  digestion  of  a  large 
amount  of  protein,  but  the  results  were  at  first  entirely  negative  because  of  the  lack 
of  methods  that  were  sufficiently  delicate  to  make  it  possible  to  detect  the  slight  increase 
that  could  be  expected  even  when  a  maximum  absorption  of  nitrogen  had  occurred. 
The  very  large  flow  of  blood  through  the  portal  vein  causes  such  extensive  dilution  of 
any  substances  added  to  it  that  the  concentration  of  the  substance  in  an  isolated 
sample  of  the  blood  can  be  only  trivial. 

This  brief  historical  survey  of  the  subject  brings  us  to  a  position  where 
we  may  proceed  to  discuss  the  present-day  teaching  regarding  protein 
metabolism.  Briefly  stated,  this  teaching  is  to  the  effect  that  the  protein 
molecule  is  broken  down  into  its  ultimate  building  stones,  the  amino  acids, 
~by  the  digestive  enzymes  of  the  gastrointestinal  tract.  These  amino 
acids  are  absorbed  into  the  blood,  by  which  they  are  carried  ta  the  various 
organs  and  tissues,  which  sift  out  the  amino  acids  and  use  'those  of  them 
which  they  require  for  the  reconstruction  of  their  broken-down  protein. 
The  amino  acids  not  required  for  the  process,  along  with  those  which  may 
'be  liberated  in  the  tissues  themselves  by  disintegration  of  tissue  proteins, 
are  then  split  into  two  portions,  one  represented  by  ammonia  and  the  other 
by  the  remainder  of  the  OMiwLJicitLjnolecide.  The  former  is  excreted  as 
urea  and  the  latter  is  oxidized  to  produce  energy. 
elusions  depend,  it  will  be  necessary  to  consider  some  of  the  most  important 

CHEMISTRY  OF  PROTEIN 

Before  proceeding  to  discuss  the  evidence  upon  which  the  above  con- 
facts  concerning  the  chemistry  of  the  protein  molecule.  We  shall  require 
this  information  not  only  to  understand  the  history  of  protein  in  the 


634  METABOLISM 

animal  body,  but  also  to  follow  intelligently  the  important  work  that 
has  already  been  discussed  concerning  the  relative  value  of  different 
proteins  as  food.  A  knowledge  of  protein  chemistry  has  come  to  be 
essential  in  practically  all  branches  of  medical  science. 

Proteins,  like  starches,  are  composed  of  numerous  smaller  molecules. 
In  the  case  of  starch  these  molecules  are  the  various  monosaccharides — 
glucose  (dextrose),  levulose  and  galactose;  in  the  case  of  proteins  they 
are  the  amino  acids.  The  breaking  apart  of  the  links  that  hold  the  mole- 
cules together  is  effected  in  both  cases  by  the  process  of  hydrolysis,  so 
called  because  of  the  fact  that  the  reaction  consists  in  the  taking  up  of  a 
molecule  of  water  at  each  of  the  places  where  the  chain  falls  apart.  This 
hydrolysis  may  be  effected  either  by  the  action  of  mineral  acids  or  alka- 
lies, or  by  enzymes,  the  only  difference  in  the  action  of  these  reagents 
being  that  in  the  former  case  the  breaking  apart  takes  place  more  or 
less  indiscriminately,  whereas  in  the  latter  it  proceeds  according  to  a 
definite  plan,  which  varies  somewhat  with  the  type  of  enzyme  employed. 
Just  as  a  chemical  knowledge  of  the  -structure  of  sugar  or  monosac- 
charides is  the  basis  of  carbohydrate  chemistry,  so  is  that  of  the  amino 
acids  the  basis  of  protein  chemistry. 

Amino  Acids. — There  are,  so  far  as  known,  eighteen  different  amino 
acids  concerned  in  the  constitution  of  protein,  but  they  are  all  alike  in 
their  characteristic  structure.  The  most  striking  characteristic  depends 
on  the  presence  in  the  molecule  of:  (1)  an  amino  group  with  a  basicity 
comparable  to  that  of  ammonia,  and  (2)  an  acid  group  with  an  acidity 
comparable  to  that  of  acetic  acid.  Let  us  take  in  illustration  one  of  the 
simplest  fatty  acids — namely,  acetic.  It  has  the  formula  CH3COOH. 
The  COOH  group  is  called  carloxyl,  and  on  it  depend  the  acid  properties 
of  the  compound.  The  CH3  group  is  known  as  methyl,  and  the  amino 
group  (NH2)  is  attached  to  it  in  place  of  one  of  the  hydrogen  atoms,  thus 
giving  the  formula  CH2NH2COOH,  which  is  aminoacetic  acid  or  gly- 
cocoll.  If  we  take  the  next  higher  acid  of  the  fatty  acid  series,  having 
the  name  propionic  and  the  formula  CH3CH2COOH,  its  amino  acid,  called 
alanine,  has  the  formula  CH3CHNH2COOH.  Now  let  us  place  the  formu- 
las of  these  two  acids  side  by  side  in  the  following  manner: 

H  CHs 

I  I 

NH2  -  C  -  COOH  NH2  -  C  -  COOH 

(amino  group)     H     (acid  group)  (amino  group)     H     (acid  group) 

Aminoacetic  acid  Aminopropionic  acid 

(glycocoll)  (alanine) 

It  will  be  observed  that  the  only  difference  between  the  two  acids  is 
dependent  upon  a  change  in  the  group  that  is  attached  to  the  upper  verti- 


THE    METABOLISM    OF    PROTEIN  635 

cal  valency  bond  of  the  central  carbon  atom,  which  therefore  must  be 
considered  as  the  center  of  the  entire  molecule.  The  various  amino  acids 
entering  into  the  structure  of  protein  differ  from  one  another  solely  with 
regard  to  the  chemical  nature  of  the  group  that  is  attached  to  this  ver- 
tical valency  bond.  Evidently,  then,  the  reactions  that  amino  acids  pos- 
sess in  common  must  depend  on  the  end  groups  containing  the  carboxyl 
and  amino  radicles,  whereas  the  characteristic  reaction  of  each  of  the  eight- 
een amino  acids  must  depend  upon  the  differences  in  the  radicles  attached 
to  the  upper  vertical  bond.  This  may  be  represented  thus : 

Any  radicle 
NH2-C-COOH 

H 

(Any  amino  acid) 

The  end  groups  endow  the  amino  acids  with  the  power  to  combine  with  both  acids 
and  bases.  With  acids  they  behave  like  substituted  ammonias  to  form  salts,  which  can 
here  ionize  into  the  amino  acid,  as  the  cation,  and  the  acid  group,  as  the  anion.  With 
bases  the  carboxyl  group  reacts  to  form' salts,  which  yield  amino  acid  as  the  anion.  A 
most  important  reaction  consists  in  the  condensation  of  aldehydes  with  the  amino  group. 
This  occurs  particularly  readily  with  formaldehyde,  water  being  eliminated  in  the  re- 
action, and  the  basic  nature  of  the  amino  acid  thus  destroyed.  Upon  this  reaction  de- 
pends the  method  of  Sorensen  for  determining  the  amount  of  amino  acid  in  a  mixture 
(see  page  641).  The  titration  is  performed  by  rendering  the  solution  of  amino  acids 
neutral,  then  adding  formaldehyde  and  titrating  with  standardized  acid,  using  phe- 
nolphthalein  as  the  indicator.  This  tells  us  to  what  degree  the  acidity  of  the  mixture 
has  become  increased  as  a  result  of  adding  the  formaldehyde,  and  since  this  increase 
in  acidity  must  depend  upon  the  number  of  amino  groups,  we  are  furnished  with  an 
indirect  estimate  of  the  concentration  of  the  amino  acids.  The  reaction  is  illustrated 
by  the  equation : 

radicle  H  radicle 

NH2-C-COOH  +  H-Cz=O    =    CH2  =  N -  0 -  COOH  +  H2O 

(amino  acid)  (formaldehyde) 

Another  reaction  of  amino  acid  of  physiological  interest  is  that  known  as  the  car- 
b amino  reaction,  consisting  in  a  union  of  the  amino  acid  with  calcium  and  carbonic  acid. 

Finally,  it  is  important  to  note  that  the  amino  group  is  very  firmly  attached;  it 
remains  intact  in  acids  and  alkalies  and  is  removable  only  by  a  process  of  oxidation. 
This  can  be  accomplished  by  treating  the  amino  acid  with  such  reagents  as  hydrogen 
peroxide  or  with  potassium  permanganate,  when  the  amino  group  is  displaced  and  a 
so-called  ketonic  acid  formed.  The  reaction  will  be  evident  from  the  accompanying 
equation : 

CH3  CH3 

I  I 

O  +  NH,-C-COOH  ^±  O  =  C-COOH+  NH3 

H 

(alanine)  (pyruvic  acid) 


636  METABOLISM 

To  illustrate  this  reaction  we  have  chosen  aminopropionie  acid  or  alanine,  because 
the  substance  formed  by  its  oxidation  and  known  as  pyruvic  acid  is  of  very  great  im- 
portance in  intermediary  metabolism.  It  serves  as  the  common  substance  from  which 
proteins,  carbohydrates  or  fats  may  be  formed,  and  therefore  as  the  intermediary  sub- 
stance through  which  one  of  them  may  pass  on  being  transformed  into  another  (page 
698).  The  use  of  two  arrows  pointing  in  opposite  directions  in  the  above  equation  in- 
dicates that  the  reaction  may  proceed  readily  in  either  direction. 

The  ammonia  set  free  from  amino  acids  may  be  oxidized  to  free  nitrogen  by  using 
nitrous  acid  according  to -the  general  equation:  NH3  +  HONO=2H2O  +  N2.  Upon  this 
reaction  depends  another  extremely  important  quantitative  metttod  for  measuring  the 
number  of  amino  groups  prese'nt  in  protein  (Van  Slyke).  To  make  the  estimation, 
nitrous  acid  is  allowed  to  act  on  the  amino  acids,  and  the  volume  of  nitrogen  gas  set 
free  by  the  reaction  is  measured,  the  principle  being  similar  to  that  used  for  the  de- 
termination of  urea  by  the  hypobromite  method. 

The  apparatus  employed  for  decomposing  the  substance  and  collecting  and  measuring 
the  evolved  nitrogen  consists  essentially  of  a  mixing  bulb,  connected  below  through  stop- 
cocks with  two  small  burettes,  one  containing  a  solution  of  sodium  nitrite  and  glacial 
acetic  acid,  and  the  other  a  solution  of  the  substance  to  be  investigated.  The  upper  end 
of  the  mixing  bulb  is  connected  through  a  three-way  cock  with  a  graduated  gas  burette 
and  with  another  bulb  containing  potassium  permanganate  solution.  By  allowing  some 
nitrite  and  acid  solution  to  run  into  it  and  shaking,  the  mixing  bulb  is  first  of  all  filled 
to  a  certain  mark  with  nitrous  oxide  gas.  A  measured  quantity  of  the  amino  solution 
is  then  allowed  to  mix  with  the  nitrite ;  the  apparatus  is  shaken  for  five  minutes  at  15 
to  20°  C.,  and  the  evolved  nitrogen  and  nitric  oxide  are  driven  over  into  the  permanganate, 
which  absorbs  the  nitric  oxide,  leaving  the  nitrogen,  which  is  then  measured  in  the  burette. 

The  apparatus  has  now  been  so  perfected  that  numerous  analyses  may  be  made  with 
it  in  a  very  short  time  and  with  a  degree  of  accuracy  that  is  scarcely  surpassed  in  any 
other  biochemical  estimation. 

Protein  Synthesis. — From  the  point  of  view  of  protein  chemistry,  the 
most  significant  reaction  of  the  amino  acids  is  their  ability  to  link  to- 
gether to  form  compounds  called  peptides.  This  linking  occurs  between 
the  amino  group  of  one  amino  acid  and  the  carboxyl  group  of  the  next. 
When  alanine  and  glycocoll,  with  which  we  are  familiar,  are  thus  linked 
together,  the  reaction  takes  place  according  to  the  equation: 

H  CH3  H 

CH,  |  | 


|         /IH  +  HO;    OC-C-NH2  =  HOOC-C-NH-CO-C-NH2 

HOOC-C-N  I  !         :         I 

\H  H  H  H 


(alanine)  (glycocoll)  (alanyl  -  glycocoll) 

In  this  manner,  then,  a  so-called  dipeptide  is  formed,  in  which  it  will 
be  observed  there  still  remain  free  carboxyl  and  amino  groups,  thus  per- 
mitting the  linking  on  of  other  amino-acid  groups  to  form  tripeptides  or 
tetrapeptides  or  other  polypeptides.  Indeed,  this  process  of  condensa- 
tion may  go  on  practically  indefinitely,  a  polypeptide  containing  eighteen 
amino-acid  groups — namely,  three  leucine  and  fifteen  glycocoll  groups — hav- 


THE    METABOLISM    OF   PROTEIN 


637 


os.5't 
If 


o—  o  -  o—  o—  s;—  o—  55 
JS      a    «    a    "    * 


,11 


s     i-S 


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»  a—  0— 

- 


8 

| 

o— 


1  1 


mi 


638  METABOLISM 

ing  actually  been  synthesized.  The  resulting  polypeptides  have  the  proper- 
ties of  derived  proteins  like  the  proteoses;  thus,  they  give  the  biuret 
and  other  reactions  characteristic  of  proteins  and  are  precipitated  by 
such  reagents  as  mercuric  chloride  and  phosphotungstic  acid.  Some  are 
also  digested  by  trypsin  and  erepsin.  They  have  the  same  optical  activities 
as  proteins.  One  of  them  has  been  prepared  which  produces  a  typical 
anaphylactic  reaction.  So  far  a  polypeptide  that  can  be  coagulated  by 
heat  or  is  in  other  ways  identical  with  the  naturally  occurring  proteins, 
has  not  been  synthetized;  but  there  is  no  doubt  that  it  is  only  a  matter 
of  time  before  this  will  be  accomplished. 

Eighteen  distinctly  different  amino  acids  have  been  isolated  from  pro- 
tein, and  it  may  assist  in  the  conception  of  our  problem  if  we  place  these 
amino  acids  side  by  side  and  link  them  together  in  the  manner  described 
above.  This  is  done  in  the  accompanying  chart  compiled  by  D.  D.  Van 
Slyke,  in  which  also  various  other  important  facts  concerning  the  chem- 
istry of  the  amino  acids  are  incidentally  added. 

At  the  lower  part  of  each  formula  will  be  seen  the  characteristic  car- 
boxyl  and  amino  groups  of  neighboring  acids  linking  together  the  ter- 
minal carbon  atoms.  The  upper  vertical  bond  of  this  carbon  atom  is  con- 
nected with  the  characteristic  group  of  the  amino  acid,  which  may  be  very 
simple  and  represented  only  by  hydrogen,  as  in  glycocoll,  or  highly  com- 
plex and  including  a  ring  formation,  as  in  tryptophane.  It  will  further 
be  observed  that  there  may  "be  other  amino  groups  connected  in  various 
positions  in  this  radicle.  This  is  particularly  the  case  in  the  first  three  of 
the  amino  acids  in  the  table — namely,  the  basic  amino  acids.  In  lysine 
the  extra  amino  group  reacts  with  nitrous  acid,  liberating  free  nitrogen 
by  the  Van  Slyke  method;  but  in  other  cases,  as  in  arginine,  it  fails  to 
give  this  and  the  other  characteristic  reactions  of  the  amino  group. 

It  will  further  be  observed  that  the  amino  acids  are  arranged  in  three 
main  groups:  one  basic,  another  neutral,  and  the  third  acid.  The  basic 
amino  acids  are  three  in  number  and  have  an  alkalinity  similar  to 
that  of  ammonia.  They  have  been  called  the  hexone  bases,  because  each 
contains  six  carbon  atoms.  They  are  alone  present  in  certain  forms  of  pro- 
tein called  protamines.  The  neutral  amino  acids  contain  one  amino  group 
and  one  carboxyl  group,  which  exactly  neutralize  each  other.  This  is 
the  largest  group  of  amino  acids,  and  is  further  subdivided  into  three: 
one  containing  aromatic  or  benzene  rings  and  including  the  very  im- 
portant amino  acids,  tyrosine  and  tryptophane;  another  containing  the 
so-called  pyrrolidine  ring;  and  the  third,  the  largest  of  all,  containing 
the  so-called  aliphatic  chains;  that  is,  the  chains  characteristic  of  the 
fatty  acids  and  which  may  be  either  straight  or  branched.  When  the  chains 
are  branched,  the  substance  is  called  an  isosubstance,  as  in  isoleucine. 
The  acid  amino  acids,  including  glutamic  acid  and  aspartic  acid,  are 


THE    METABOLISM    OF    PROTEIN  639 

characterized  by  containing  two  carboxyl  groups  and  only  one  amino 
group.  They  therefore  resemble  acetic  acid  in  acidity. 

It  may  be  of  assistance  to  some  if  we  restate  these  chemical  facts 
from  a  slightly  different  standpoint  as  follows: 

Glycine,  or  glycocoll,  is  aminoacetic  acid,  CH2NH2COOH 

Alanine   is   glycine   plus    a    methyl   group,    CH3CH  ;   it  is  therefore   amino- 

COOH 

OH 

propionic  acid  and  is  closely  related  to  lactic  acid,  which  is  CH3CH  .     Many  of 

COOH 

the  other  amino  acids  may  be  considered  as  derivatives  of  alanine,  thus: 

1.  Serine  is  alanine  with  an  "OH"  (hydroxyl)   group  in  place  of  one  of  the  "H" 

NH2 

atoms  of  the  methyl  group,  CH2OH  -  CH 

COOH 

2.  Cysteine  is  alanine  with  an  "SH"   (thio)  group  in  this  position, 

CH2SH  -  CH 

COOH 

Two  cysteine  molecules  united  at  the  ' '  S "  groups  give  cystine. 
NH2      1 

CH2S  -  CH 

COOH 

NH2 

3.  Phenylalanine  has  a  C6H4    (phenyl)    group,   CH2C6H5-CH 

COOH 
NH2 

4.  Tyrosine  has  a  C6H4OH    (phenol)    group,  CH2C6H4OH  -  CH 

COOH 
C 

5.  Tryptophane  has  a  C6H4  CH  (indole)  group : 

NH 
C  —  CH2  -  CH  -  NH2  -  COOH. 

C6H4  CH 

NH 
CH 

N  NH 

6.  Histidine  has  a  CH    —    C  -  (imidazole)  group: 


640 


METABOLISM 


CH 
N  NH 


CH    =    C.CH2  .  CH.   NH2-COOH. 


The  last  two  are  also  called  heterocyclic  compounds,  of  which  there 
is  another,  viz.; 

Proline  (and  oxyproline),  which  is  a-pyrrolidine  carboxylic  acid: 

CHa      —      CH3 


CH2 


CH.COOH 


\ 


Other  ami/no  acids  are: 


CHS              CH3 

CH3              CH8 

CH3              C2I 

\      / 

\       / 

\       / 

CH 

CH 

CH 

(1)  Valine 
Leucine 

CH.NH2 

ok 

CH.NH. 

Isoleuciue 

I 

1 

I 

thus: 

COOH 

CH.NH2 

1 

COOH 

(valine) 

COOH 

(isoleucine) 

(leucine) 

(2)   The  amino  dibasic  acids: 

Aspartic,  which  is  aminosuccinic  acid, 
CH2COOH 

I 
CHNH2COOH;  and 

Glutaminic,  which  is  aminoglutaric  acid, 
CH2 

CH2  -  COOH 

CHNH,  COOH. 
Lastly  there  are  the  diamino  acids,  in  which  two  groups  exist  : 

Lysine  a  e-diaminocaproic  acid. 

NH2 


NH2CH2  -  CH2  -  CH2  -  CH2  -  CH2  -  CH 

Arginine  a-animo  —  5-guanidine-valerianic  acid. 

NH2 

HN  =  C 


COOH. 


NH2 


NH.CH2  -  CH2  -  CH2  -  CH 

COOH 

The   guanidine  group  in  this  acid  is  of  interest  because  of  its  close  relationship  to 
NH2 

urea,  which  is  O=C 

NH2 


CHAPTER  LXX 

THE  METABOLISM  OF  PROTEIN   (Cont'd) 
AMINO  ACIDS  IN  THE  BLOOD  AND  TISSUES 

In  the  Blood. — Furnished  with  the  general  facts  concerning  the  chem- 
istry of  protein,  we  may  now  proceed  to  consider  the  more  precise 
knowledge  recently  acquired  concerning  the  history  of  this  substance 
in  the  animal  economy.  Although  no  one  has  succeeded  in  separating 
amino  acids  in  pure  condition  from  drawn  blood  even  during  the  height 
of  digestion,  it  has  nevertheless  been  possible  to  do  so  from  circulating 
blood  by  a  method  of  dialysis,  known  as  vividiffusion,  elaborated  by 
Abel33  and  his  pupils.  The  method  consists  in  connecting  a  long  tube 
of  collodion  with  the  two  ends  of  a  cut  artery  in  an  anesthetized  animal. 
(Fig.  187.)  The  tube,  coiled  many  times,  is  then  immersed  in  a  solution 
containing  approximately  the  same  salt  content  as  the  blood  plasma  of  the 
animal.  The  diffusible  constituents  of  the  blood  plasma  dialyze  into  the 
saline  solution ;  or  any  one  of  them  may  be  prevented  from  dialyzing  by  add- 
ing that  particular  substance  to  the  saline  in  such  amounts  as  will  make  its 
concentration  in  plasma  and  saline  alike.  It  has  been  possible  in  this 
way  to  isolate  several  of  the  amino  acids  and  other  ammonia-yielding 
substances  from  blood.  Thus,  alanine  and  valine  have  been  obtained  as 
crystalline  salts,  and  histidine  and  creatine  have  been  (see  page  656) 
shown  to  be  present  by  their  reactions.  All  of  the  amino  substances, 
however,  do  not  dialyze,  and  these  exceptions  are  further  characterized 
by  the  fact  that  they  do  not  readily  give  up  their  ammonia  on  the  ad- 
dition of  sodium  carbonate,  as  do  the  diffusible  substances  (Rohde). 

Although  amino  acids  can  thus  be  separated  in  a  pure  state  from  cir- 
culating blood,  their  concentration  in  a  drawn  specimen  is  too  low  to 
ike  direct  quantitative  estimation  possible.  By  the  methods  of  Van 
ttyke  and  Sorensen,  already  described,  however,  it  has  been  shown 
imong  other  things  that  the  blood  always  contains  a  certain  concentra- 
;ion  of  amino  acids ;  thus,  in  that  of  fasting  animals  from  3  to  5  mg.  per 
LOO  c.c.  of  blood  are  usually  found  present.  During  the  absorption  of  a 
)rotein  meal,  the  amino  content  of  the  blood  undergoes  a  marked  in- 
crease, becoming  doubled  or  more;  and  a  similar  result  has  been  ob- 
tained by  placing  pure  amino  acids  in  the  small  intestine.  After  10 
grams  of  alanine,  for  example,  the  amino  nitrogen  of  the  mesenteric 
blood  rose  from  3.7  to  6.3  mg.  per  cent.* 

"This  is  a  convenient  way  of  stating  per   100  c.c.   of  blood. 

641 


642 


METABOLISM 


In  the  Tissues. — After  entering  the  circulation,  the  excess  of  ammo  acids 
very  quickly  disappears  from  it  again.  This  has  been  demonstrated  by 
observing  the  amount  of  amino  acids  in  the  blood  after  the  intravenous 
injection  of  a  solution  of  amino  acid  into  an  anesthetized  animal.  After 
injecting  12  gm.  of  alanine  into  the  vein  of  a  dog,  90  per  cent  was  found 
to  have  disappeared  from  the  circulation  within  five  minutes.  The  ques- 
tion is,  What  becomes  of  the  amino  acids  that  rapidly  disappear?  Are 
they  decomposed  in  the  blood,  or  do  they  become  absorbed  by  the  tis- 
sues? This  problem  has  been  attacked  by  analyzing  portions  of  various 
organs  and  tissues  removed  before  and  some  time  after  the  injection 


Fig.  187. — Vividiffusion  apparatus  of  J.  J.  Abel. 

into  an  animal  of  solutions  of  amino  acids.  In  the  case  of  the  muscles  it 
has  been  found  that  the  amino-acid  content  increases  until  from  60  to 
80  mg.  per  cent  of  amino  acid  has  accumulated.  Beyond  this  point, 
however,  the  muscles  do  not  seem  to  be  able  to  take  up  any  more  amino 
acid  (Fig.  188).  The  capacity  of  the  abdominal  organs,  however,  is  more 
elastic;  for  example,  the  amino  nitrogen  of  the  liver  has  been  observed  to 
become  increased  to  125  or  150  per  cent  of  the  original  amount.  Al- 
though this  absorption  of  amino  acids  by  the  tissues  is  extremely  rapid,  it 
never  proceeds  to  such  a  point  that  the  blood  becomes  entirely  free  of  them, 
for  even  after  many  days'  starvation  the  blood  contains  its  normal  quota 
of  from  3  to  10  mg.  per  cent  (Fig.  189).  This  indicates  that  under  these 


THE    METABOLISM    OF    PROTEIN 


643 


conditions  a  certain  equilibrium  must  become  established  between  the 
ammo-acid  content  of  the  blood  and  that  of  the  tissues,  the  concentration 
in  the  tissues  being  approximately  from  five  to  ten  times  greater  than  in 
the  blood. 

The  absorbed  amino  acids  are  very  loosely  combined  with  the  tissues, 
for  they  can  be  extracted  by  such  feeble  reagents  as  water  or  dilute  al- 
cohol. Their  presence  can  not,  however,  be  merely  due  to  diffusion; 
for  if  it  were,  the  concentration  could  not  become  greater  in  the  tis- 
sues than  in  the  blood.  The  further  fate  of  the  amino  acids  is  difficult 


150 


100 


50 


Injectio 


Muscle 


NH 


1        2 

Hours 

Fig.  188. — Curves  showing  the  amount  of  amino  nitrogen  taken  up  by  different  tissues  after 
the  intravenous  injection  of  amino  acids.  The  lowermost  curve  shows  the  urea  concentration  of  the 
blood.  (From  D.  D.  Van  Slyke.) 

to  follow.  We  know  that  they  do  not  remain  in  the  body  for  a  long  time, 
because  most  of  the  protein  nitrogen  in  the  food  is  excreted  as  urea 
within  twenty-four  hours  after  ingestion;  and  when  single  amino  acids 

I  are  fed,  they  quickly  reappear  in  the  urine  as  urea. 
The  tissues  can  therefore  be  only  a  stopping-place  for  the  amino 
icids.  When  the  latter  are  determined  in  blood  collected  from  different 
3arts  while  absorption  of  protein  from  the  intestine  is  in  progress,  it 
las  been  found,  as  shown  in  Fig.  189,  that  during  the  passage  of  the 
)lood  through  the  liver  there  is  a  greater  fall  in  the  concentration  of 


644 


METABOLISM 


amino  acids  than  during  its  passage  through  the  entire  remainder  oi' 
the  body. 

It  will  be  seen  that  the  above  conclusions  are  drawn  from  estimations 
made  on  blood  taken  from  the  vena  cava,  the  portal  vein,  and  the  hepatic 
artery,  the  upper  curve  in  the  chart  being  from  animals  during  digestion 
and  the  lower,  from  fasting  animals.  The  results  show  that  the  liver  must 
be  particularly  greedy  of  amino  acids,  which,  however,  must  rapidly  be- 
come transformed  into  other  substances,  since  no  conspicuous  varia- 
tion has  been  found  to  occur  in  the  amino-acid  content  of  the  tissues 


Fig.    189. — Curves   showing   the    concentration    of   amino-acid    nitrogen    in    the    blood    during    fasting 
and  protein  digestion.     (From  D.  D.  Van  Slyke.) 

according  to  whether  the  animal  is  fasting  or  is  digesting  protein  food. 
This  result,  it  is  to  be  noted,  is  quite  different  from  that  which  is  ob- 
tained after  the  intravenous  injection  of  amino  acids,  and  the  results  of 
the  two  experiments  taken  together,  indicate  that  the  amino  acids  after 
their  absorption  can  not  remain  in  the  tissues,  in  a  free  condition  for  a 
long  time.  It  means  that  the  amino  acids  during  natural  digestion  must 
be  disposed  of  at  a  rate  which  is  practically  the  same  as  that  at  which  ab- 
sorption is  proceeding. 


THE    METABOLISM    OF    PROTEIN  645 

THE  FATE  OF  THE  AMINO  ACIDS 

To  follow  the  metabolism  of  the  amino  acids  further  we  must  deter- 
mine the  end  product  into  which  they  are  converted.  This  is  urea, 
the  estimation  of  which  can  nowadays  be  made  with  considerable  accuracy 
on  account  of  the  discovery,  by  Marshall,  of  the  action  of  urease  in  con- 
verting its  nitrogen  into  ammonia,  which  can  then  be  estimated  by  com- 
paratively simple  methods  (Folin). 

When  the  viscera  are  compared  before  and  at  various  periods  after 
the  intravenous  injection  of  amino  acids,  the  immediate  increase  in 
amino  nitrogen  remains  undiminished  in  all  of  them  except  the  liver,  in 
which  a  very  rapid  reduction  is  observed  to  occur.  At  the  same  time 
the  percentage  of  urea  in  the  blood  steadily  rises.  These  facts  are  illus- 
trated in  Fig.  188. 

The  simplest  interpretation  of  these  results  is  that  the  liver  converts 
the  amino  acids  into  urea  and  discharges  this  urea  into  the  blood.  This 
conclusion,  however,  it  must  be  observed,  is  not  inevitable;  for  it  is  pos- 
sible that  the  amino  acids  may  be  condensed  into  polypeptides  in  the 
liver,  just  as  sugar  is  condensed  by  this  organ  into  glycogen,  and  that 
the  increase  in  urea  in  the  blood  is  merely  coincident  (Fiske). 

It  must  not  be  imagined  that  the  conversion  of  the  amino  acids  into 
urea  is  exclusively  a  function  of  the  liver.  On  the  contrary,  it  is  well 
known  that  this  process  may  occur  in  animals  from  which  the  liver  has' 
been  entirely  removed.  It  is  probably  safe  to  conclude,  however,  that 
the  liver  is  the  most  active  center  for  amino-acid  transformation  and 
urea  formation. 

When  urea  is  estimated  in  samples  of  blood  removed  at  short  inter- 
vals of  time  after  the  ingestion  of  a  large  amount  of  protein,  it  is  found 
that  the  increase  becomes  very  early  established.  In  one  experiment, 
before  the  food  was  taken  the  concentration  of  urea  nitrogen  in  the  blood 
was  a  little  over  10  mg.  per  cent;  one  hour  after  taking  500  grams  of 
meat,  it  had  risen  to  about  18,  and  in  two  hours  to  nearly  25.  Evidently 
the  increase  had  occurred  about  the  same  time  as  the  passage  of  food 
from  the  stomach  into  the  duodenum.  These  facts  indicate  that  urea 
formation  in  the  liver  becomes  stimulated  long  before  the  other  tissues, 
such  as  the  muscles,  have  had  time  to  take  up  their  full  quota  of  amino 
acids.  During  digestion  of  protein  the  liver  does  not  appear  to  wait 
until  the  other  tissues  have  become  saturated  with  amino  acids  before  it 
begins  to  destroy  the  unnecessary  excess  by  conversion  into  urea;  on 
the  contrary,  this  process  sets  in  with  the  very  first  installment  of  amino 
acid  that  reaches  the  liver  by  the  portal  blood.  This  conclusion  is  in 
harmony  with  the  well-established  fact  that,  when  protein  is  given  to  a 


646  METABOLISM 

starving  animal,  the  greater  part  of  its  nitrogen  is  soon  excreted  as 
urea,  leaving  only  a  small  fraction  to  be  used  for  rebuilding  the  wasted 
tissues. 

The  amino  acids  that  are  absorbed  by  the  extrahepatic  tissues  become 
very  quickly  converted  into  formed  protein,  as  is  evident  from  the  fact 
that  the  concentration  of  free  amino  acids  in  the  tissues  of  an  animal 
during  absorption  of  protein  is  not  perceptibly  greater  than  in  those  of 
a  fasting  animal,  and  the  question  remains  to  be  considered,  What  be- 
comes of  the  protein  thus  formed?  The  answer  is,  that  it  is  gradually 
/used  up  in  the  metabolic  processes,  so  as  to  liberate  again  the  amino 
iacids,  which  add  themselves  to  those  absorbed  from  the  intestine  and  be- 
y?ome  used  again  or  excreted,  according  to  the  demands  of  the  tissues  at 
the  time  for  amino  acid. 

This  process  of  liberation  of  ammo  acid  from  the  breakdown  of  body 
protein  goes  on  of  course  irrespective  of  absorption  of  amino  acid  from 
the  intestine.  It  goes  on,  for  example,  during  starvation;  indeed,  in 
this  condition  the  percentage  of  free  amino  acids  in  the  muscles  is,  if 
anything,  somewhat  higher  than  that  observed  in  an  ordinarily  fed  an- 
imal. In  starvation  also  the  migration  of  amino  acid  is  going  on  among 
the  various  organs,  of  which  those  whose  activity  is  essential  to  the 
maintenance  of  life,  such  as  the  heart  and  the  respiratory  muscles,  are 
supplied  with  amino  acids  from  tissues  that  are  less  vital,  such  as  the 
•  skeletal  muscles  (see  page  602).  These  experiments  further  show  that- 
free  amino  acids  can  not  serve  to  any  significant  extent  as  food  reserves 
in  the  same  way  as  glycogen  and  fat.  If  amino  acids  were  of  value  as 
food  reserves,  we  should  expect  the  store  of  them  to  be  depleted 
by  starvation.  As  to  how  long  a  period  of  time  elapses  between  the 
incorporation  of  the  absorbed  amino  acids  into  tissue  protein  and  their 
subsequent  liberation  again  by  autolysis,  we  are  entirely  ignorant. 

The  researches  which  we  have  just  been  considering  do  not  throw  any 
light  on  the  relative  value  of  different  proteins  in  tissue  metabolism. 
They  do  not  inform  us  as  to  which  of  the  amino  acids  must  be  absorbed 
ready-made  from  the  digested  food,  and  which  of  them  may  be  dispensed 
with  since  the  organism  can  manufacture  them  for  itself.  We  know  that 
the  higher  animals  can  synthetize  some  amino  acids,  such  as  glycocoll, 
but  not  others,  such  as  tryptophane ;  but  which  amino  acids  belong  to 
the  glycocoll  and  which  to  the  tryptophane  groups,  can  not  as  yet 
be  definitely  stated.  The  investigation  of  this  problem  has  to  be  under- 
taken by  experiments  of  an  entirely  different  type — namely,  by  observing 
the  welfare  and  growth  of  animals  fed  on  proteins  of  varying  amino- 
acid  composition.  A  full  discussion  of  these  experiments  is  given  in 
the  chapters  on  Nutrition  and  Growth. 


CHAPTER  LXXI 
THE  METABOLISM  OF  PROTEIN  (Cont'd) 

THE  END  PRODUCTS  OF  PROTEIN  METABOLISM 

Introductory. — So  far  we  have  approached  the  problem  of  protein 
metabolism  by  studying  the  behavior  of  the  absorbed  products  of  pro- 
tein breakdown,  and  we  have  seen  that  these  become  gradually  assimilated 
by  the  tissues  and  used  by  them  in  their  metabolic  processes.  We  have 
been  unable,  however,  to  offer  any  facts,  regarding  the  exact  chemical 
changes  which  each  amino  acid  undergoes  during  this  process  of  tissue 
metabolism.  At  first  sight  it  might  appear  an  easy  matter  to  collect 
such  information  by  direct  examination  of  the  tissues  themselves,  either 
by  searching  in  them  for  amino  derivatives  which  might  be  derived  from 
absorbed  amino  acids,  or  by  studying  the  changes  which  occur  when 
the  amino  acids  are  subjected  to  the  action  of  the  isolated  tissue  en- 
zymes that  must  be  responsible  for  the  change.  Such  methods  of  in- 
vestigation are,  however,  fraught  with  technical  difficulties  so  great  that 
very  little  can  be  learned  from  them,  and  for  the  present  at  least  we 
must  be  content  to  piece  our  information  together  from  facts  derived 
by  less  direct  methods.  Such  a  method  is  offered  by  investigating 
the  behavior  of  the  en^.  products  of  protein  metabolism. 

The  main  end  product  is  urea  along  with  traces  of  its  precursor  am- 
monia, but  these  are  not  the  only  ones,  for  some  amino  acids  after  being 
incorporated  with  the  tissue  proteins  break  down  into  products  that 
are  no  longer  members  of  the  amino-acid  series,  although  they  may  be 
closely  related  to  certain  amino  acids.  Such  substances  are  creatine  and 
its  anhydrid  creavtmne.  A  part  of  the  amino  acids  during  their  pres- 
ence in  a  free  state  in  the  blood  may  also  be  excreted  unchanged  by 
the  kidney.  Our  list  so  Jar  therefore  includes  urea,  ammonia,  creatine, 
creath^ijie,  and  amino  nitrogen,  of  which  the  last  is  usually  included  in 
metabolism  investigations  in  the  fraction  designated  undetermined 
nitrogen. 

Another  group  of  closely  related  substances  coming,  not  from  the 
general  protein  metabolism  of  the  tissues,  but  from  the  metabolism 
which  is  peculiar  to  the  nuclei,  consists  of  the  so-calleds^pt/rme  bodies. 
Furthermore,  so  as  to  serve  as  a  check  on  results  obtained  by  examining 
these  nitrogenous  metabolites,  it  is  important  to  observe  the  manner  of 

647 


648 


METABOLISM 


excretion  of  the  sulphur  moiety  of  the  protein  molecule,  for  it  will  be 
remembered  that  it  is  in  protein  alone  that  sulphur  is  usually  taken  into 
the  animal  body.  .The  excretion  of  sulphur  therefore  runs  more  or  less 
parallel  with  the  intensity  of  protein  metabolism. 

After  selecting  the  end  products  that  are  most  likely  to  be  of  signif- 
icance, the  first  question  concerns  the  amount  of  each  of  them  excreted 
during  twenty-four  hours  on  diets  that  are  either  rich  or  poor  in  pro- 
tein. The  possibility  of  conducting  such  investigations  obviously  de- 
pends on  the  use  of  quick  and  yet  reliable  methods  for  the  estimation 
of  the  nitrogenous  metabolites.  Such  methods  have  been  furnished  by 
the  painstaking  and  careful  work  of  Folin,  an  example  of  whose  results 
is  given  in  the  accompanying  table. 


NITROGEN-RICH    DIET 

NITKOGEN-POOR    DIET 

Volume  of  urine 

117U  c.c. 

385    C.C. 

-^^^  Total  nitrogen 

16.8  grams 

3.60  grams 

^SJrea  nitrogen 

14.7     grams  —  87.5% 

2.20  grams  =  61.7% 

^Ammonia  nitrogen 
^HJric-acid  nitrogen 
Crea,tinine  nitrogen 

0.49  gram    —    3.0% 
0.18  gram    —    1.1% 
0.58  gram    —    3.6% 

0.42  gram    —11.3% 
0.09  gram    —    2.5% 
0.60  gram    =17.2% 

Undetermined  nitrogen 

0.85  gram    —    4.9% 

0.27  gram    —    7.3% 

Total  S03 

3.64  grams 

0.76  gram 

Inorganic  SO3 
Ethereal  SO,    ' 

3.27  grams  —  90.0% 
0.19  gram    —    5.2% 

0.46  gram    —60.5% 
0.10  gram    —13.2% 

MeutraT"SO3 

0.18  gram    —    4.8% 

0.20  gram    —26.3% 

(Folin.) 

The  general  conclusions  which  may  be  drawn  from  these  results  are 
s  follows: 

1.  With  a  protein-rich  diet  much  more  urine  is  excreted  in  twenty- 
four  hours  than  with  one  that  is  protein-poor.    Evidently  the  nitrogenous 
metabolites  act  as  diuretics. 

2.  The  total  or  absolute  amounts   of  nitrogen  and  of  all  the   other 
nitrogenous  metabolites,  save  creatinme,  become  diminished  during  the 
starvation  period.     The  same  is  true  of  the^sulphur  derivatives,  except 
in  the  case  of  the  neutral  sulphur,  which  behaves  like  creatinine. 

3.  The  decrease  in  nitrogen  is  not  borne  proportionately  by  all  of 
the  metabolites.     This  is  seen  by  examination  of  the  percentage  figures 
which  are  obtained  by  calculating  the  nitrogen  of  each  substance  as  a 
percentage  of  the  total  nitrogen.  SThe  urea  decreases  relatively  much 
more  than  the   total  nitrogen.     The   inorganic   sulphate   behaves    in   a 
manner  similar  to  the  urea — that  is,  the  percentage  of  total  sulphate 
excreted  in  the  inorganic  form  becomes  much  less  during  starvation. 

4.  The  relative  amount  of  all  the  other  nitrogenous  metabolites,  as 
well  as  that  of  the  ethereal  and  neutral  sulphates,  becomes  increased 
during  starvation. 

The  most  striking  results  of  the  above  investigation  are  that  creatinme 
remains  unchanged. during  starvation,  but  that  urea  becomes  relatively 


THE    METABOLISM    OF    PROTEIN  649 

increased.  The  former  must  be  derived  from  metabolic  processes  going 
on  in  the  tissues  independently  of  the  supply  of  foodstuff  carried  to 
them,  whereas  the  latter  must  depend,  if  not  entirely,  yet  very  largely, 
on  the  protein  content  of  the  food.  Creatinine  may  therefore  be  called 
an  end  product  of  endogenous  metabolism,  and  urea  an  end  product  of 
exogenous  metabolism. 

Other  metabolites — namely,  ammonia,  uric  acid  and  the  undetermined 
nitrogen,  as  well  as  the  ethereal  sulphates — must  represent  processes 
of  metabolism  that  are  partly  exogenous  and  partly  endogenous. 

Having  made  ourselves  acquainted  with  the  general  nature  of  the 
changes  that  occur  in  the  nitrogenous  metabolites  when  protein  metab- 
olism is  stimulated  by  the  taking  of  food  or  is  depressed  by  starvation, 
we  may  now  proceed  to  a  study  of  the  source  and  origin  in  the  animal 
body  of  each  of  the  metabolites. 

UREA  AND  AMMONIA 

For  various  reasons  it  is  important  to  consider  these  two  metabolites 
together.  During  the  intermediary  metabolism  of  the  majority  of  the 
amino  acids,  the  amino  group  becomes  broken  off  as  ammonia,  which 
immediately  combines  with  the  available  acids  to  form  neutral  ammonium 
salts.  The  most  available  acid  for  this  purpose  is  carbonic  acid;  there- 
fore ammonium  carbonate  is  formed  in  large  amounts.  A  small  propor- 
tion of  the  ammonia  may  combine  with  other  acid  radicles,  such  as 
chlorine,  to  form  ammonium  chloride.  The  fate  of  these  two  types  of 
salt  is  very  different.  The  ammonium  carbonate  becomes  quickly  trans- 
formed into  urea,  whereas  the  ammonium  chloride  is  excreted  in  the 
urine.  The  process  of  urea  formation  may  therefore  be  considered  as 
having  the  function  of  preventing  the  accumulation  of  ammonium  car- 
bonate in  the  animal  body.  It  is  the  means  by  which  a  harmful  substance 
is  converted  into  an  innocuous  substance — a  detoxication  process,  in 
other  words. 

Regarding  the  nature  of  the  chemical  process  involved  in  this  trans- 
formation of  ammonium  carbonate  into  urea,  reference  to  the  following 
formulae  will  show  that  the  ammonium  carbonate  that  is  formed  by  the 
union  of  carbonic  acid  with  ammonia,  by  losing  one  molecule  of  water 
becomes  ammonium  carbamate,  which  by  repetition  of  the  process  be- 
comes transformed  into  urea : 

OH  ONH4  ONH4  NH, 

/  \]  /  /  / 

CO  +  2NH3  <=»  CO  -H0O^±CO  -  H.,O  =  CO 

\  \  \                                   \ 

OH  ONH,                               NH,                                NIT, 

(carbonic  (ammo-        (ammonium  (ammonium  (urea) 

acid)  nia)              carbonate)  cnrbnmate) 


650  METABOLISM 

Some  of  the  urea  may  come  from  metabolic  processes  of  an  entirely 
different  type.  One  of  these  at  least  is  known ;  namely,  the  splitting-off 
of  urea  from  arginine,  which  it  will  be  remembered  is  guanidine-amino- 
valerianic  acid  (see  page  640).  An  enzyme  called  arginase,  having  this 
action,  has  been  isolated  from  various  organs  and  tissues.  The  diamino- 
valerianic  acid,  or  ornithine,  which  remains  after  the  urea  is  split  off, 
may  be  further  used  in  protein  metabolism.  The  reaction  is  shown  in 
the  following  equation: 

NH2  -  C  -  NH  -  CH2  -  CH2  -  CH2  -  CHNH2  -  COOH  +  H2O 
NH  (arginine) 

—  NH2-CO 

I         4-  NH2  -  CH2  -  CH2  -  CH2  -  CHNH2  -  COOH 
NH2 
(urea)  (ornithine) 

On  an  ordinary  diet,  as  we  have  seen,  a  man  excretes  somewhat  more 
than  90  per  cent  of  his  total  nitrogen  as  urea  and  about  3  per  cent  as 
ammonia,  the  remainder  of  the  nitrogen  appearing  in  the  other  nitrog- 
enous metabolites. 

Influence  of  Acidosis  on  Ammonia-Urea  Ratio. — It  sometimes  happens 
that  a  large  proportion  of  the  ammonia  is  used  for  the  purpose  of  neu- 
tralizing abnormal  acids  present  in  the  organism.  The  ammonia  is  appar- 
ently produced  in  the  kidney  (page  563).  When  mineral  acids  are  given 
to  an  animal,  or  when  acids  are  produced  in  the  organism  itself  by  some 
faulty  type  of  metabolism,  the  ammonia  excretion  by  the  urine  immedi- 
ately rises.  In  diabetes,  for  example,  where  considerable  quantities  of 
/?-oxybutyric  acid  are  produced  (see  page  715),  a  decided  increase  in  the 
ammonia  excretion  is  observed.  A  milder  type  of  acidosis  may  also  be  in- 
duced in  normal  persons  by  withholding  carbohydrates  from  the  diet,  and 
here  again  the  ammonia  excretion  is  relatively  increased. 

In  such  cases  the  ammonia  is  to  be  regarded  as  an  alkaline  re- 
serve in  the  sense  that  it  carries  the  excess  of  acids  out  of  the  body 
and  so  saves  fixed  alkalies.  It  does  not  appear,  however,  that  all 
types  of  acidosis  entail  the  utilization  of  ammonia  as  reserve  alkali, 
and  an  increase  in  the  relative  amount  of  ammonia  in  the  urine  does 
not  necessarily  indicate  a  condition  of  acidosis.  In  the  pernicious 
vomiting  of  pregnancy,  for  example,  a  relatively  high  excretion  of  am- 
monia has  been  found  associated  with  no  greater  a  degree  of  acidosis 
than  in  normal  cases  of  pregnancy,  as  determined  by  the  power  of  the 
plasma  to  absorb  carbonic  acid.  When  there  is  a  relative  excess  of  al- 
kali in  the  blood  (alkalosis)  the  ammonia  excretion  becomes  depressed, 
as  is  the  case  after  taking  alkali  with  the  food,  or  in  the  alkalosis  pro- 
duced by  forced  breathing  (page  382). 


THE    METABOLISM    OF   PROTEIN  651 

Influence  of  Liver  on  Ammonia-Urea  Ratio. — Experimental  Observa- 
tions: (1)  REMOVAL  OF  LIVER. — There  are  several  facts  which  indicate  that 
other  causes  than  acid-production  may  interfere  with  the  conversion  of  am- 
monia into  urea.  What  are  these  causes?  Since,  as  we  have  seen, 
the  liver  is  the  organ  which  most  actively  converts  amino  acids 
into  urea,  it  would  be  natural  to  expect  that,  when  the  functions  of 
this  organ  were  interfered  with,  relatively  more  of  the  nitrogen  excre- 
tion would  occur  as  ammonia  and  relatively  less  as  urea.  In  order  to 
determine  the  exact  significance  of  the  liver  as  a  urea-forming  organ, 
two  types  of  investigation  have  been  used;  namely,  (1)  observation  of 
the  changes  produced  in  the  ammonia-urea  ratio  in  the  urine  by  partial 
or  total  removal  of  the  liver;  and  (2)  observation  of  the  urea-forming 
power  of  a  liver  perfused  outside  the  body. 

To  remove  the  liver  from  the  circulation  the  portal  vein  is  brought 
in  apposition  with  the  vena  cava,  the  two  are  sewed  together,  and  a 
passage  opened  between  them,  after  which  the  portal  vein  is  ligated  above 
the  anastomosis  (forming  the  so-called  Eck  fistula).  The  portal  blood 
then  passes  directly  into  the  vena  cava,  and  the  liver  is  now  supplied 
only  by  the  hepatic  artery.  The  animals  live  for  a  considerable  time 
after  the  operation,  and  the  urine  frequently  contains  relatively  less 
urea  and  more  ammonia  than  normal.  The  results  are,  however,  not 
nearly  so  striking  as  would  be  expected  if  the  liver  were  the  main  seat 
of  urea  formation.  The  experiments  have  nevertheless  brought  to  light 
a  fact  of  considerable  clinical  interest — namely,  although  the  animals 
may  thrive  if  kept  on  a  diet  not  containing  an  excess  of  flesh,  they  im- 
mediately begin  to  develop  peculiar  symptoms,  not  unlike  those  of  ec- 
lampsia or  uremia,  when  they  are  fed  with  large  amounts  of  flesh  food. 
Most  of  the  symptoms  can  be  referred  to  abnormal  stimulation  of  the 
central  nervous  system,  and  examination  of  the  urine  has  shown  a  large 
increase  in  the  excretion  of  ammonia  and  a  change  from  the  normal 
acid  reaction  to  an  alkaline  one. 

At  one  time  it  was  assumed  that  the  toxic  symptoms  were  caused  by 
the  presence  in  the  blood  of  ammonium  carbamate,  since  large  quantities 
of  the  calcium  salt  of  this  substance  could  be  separated  from  the  urine. 
It  is  now  known,  however,  that  the  ammonium  carbamate  is  present  only 
because  of  the  excess  of  ammonium  carbonate,  the  two  salts  existing  to- 
gether in  solution  according  to  the  laws  of  mass  action.  That  the  intox- 
ication is  not  due  to  ammonium  carbamate  does  not  exclude  the  pos- 
sibility that  it  may  be  due  to  ammonia  itself,  although  it  is  more  likely 
that  other  nitrogenous  metabolites,  produced  when  excess  of  flesh  food 
is  taken,  are  the  responsible  agents. 

If  the  liver  is  entirely  removed  by  ligating  the  hepatic  arteries  in  an 


652  METABOLISM 

animal  with  an  Eck  fistula,  a  more  pronounced  decrease  in  urea  and 
increase  in  ammonia  occur  during  the  short  period  of  time  that  the 
animal  survives  the  operation. 

The  percentage  of  blood  sugar  falls  steadily  after  the  removal  of  the 
liver,  and  when  it  reaches  about  0.05,  the  toxic  symptoms  appear,  soon' 
followed  by  death.  If  glucose  solutions  be  now  given  intravenously,  the 
symptoms  are  immediately  relieved  and  the  life  of  the  animal  prolonged 
(Mann). 

In  corroboration  of  these  observations  on  mammals,  it  may  be  of  in- 
terest to  note  that  when  the  liver  is  removed  from  birds,  which  is  a  com- 
paratively simple  operation  on  account  of  a  natural  anastomosis  between 
the  portal  and  renal  veins,  there  is  a  marked  decrease  in  the  excretion 
of  uric  acid  and  a  corresponding  increase  in  the  excretion  of  ammonia 
during  the  twelve  hours  or  so  that  the  birds  survive.  In  birds  and 
reptiles  urea  is  excreted  as  uric  acid,  being  produced  by  a  synthetic 
process  in  the  liver  (see  page  677).  The  changes  in  this  experiment  are 
of  considerable  magnitude;  thus,  before  the  operation  the  amount  of 
ammonia  nitrogen  relative  to  total  nitrogen  has  been  found  to  vary  be- 
tween 10  and  18  per  cent;  after  the  operation  it  may  be  increased  to 
between  45  and  60  per  cent.  The  uric-acid  nitrogen  normally  varies  be- 
tween 60  and  70  per  cent  of  the  total  nitrogen;  after  the  operation  it  may 
fall  to  between  3  and  6  per  cent. 

In  animals  with  an  Eck  fistula  and  with  the  hepatic  artery  ligated, 
an  increase  in  the  urea  output  occurs  when  amino  acids  are  injected  under 
the  skin.  This  result  corroborates  the  conclusion  that  the  liver  can  not 
alone  be  responsible  for  the  conversion  of  ammonia  into  urea. 

(2)  PERFUSION  OP  ORGANS. — This  method  consists  in  removing  the  or- 
gan into  a  warm  chamber  or  bath  and  perfusing  it,  through  cannulae 
inserted  in  its  main  artery  and  vein,  with  a  solution  of  defibrinated  blood 
or  of  defibrinated  blood  mixed  with  saline  solution.  The  perfusion 
liquid  is  kept  at  body  temperature  and  is  saturated  with  oxygen.  By 
means  of  a  pump  it  is  made  to  circulate  in  a  pulsatile  flow,  and  the  total 
amount  of  urea  or  other  metabolite  in  the  circulating  fluid  is  determined 
before  and  after  the  fluid  has  been  circulated  several  times  through  the 
organ.  When  the  liver  is  perfused,  urea  gradually  accumulates  in  the 
fluid,  particularly  after  the  addition  of  one  of  its  known  precursors — 
for  example,  ammonium  carbonate.  When  other  organs  or  viscera  are 
perfused,  no  urea  is  formed.  The  evidence  shows  that  the  liver  is  an 
important  seat  of  urea  formation,  but  not  necessarily  that  other  organs 
are  unable  to  form  it  in  the  intact  animal,  for  there  are  many  sources 
of  inaccuracy  in  perfusion  experiments,  for  although  we  exercise  the 


THE    METABOLISM    OF   PROTEIN  653 

greatest  care,  we  can  not  hope  to  maintain  the  organ  in  other  than  a 
slowly  dying  condition.  It  is  certainly  far  removed  from  the  normal- 
state,  as  is  revealed  not  only  by  histological  examination,  but  by  the  fact 
that  edema  almost  invariably  sets  in  and  the  blood  vessels  become  ex- 
tremely constricted,  thus  necessitating  a  gradual  increase  in  the  per- 
fusion  pressure  as  the  perfusion  goes  on.  Furthermore,  the  organ  being 
isolated-  from  the  nervous  system,  there  can  be  no  control  of  the  rela- 
tive blood  supply  of  different  parts.  In  the  intact  animal  the  circula- 
tion is  more  or  less  distributed  according  to  the  particular  needs  of  the 
different  viscera,  and  such  conditions  obviously  can  not  be  simulated  in 
a  perfusion  experiment.  Another  objection  to  perfusion  experiments  in 
general  depends  on  the  fact  that  the  well-being  of  the  organs  in  the 
intact  animal  is  largely  dependent  on  hormones  conveyed  to  them  from 
other  organs.  Such  hormones  are  frequently  quite  labile  in  nature,  and 
soon  disappear  from  the  perfusion  fluid. 

Notwithstanding  these  objections,  there  can  be  no  doubt  that  many 
of  the  functions  of  an  organ  are  retained  much  longer  than  they  would 
be  if  the  organ  were  not  perfused ;  for  example,  the  contractility  of  the 
muscle  or  the  power  of  forming  urea  in  the  liver.  Perfusion  experiments 
are  of  value  therefore  when  they  yield  positive  results.  Negative  re- 
sults may  indicate  either  that  the  organ  does  not  perform  the  particular 
function  that  is  being  investigated  or  that  it  has  lost  this  function  as  a 
result  of  partial  death.  That  a  perfused  muscle  retains  its  power  of 
contraction  does  not  necessarily  indicate  that  it  maintains  all  of  its 
metabolic  functions;  neither  does  the  fact  that  the  liver  forms  urea 
prove  that  it  is  capable  of  performing  its  other  functions.  It  is  easy  to 
show  that  the  liver  dies  piecemeal;  some  functions,  such  as  glycogen- 
formation,  die  early,  while  others,  such  as  urea-formation,  remain  for  a 
long  time  intact.  The  use  of  perfusion  experiments  in  the  investigation 
of  problems  of  metabolism  should  always  be  very  carefully  controlled  and 
the  results  should  never  constitute  the  only  evidence  upon  which  impor- 
tant conclusions  are  based. 

(3)  Before  leaving  this  subject  it  may  be  well  to  point  out  that  the 
method  which  at  first  sight  might  appear  to  be  the  simplest  for  throwing 
light  on  such  problems  as  that  under  consideration — namely,  the  examina- 
tion of  the  inflowing  and  outflowing  blood  of  different  parts  or  organs — is 
not  applicable  in  most  cases.  This  is  because  of  the  extremely  small 
changes  in  concentration  which  may  occur  even  although  large  amounts 
of  the  particular  substance  in  question  are  being  absorbed  or  produced. 
As  we  shall  see  later,  this  criticism  is  particularly  applicable  in  the  case 
of  sugar.  Even  during  the  injection  of  considerable  quantities  of  sugar 
into  the  portal  vein,  no  difference  in  percentage  can  be  demonstrated 


654  METABOLISM 

between  the  blood  of  the  two  sides  of  the  liver,  although  we  know  that 
•sugar  is  being  retained  to  form  glycogen.  For  the  same  reasons,  differ- 
ences in  the  percentage  amounts  of  ammo  acids  or  of  urea  are  often  dif- 
ficult to  demonstrate  in  the  blood  entering  and  leaving  the  liver  even 
when  we  know  that  large  quantities  of  them  are  being  added  to  or  re- 
moved from  it. 

Clinical. — Since  the  liver  is  an  important  seat  of  urea  formation,  the 
question  arises  as  to  whether  the  relative  percentage  of  urea  and  am- 
monia in  the  urine  will  become  altered  by  disease  of  the  liver.  Many 
observations  with  this  point  in  view  have  been  undertaken,  but  it  can 
not  be  said  that  the  results  are  very  striking.  In  extreme  destruction, 
such  as  that  produced  by  phosphorus  poisoning,  there  may  indeed  be 
a  great  increase  in  the  relative  amount  of  ammonia  and  a  decrease  in 
that  of  urea.  The  same  is  true  in  acute  yellow  atrophy  of  the  liver,  in 
which  disease  the  nitrogen  excreted  as  ammonia  may  amount  to  as  much 
as  70  per  cent  of  that  excreted  as  urea.  In  milder  forms  of  liver  dis- 
turbance, however,  such  as  cirrhosis,  the  figures  are  much  less  striking. 
When  an  increased  ammonia  excretion  is  observed  in  such  cases,  we 
must  be  cautious  in  drawing  the  conclusion  that  it  is  due  primarily  to 
interference  with  the  hepatic  function.  It  may  just  as  well  be  caused  by 
the  development  of  acids  in  the  organism  that  require  the  ammonia  for 
their  neutralization.  It  is  significant,  for  example,  that  considerable 
quantities  of  acids  are  produced  in  phosphorus  poisoning. 

Although  the  urea  and  ammonia  excretions  become  altered  by  exten- 
sive destruction  of  liver  tissue,  it  is  a  remarkable  fact  that  very  little  if 
any  change  occurs  in  the  amino  nitrogen,  either  of  the  urine  or  of  the 
blood.  In  experimental  necrosis  of  the  liver  caused  by  chloroform 
or  by  phosphorus,  it  is  only  in  the  latest  stages  of  the  condition  and 
when  it  is  of  the  very  severest  type  that  the  amino  acids  have  been 
found  to  increase  in  the  blood  and  urine.  The  conditions  seem  to  be  some- 
what different  in  man,  abnormally  high  amounts  of  amino  nitrogen  hav- 
ing been  observed  in  the  blood  in  a  considerable  proportion  of  patients 
with  impaired  liver  function.  In  very  severe  cases  of  diabetes,  for  ex- 
ample, figures  that  are  distinctly  higher  than  normal  have  been  observed 
(VanSlyke,  etc.).  In  eclampsia  the  marked  pathological  changes  in  the 
liver  might  be  expected  to  be  associated  with  an  upset  in  the  metabo- 
lism of  amino  acids.  Losee  and  Van  Slyke35  have,  however,  recently 
shown  by  the  most  accurate  methods  that  neither  in  the  blood  nor  in  the 
urine  is  any  excess  of  amino  acids  to  be  found  in  this  condition,  although 
in  cases  of  pernicious  vomiting  of  pregnancy,  there  was  a  relative  in- 
crease in  the  ammonia  excretion.  We  have  already  seen  that  this 


THE    METABOLISM    OF    PROTEIN  655 

increase  did  not  bear  any  relationship  to  the  acid-absorbing  power  of 
the  blood  plasma  (see  page  650). 

The  importance  of  the  kidneys  in  removing  the  urea  from  the  blood 
is  readily  seen  from  the  change  in  the  percentage  of  urea  in  this  fluid 
after  the  partial  or  complete  removal  of  the  kidneys.  Animals  sur- 
vive nephrectomy  for  about  three  days,  and  during  this  time  urea  rapidly 
accumulates  in  the  blood  and  begins  to  make  its  appearance  in  the 
saliva  and  the  intestinal  secretions.  In  man  also  where  the  kidneys 
are  extensively  diseased,  a  similar  accumulation  of  urea  occurs  in  the 
blood,  some  of  the  excess  being  got  rid  of  through  the  sweat  and  to  a 
certain  extent  through  the  intestine.  The  importance  of  encouraging 
perspiration  and  a  free  movement  of  the  bowels  in  cases  of  nephritis  is 
thus  indicated.  It  must  not  be  concluded  that  the  accumulation  of 
urea  in  the  organism  is  the  direct  cause  of  the  symptoms.  Urea  itself 
is  comparatively  inert,  and  it  is  generally  believed  that  other  metabolic 
products  with  which  the  urea  runs  parallel  in  amount  are  the  toxic 
agents.  Hewlett  has  found,  however,  that  very  large  injections  of  urea 
cause  certain  symptoms.34 


CHAPTER  LXXII 
THE  METABOLISM  OF  PROTEIN  (Cont'd) 

CREATINE  AND  CREATININE 

Creatine  and  creatinine  are  very  largely  products  of  endogenous  metab- 
olism; they  are  mainly  derived  from  chemical  processes  occurring  in 
the  tissues  although  some  of  the  creatine  and  creatinine  present  in  the 
food  may  appear  as  creatine  in  the  urine. 

Essential  Chemical  Facts 

Before  we  proceed  to  discuss  the  metabolism  of  these  important  substances,  it  will 
be  necessary  to  refer  briefly  to  some  points  in  their  chemistry.  The  simpler  of  the 
two  bodies  is  creatine,  which  is  methyl-guanidine-aeetic  acid;  creatinine  is  its  anhydrid, 
being  formed  from  creatine  by  the  removal  of  a  molecule  of  water,  so  that  the  NH2 
groups  become  joined  together  in  the  same  way  as  they  do  in  the  formation  of  pep- 
tides  from  ammo  acids  (page  636).  The  relationships  are  illustrated  in  the  following 
formulas  : 

CH3-N-CH-CO 

(methyl)  , 

CH3—  N 

/    \ 

/  CH..COOH  NH  =  C 

NH  —  C  -  H20  =  \ 

\  (acetic  acid)  \ 

\  \   i 

(guanidine)    -NH.,  NH 

(creatine)  (creatinine) 

It  should  be  noted  that  guanidine  is  closely  related  to  urea,  0:=C(NH2)2,  and  that 
when  creatinine  is  formed  from  creatine  a  ring  formation  occurs,  giving  what  may  be 
regarded  as  an  imidazole  derivative  (see  page  639).  Creatine  is  also  related  to  one 
of  the  important  diamino  acids,  arginine,  since  both  contain  guanidine  radicles,  NH= 
0(NH2)2,  and  to  histidine  and  the  purines  (see  page  669),  both  of  which  contain  the 
imidazole  ring.  The  close  relationship  which  creatine  bears  to  urea  is  illustrated  by 
the  fact  that  urea  is  formed  when  creatine  is  subjected  to  the  action  of  boiling  barium 
hydrate.  When  it  is  oxidized  by  means  of  potassium  permanganate,  urea  is  also 
formed,  the  remainder  of  the  molecule,  more%or  less  intact,  being  split  off  as  methyl- 

"NTTT  f^TT 

amino-acetic  acid   (CH  <          ',-r3),  also  known  as  sarcosine. 


The  conversion  of  creatine  to  creatinine  goes  on  slowly  in  aqueous  solutions,  but  is 
much  accelerated  by  heating  with  acid.  Heated  in  an  autoclave  at  a  temperature  of 
117°  C.  for  thirty  minutes,  with  half  normal  hydrochloric  acid,  the  creatine  goes  over 
almost  quantitatively  into  creatinine.  It  will  be  noted  that  the  creatinine  ring  is 
partly  oxidized.  This  renders  it  unstable,  so  that  creatinine  in  the  presence  of  alkalies 

656 


THE    METABOLISM    OF    PROTEIN  657 

has  the  power  of  reducing  metallic  oxides.  Like  glucose  it  can  reduce  alkaline  solu- 
tions of  copper,  silver  and  mercuric  salts;  it  also  reduces  picric  acid  in  weakly  alkaline 
solution  to  picramic  acid,  which,  being  red,  furnishes  us  with  a  solution  the  strength 
of  which  can  be  estimated  colorimetrically. 

Quantitative  Estimation. — Although  the  presence  of  creatinine  in  the  urine  has  been 
known  for  many  years,  there  being  from  1  to  2  grams  of  it  in  the  twenty-four-hour 
urine,  little  progress  was  made  in  the  study  of  its  metabolism  because  of  the  absence 
of  a  reliable  method  for  its  estimation.  The  elaboration  by  Folin  of  a  colorimetric 
quantitative  method  for  creatinine,  depending  on  the  reduction  of  picric  acid,  has 
furnished  the  starting  point  for  the  modern  work  which  has  been  done.  To  estimate 
the  creatine  by  this  method,  it  is  usual  to  proceed  as  follows:  The  creatinine  content 
is  first  of  all  determined,  another  portion  of  urine  being  then  heated  with  acid  in  the 
autoclave  until  all  of  its  creatine  has  been  converted  into  creatinine.  A  second  de- 
termination of  creatinine  is  then  made,  and  the  difference  between  the  two  is  calculated 
as  creatine. 

It  should  be  pointed  out  that,  since  the  creatine  is  estimated  by  an  indirect  method, 
there  are  considerable  chances  for  inaccuracy.  Indeed,  it  has  been  shown  that  errors 
may  have  been  incurred  in  some  of  the  recent  work  on  account  of  the  fact  that  when 
aeetoacetic  is  present  in  the  urine  it  prevents  the  creatinine  from  developing  its 
full  reducing  power  on  picric  acid  in  the  cold,  so  that  when  subsequently  the  urine  is 
heated  with  acid  for  the  purpose  of  converting  the  creatine  into  creatinine,  the 
destruction  of  aeetoacetic  acid  allows  the  reducing  power  of  the  creatinine  to  develop 
to  full  intensity.  It  is  obvious  that  this  would  make  it  appear  as  if  creatine  had  been 
converted  into  creatinine.  It  is  particularly  in  the  urine  of  diabetic  patients,  in  which 
aeetoacetic  acid  is  present  that  mistakes  are  likely  to  be  made. 

Metabolism 

When  we  come  to  consider  the  metabolism  of  creatine  and  creatinine, 
we  find  that  there  are  remarkably  few  facts  definitely  known  concerning 
it.  The  average  amount  excreted  daily,  expressed  as  the  number  of  milli- 
grams of  creatinine  in  twenty-four  hours  per  kilogram  body  weight, 
is  known  as  the  creatinine  coefficient  (Shaffer).36  For  a  lean  person  this 
is  about  25  mg. ;  for  a  corpulent  person,  about  20  mg.,  the  difference  in- 
dicating that  muscle  mass,  and  not  body  weight,  is  the  important  factor 
determining  the  coefficient.  Further  evidence  that  this  relationship  ex- 
ists is  furnished  by  the  fact  that  in  the  muscular  atrophies  creatine  ex- 
cretion is  distinctly  below  normal.  It  must  be  the  mass  of  the  muscles 
rather  than  their  activities  that  is  the  determining  factor,  for  the  creatine 
excretion  does  not  become  increased  by  muscular  exercise. 

Influence  of  Food,  Age,  and  Sex.— Although  creatine  and  creatinine  are 
endogenous  metabolites,  it  must  be  remembered  that,  under  ordinary 
dietetic  conditions,  a  part  of  each  is  derived  from  these  substances  pres- 
ent in  the  food.  It  is  important  therefore  to  consider  the  conditions 
under  which  the  creatine  and  creatinine  in  the  food  appear  in  the  urine. 
Regarding  creatinine,  it  is  pretty  well  established  that  practically  all 
that  is  taken  with  the  food  reappears  as  creatinine  in  the  urine.  Shaffer 


I 


658  METABOLISM 

has,  for  example,  succeeded  in  recovering  76  per  cent  of  ingested  creat- 
inine  in  the  urine  excreted  during  twenty-one  hours  following  the  in- 
gestion  of  0.7  gm.  creatinine. 

The  conditions  for  the  excretion  of  creatine  are  more  complex.  It  is 
present  in  the  urine  of  children  in  considerable  amount,  but  in  that  of 
adults,  only  as  traces.  In  the  first  years  of  life  the  creatine  in  boys' 
urine  may  amount  to  one-half  of  the  total  creatine  and  creatinine,  but 
it  becomes  gradually  less  and  practically  disappears  at  about  seven 
years  of  age.  Girls,  on  the  other  hand,  continue  to  excrete  creatine  until 
about  puberty,  after  which,  although  ordinarily  absent,  it  reappears  in 
the  urine  at  each  monthly  sexual  cycle,  and  is  present  during  pregnancy 
fend  for  some  days  after  delivery.  Feeding  creatine  to  children  causes 
it  to  appear  in  the  urine,  accompanied  usually  by  a  slight  increase  in 
the  creatinine.  The  same  results  can  be  observed  in  women  during  the 
monthly  periods,  when  as  much  as  0.1  gm.  may  be  present,  and  during 
pregnancy.  Creatine  is  also  present  in  the  urine  of  most  if  not  all  of 
the  other  mammalia.  Some  of  these  facts  are  shown  in  the  following 
table: 


AGE 

CREATININE-N 

CREATINE-N  EXCRETED 
IN  24-HR.  URINE 

2 

0.025 

0.023 

3 

0.057 

0.022 

Boys 

5 

8 

0.112 
0.163 

0.025 
0.0 

11 

0.157 

0.0 

15 

0.378 

0.0 

5 

0.069 

0.005 

6 

0.032 

0.003 

Girls 

7 

0.157 

0.066 

10 

0.147 

0.020 

12 

0.201 

0.011 

(From  Mathews.) 

When  creatine  is  given  to  an  animal  that  has  been  kept  in  a  starved 
condition,  most  of  it  seems  to  disappear.  It  can  not  be  recovered  in  the 
urine  either  as  creatine  or  as  any  other  nitrogenous  metabolite.  It  seems 
to  functionate  more  as  a  food  than  as  a  useless  substance.  The  possi- 
bility that  some  of  it  can  be  destroyed  by  the  intestinal  bacteria  being 
admitted,  there  is  nevertheless  some  justification  for  the  view  that  the 
creatine  finds  a  useful  function  in  the  anabolic  process  of  the  muscles. 

Influence  of  Complete  and  Partial  Starvation. — Although,  as  we  have 
seen,  the  creatinine  excretion  remains  constant  when  the  amount  of  pro- 
tein in  the  diet  is  greatly  reduced,  yet  it  does  not  remain  constant  during 
complete  fasting  or  when  carbohydrates  are  entirely  withheld  from  the 
diet.  In  fasting  it  has  been  found  that  creatine  appears  in  place  of  the 
creatinine  which  has  disappeared,  so  that  if  both  creatine  and  creatinine 


THE    METABOLISM    OF   PROTEIN  659 

are  determined,  very  little  if  any  diminution  will  be  found  to  have  oc- 
curred. Fasting,  therefore,  causes  the  creatine  and  creatinine  metabol- 
ism of  the  adult  to  become  like  that  of  the  juvenile  metabolism.  As 
pointed  out  by  Mathews,  it  would  be  interesting  in  the  light  of  this  ob- 
servation to  see  whether  other  substances,  passed  in  the  urine  of  young 
animals  but  absent  in  that  of  the  adult,  would  reappear  in  the  urine  when 
the  animals  were  made  to  fast. 

A  similar  replacement  of  some  of  the  creatinine  by  creatine  appears 
when  carbohydrate  is  entirely  withheld  from  the  diet,  or  in  diabetic 
animals,  either  in  the  disease  diabetes  mellitus  in  man  or  in  the  experi- 
mental condition  induced  in  animals  by  giving  phlorhizin.  Unfortu- 
nately, in  a  considerable  part  of  the  work  that  has  been  done  on  this 
phase  of  the  subject  a  method  of  estimation  was  employed  which  did  not 
take  sufficiently  into  account  the  influence  of  acetoacetic  acid  on  the 
creatine  estimation;  but  even  after  allowing  for  this  possible  source  of 
error,  there  can  be  no  doubt  that  creatine  appears  in  the  urine  when 
carbohydrates  are  improperly  metabolized.  If  carbohydrates  are  given 
to  a  starving  animal,  for  example,  the  creatine  is  replaced  in  its  urine  by 
creatinine,  although  this  will  not  occur  when  either  protein  or  fat  is  fed. 
The  general  conclusion  which  may  be  drawn  from  these  observations  is 
that  carbohydrates  in  some  way  are  required  for  the  proper  conversion 
of  creatine  into  creatinine  in  the  animal  body  (Cathcart)37. 

Origin  of  Creatine  and  Creatinine 

Notwithstanding  the  large  amount  of  excellent  work  that  has  recently 
been  done  on  the  metabolism  of  creatine'  and  creatinine,  we  know  very  little 
indeed  regarding  the  origin  of  these  bodies  in  the  animal  organism.  It 
would  be  profitless  to  discuss  this  problem  to  any  great  extent,  but  a 
few  of  the  most  important  facts  so  far  established  may  be  of  interest  and 
of  value.  The  first  step  in  attacking  such  a  problem  is  to  compare  the 
amounts  present  in  the  various  organs  and  tissues,  in  the  blood,  and  in 
the  excreta.  Of  the  approximately  120  grams  of  creatine  and  creatinine 
in  the  body  of  an  average  adult,  a  very  large  proportion  is  in  the  muscles, 
the  voluntary  muscles  containing  the  largest  percentage,  the  heart  con- 
taining a  medium  percentage,  and  the  involuntary  (intestinal)  muscles 
containing  relatively  a  small  amount  (Mye'rs  and  Fine)38.  Next  to  the 
skeletal  muscles,  but  containing  more  than  the  involuntary  muscles, 
come  the  testes  and  brain.  The  liver,  pancreas,  thyroid,  kidneys,  spleen, 
etc.,  contain  traces.  The  blood  (human)  contains  about  1  mg.  creatinine 
per  100  c.c.  and  about  3  mg.  creatine,  the  former  being  equally  distrib- 
uted between  plasma  and  corpuscles,  whereas  the  latter  is  contained 
mainly  in  the  corpuscles.  (Hunter  and  Campbell,58) 


METABOLISM 

In  all  these  places  by  far  the  greatest  proportion  of  the  total  creatine- 
creatinine  exists  as  creatine,  which  is  exactly  the  reverse  of  the  condi- 
tion obtaining  in  the  urine  of  adults,  where  practically  all  is  excreted  as 
creatinine.  The  close  chemical  relationship  between  creatine  and  creat- 
inine,  considered  along  with  the  above  facts  regarding  their  quantitative 
distribution  in  the  body,  indicates  that  the  creatinine  of  the  urine  is  de- 
rived from  the  creatine  of  the  tissues.  The  question  is,  How  does  the 
creatine  come  to  be  converted  into  creatinine  f  Such  a  transformation  is 
probably  effected  by  many  of  the  tissues  of  the  body  and  certainly  by 
the  blood,  the  active  agency  in  all  cases  being  no  doubt  an  enzyme.  That 
the  blood  contains  such  an  enzyme  is  indicated  by  the  fact  that  creatine 
is  transformed  to  creatinine  by  blood  serum  more  quickly  than  it  is 
when  merely  dissolved  in  water.  Even  heated  blood  serum  possesses 
some  of  this  power.  The  liver  also  probably  brings  about  the  transfor- 
mation, as  has  been  shown  by  perfusion  experiments,  and  by  the  fact 
that  in  cases  of  phosphorus  or  hydrazine  poisoning  creatine  displaces 
creatinine  in  the  urine. 

The  problem  therefore  narrows  itself  down  to  the  question  of  the 
origin  of  creatine.  In  the  light  of  chemical  knowledge  there  are  several 
precursors  from  which  creatine  might  be  formed.  One,  for  example,  is 
arginine,  which  it  will  be  remembered  is  guanidine-amino-valerianic  acid 
(see  page  640).  By  oxidation  this  might  become  changed  into  guani- 
dine-amino-acetic  acid,  which  by  methylation  would  then  be  changed  into 
creatine.  That  such  a  process  of  methylation  may  actually  occur  in  the 
animal  body  is  definitely  known,  for  it  happens  when  such  substances  as 
pyridine  or  naphthalene  are  given  with  the  food.  They  appear  in  the 
urine  as  methyl  derivatives.  The  possibility  of  the  derivation  of  creatine 
by  methylation  of  arginine  is  suggested  by  the  result  of  the  injection 
into  ducks  of  arginine,  combined  with  such  substances  as  paraformalde- 
hyde  (Thompson59).  Even  in  this  case  however  the  results  are  not  very 
convincing.  The  closely  related  substance,  guanidine-acetic  acid,  when 
fed  to  animals  (rabbits)  also  causes  a  slight  increase  in  the  excretion  of 
creatine  (Jaffe),  and,  it  is  said,  an  increase  in  the  creatine  content  of  the 
muscle.  Even  in  this  case,  however,  by  far  the  largest  proportion  of  the 
administered  guanidine-acetic  acid  is  excreted  in  the  urine  unchanged. 

The  large  percentage  of  creatine  in  muscle  tissue  leads  one  to  expect 
that  some  relationship  must  exist  between  muscular  metabolism  and  the 
amount  of  creatine  present  either  as  such  in  the  muscles  or  as  creatinine 
in  the  urine.  Regarding  the  latter  point  it  is  definitely  established  that 
muscular  exercise  leads  to  no  increase  in  the  creatinine  excretion,  al- 
though it  is  said  that  such  an  increase  occurs  following  a  state  of  tonic 
muscular  contraction.  In  the  light  of  the  fact  already  stated  that  there 


THE    METABOLISM    OF   PROTEIN  661 

is  creatine  in  other  organs  than  the  muscles,  it  seems  probable  that  the 
substance  has  really  little  to  do  with  muscular  contraction  as  such,  but 
rather  is  concerned  in  some  way  in  the  formative  metabolism  of  the  cell, 
with  its  general  growth  or  maintenance.  Indeed,  it  is  a  question  whether 
creatine  is  an  actual  constituent  of  the  living  tissue.  It  may  rather,  as 
has  been  suggested  by  Folin,  be  a  postmortem  product,  represented  dur- 
ing life  by  creatinine. 

Creatine  appears  in  the  urine  in  phosphorus  poisoning,  in  carcinoma  of 
the  liver  and  during  postpartum  involution  of  the  uterus.  It  is  not  de- 
rived from  the  disappearing  uterine  muscle,  however,  for  creatinuria  also 
occurs  after  cesarean  section  with  removal  of  the  uterus.  Creatine 
elimination  is  not  an  index  of  cellular  destruction.  Muscular  fatigue  also 
leaves  the  creatine  content  of  muscle  unchanged.  In  late  stages  of 
nephritis,  creatinine  accumulates  in  the  blood  and  serves  as  an  index  of 
the  gravity  of  the  condition  (page  683). 


CHAPTER  LXXIII 
THE  METABOLISM  OF  PROTEIN  (Cont'd) 

UNDETERMINED  NITROGEN  AND  DETOXICATION 
COMPOUNDS 

In  the  present  chapter  we  shall  refer  briefly  to  the  groups  of  urinary 
substances  styled  undetermined  nitrogenous  compounds  and  to  the  com- 
pounds that  are  excreted  in  the  urine  as  the  result  of  the  combination  in 
the  body  of  certain  toxic  bodies  with  chemical  substances  that  render 
them  harmless  (detoxication  compounds). 

Undetermined  Nitrogen 

Included  under  undetermined  nitrogen  are  amino  acids,  peptides  and 
basic  substances.  The  amount  of  amino  acids  and  peptides  in  normal 
urine  is  very  small  but  may  become  considerable  in  disease,  especially 
of  the  liver,  when  leucine  and  tyrosine  may  appear.  The  presence  of 
traces  of  amino  acid  and  peptone  in  normal  urine  is  to  be  expected, 
for  although  the  actual  concentration  of  amino  acids  in  the  blood  is 
never  very  great,  a  certain  leakage  of  amino  acids  must  occur  into  the 
urine. 

The  peptide  is  sometimes  known  as  oxyproteic  acid.  It  becomes  dis- 
tinctly increased  in  phosphorus  poisoning  and  in  such  conditions  as  are 
accompanied  by  excessive  protein  metabolism.  The  basic  constituents 
include  such  substances  as  trimethylamine,  ethylamine,  putrescine  and 
cadaverine  (page  536),  and  there  are  probably  many  more  of  a  similar 
nature.  Many  of  these  substances  are  similar  to  the  so-called  ptomaines 
found  in  meat,  etc.,  and  they  have  been  called  the  ptomaines  of  urine, 
from  which  they  can  be  isolated  by  rendering  the  urine  alkaline  and 
shaking  out  with  ether.  It  is  probably  to  the  presence  of  these  sub- 
stances that  urine  mainly  owes  its  toxic  action. 

The  Detoxication  Compounds 

Certain  nocuous  substances  are  produced  in  the  intestine  during  the 
digestive  process  (see  page  535),  and  others  may  result  from  the  meta- 
lic  processes  in  the  tissues.  To  guard  against  the  harmful  action  of 
these  substances  on  the  organism,  they  become  detoxicated  in  various 

662 


THE    METABOLISM   OF   PROTEIN  663 

ways,  mainly  by  forming  inert  compounds  with  other  substances,  par- 
ticularly with  glycocoll,  sulphuric  acid  or  glycuronic  acid.  The  com- 
pound thus  formed  is  then  excreted  in  the  urine. 

Hippuric  Acid, — Glycocoll  is  used  mainly  to  detoxicate  the  benzoic 
acid  which  results  from  the  oxidation  of  the  aromatic  substances  pres- 
ent in  large  quantities  in  vegetable  food  and  fruit  (particularly  in  cran- 
berries). Some  benzoic  acid  may  also  be  produced  by  the  breakdown 
of  the  aromatic  group  of  the  protein  molecule;  phenylalanine,  for  ex- 
ample, gives  rise  to  benzoic  acid  by  bacterial  decomposition.  The  com- 
pound formed  is  hippuric  acid,  this  name  indicating  that  it  is  present  in 
large  quantities  in  the  urine  of  the  horse,  as  it  is  also  in  the  urine  of 
all  herbivorous  animals. 

Hippuric  acid  is  benzoyl-glycine  (C6H5.CO.NH.CH2COOH),  and  it 
can  readily  be  produced  in  the  laboratory  by  bringing  together  benzoyl 
chloride  with  glycocoll,  thus: 


C6H5 .CO  :  Cl  +  H •  HN . CH2COOH  =  C6H5CO . NH . CH2COOH  +  HC1. 
(benzoyl  chloride)       (glycocoll)  (hippuric  acid) 

Under  ordinary  dietetic  conditions  only  a  trace  of  hippuric  acid  is 
present  in  the  urine  of  man,  but  much  larger  quantities,  2  grams  a  day 
for  example,  may  appear  when  the  diet  contains  a  large  proportion  of 
fruit  or  vegetables.  It  is  not  known  to  undergo  any  characteristic  varia- 
tions in  disease.  The  benzoic  acid  which  is  contained  in  certain  canned 
foods  as  preservative  also  combines  in  the  body  with  glycocoll,  so  that 
any  toxic  effect  which  it  might  produce  is  practically  negligible.  There 
is  certainly  no  very  evident  reason  why  canned  foods  containing  benzoic 
acid  should  be  tabooed,  for  in  so  far  as  the  benzoic  acid  is  concerned,  they 
can  be  no  more  toxic  than  a  diet  composed  largely  of  vegetables  and 
fruit. 

This  detoxication  of  benzoic  acid  requires  the  presence  in  the  organ- 
ism of  a  constant  supply  of  glycocoll,  which,  it  will  be  recalled, 
is  the  lowest  in  the  series  of  amino  acids,  being  aminoacetic  acid 
(CH2NH2COOH).  It  is  present  in  greatest  amount  in  the  protein  of  the 
connective  tissues.  It  is  said,  however,  that  not  more  than  from  2  to 
3.5  per  cent  of  glycocoll  is  available  in  the  proteins  of  the  body.  Al- 
though this  amount  of  glycocoll  would  amply  suffice  to  detoxicate  the 
benzoic  acid  produced  by  the  metabolism  of  the  food  in  carnivora,  it 
is  quite  inadequate  for  this  purpose  in  the  case  of  herbivora,  and  the 
question  naturally  presents  itself  as  to  where  the  glycocoll  in  these 
animals  comes  from.  It  is  said,  for  example,  that  of  the  total  nitrogen 
excretion  in  herbivora  50  per  cent  may  appear  as  glycocoll  under  cer- 
tain conditions.  These  facts  along  with  those  gained  by  observations  on 


664  METABOLISM 

the  growth  curves  (see  page  610)  indicate  that  the  organism  is  capable  of 
producing  new  glycocoll  for  itself,  and  it  is  interesting  to  consider  how 
this  glycocoll  may  be  derived.  A  very  probable  source  is  by  synthesis 
between  ammonia  and  glyoxylic  acid  (CHO.  COOH).  That  glyoxylic  acid 
or  its  aldehyde,  glyoxal,  is  readily  produced  during  metabolism  from  car- 
bohydrates and  that  ammonia  is  always  available  would  seem  to  lend 
some  support  to  this  view  (see  page  698).  The  synthesis  of  glycocoll 
from  glyoxal  and  ammonia  occurs  thus: 

H.COCHO  +  NH3  —  CH,NH2COOH. 

(glyoxal)  (glycocoll) 

The  linking  up  of  glycocoll  with  benzoic  acid  occurs  in  various  organs, 
particularly  the  kidneys  and  the  liver.  An  isolated  perfused  preparation 
of  the  kidney  produces  hippuric  acid  provided  benzoic  acid  is  added  to 
the  perfusion  fluid,  and  the  latter  also  contains  an  abundance  of  oxy- 
gen, which  is  best  secured  by  using  defibrinated  arterialized  blood  in- 
stead of  artificial  serum  (Locke's  solution).  The  necessity  of  a  plentiful 
supply  of  oxygen  is  further  shown  by  the  fact  that,  if  the  hemoglobin  of 
the  blood  is  rendered  incapable  of  carrying  02  by  bubbling  carbon  mon- 
oxide gas  through  it,  no  synthesis  of  hippuric  acid  will  result  from  per- 
fusing the  blood  through  the  kidney.  The  kidneys  are  not  the  only  site 
of  this  synthesis,  since  hippuric  acid  is  still  formed  after  nephrectomy, 
in  both  carnivorous  and  herbivorous  animals.  It  has  been  isolated  from 
the  liver  of  nephrectomised  dogs  after  injection  of  glycocoll  and  benzoic 
acid  (Kingsbury  and  Bell60)  ;  and  after  damaging  the  liver  cells  by  poi- 
soning with  hydrazin,  in  dogs,  it  has  been  found  that  the  excretion  of 
hippuric  acid  falls  decidedly.  Hydrazin  does  not  act  on  the  kidney 
cells.61 

The  actual  chemical  process  by  which  the  synthesis  occurs  (de- 
hydration) is  similar  to  that  by  which  polypeptides  are  formed  by  the 
union  of  amino  acids,  or  creatinine  from  creatine. 


(C6H5co  ;OH+H;  HNCH2coon). 

Glycocoll  may  be  used  for  detoxicating  other  substances  than  benzoic 
acid,  particularly  cholic  acid,  forming  the  glycocholic  acid  of  the  bile 
(see  page  528)  and  phenylacetic  acid.  In  birds  the  benzoic  acid  be- 
comes combined  with  diamino-valerianic  acid  or  orni thine  (NH2  -  CH2  - 
CH2-CH2-CH-NH2-COOH)  in  place  of  glycocoll,  so  that  in  the  urine 
of  these  animals  in  place  of  hippuric  acid  a  compound  called  ornithuric 
acid  occurs. 

It  is  of  importance  to  point  out  here  that  this  pairing  of  aromatic  toxic 
substances  with  certain  of  the  metabolic  products  of  the  organism  has 


THE    METABOLISM    OF    PROTEIN  665 

frequently  been  found  an  excellent  experimental  method  for  demon- 
strating the  presence  of  intermediary  metabolic  substances  that  other- 
wise would  not  have  appeared  in  the  excreta.  These  substances  are 
thus  diverted  from  their  normal  course  in  metabolism  so  as  to  form 
neutralization  or  detoxication  compounds.  Glycuronic  acid  is  an  example. 

Ethereal  Sulphates  and  Glycuronates. — The  other  substances  used  for 
detoxication  purposes  are  sulphuric  and  glycuronic  acids.  Phenol,  and 
its  derivative  cresol,  after  being  absorbed  from  the  intestine,  in  the 
contents  of  which  they  are  produced  by  the  bacterial  decomposition  of 
protein  (see  page  535)  become  combined  in  the  body,  probably  in  the 
liver,  with  sulphuric  acid  or  with  glycuronic  acid  to  form  the  sulphate 
or  glycuronate.  The  aromatic  sulphate  further  combines  with  potassium 
to  form  the  so-called  ethereal  sulphates,  as  which  the  substance  is  excreted 
in  the  urine.  A  small  amount  of  phenol  may  however  appear  in  the 
urine  unchanged.  As  we  have  already  seen,  the  sources  of  the  phenol 
in  the  intestine  are  tyrosine  and  phenylalanine  (see  page  564),  and 
since  these  ammo  acids  are  also  present  in  the  tissues,  it  might  be  sup- 
posed that  some  of  the  phenol  sulphate  of  potassium  present  in  the 
urine  could  come  from  the  tissues.  It  is  usually  assumed,  however,  that 
derivation  from  the  tissues  does  not  occur. 

Another  ethereal  sulphate  is  indoxyl  sulphate  of  potassium,  which  re- 
sults from  the  absorption  into  the  blood  of  the  indole  and  skatole  pro- 
duced by  intestinal  putrefaction  from  tryptophane  (see  page  536). 
Immediately  after  absorption  indole  is  oxidized  to  indoxyl,  which  then 
combines  with  sulphuric  acid  and  with  potassium  to  form  indoxyl  sul- 
phate of  potassium,  which  is  the  well-known  indican  of  the  urine.  As 
in  the  case  of  phenol  sulphate  of  potassium,  none  of  the  urinary  indican 
seems  to  come  from  the  normal  metabolism  (of  the  tryptophane)  of  the 
tissue  proteins.  It  is  a  much  more  reliable  indicator  of  the  extent  of  intes- 
tinal putrefaction  than  is  phenol  sulphate  of  potassium,  but  it  also  becomes 
increased  in  amount  during  putrefaction  in  the  body  itself,  as  for  example 
in  abscess  formation. 

The  amount  of  indican  in  the  urine  may  be  roughly  gauged  by  oxi- 
dizing the  urine  by  means  of  hypochlorite  and  then  shaking  out  with 
phloroform.  If  the  resulting  extract  is  more  than  light  blue  in  color, 
it  indicates  excessive  putrefaction.  A  negative  test  does  not  neces- 
sarily mean  that  intestinal  putrefaction  is  absent,  but  a  markedly  positive 
test  always  indicates  that  it  is  occurring.  Skatole,  the  methyl  deriva- 
tive of  indole,  may  undergo  similar  processes  and  appear  in  the  urine 
during  excessive  intestinal  putrefaction.  Its  presence  in  the  blood  some- 
times confers  on  the  breath  a  distinctly  fecal  odor,  for  this  body,  as  its 
name  indicates,  is  that  to  which  the  odor  of  the  feces  is  due. 


666 


METABOLISM 


Glycuronic  acid,  the  other  substance  used  for  detoxication  processes, 
is  of  the  nature  of  a  dextrose  molecule  with  the  one  end-group  oxidized 
to  carboxyl  (CHO-  (CHOH)4-  COOH).  It  is  probably  produced  under 
normal  processes  of  metabolism  in  the  animal  body,  but  is  destroyed 
except  when  such  poisonous  substances  as  camphor,  chloral  hydrate  or 
certain  aromatic  alcohols  are  given,  when  it  is  used  for  the  purpose  of 
detoxicating  them.  The  resulting  glycuronates  have  reducing  powers 
and  may  be  confused  with  glucose  when  present  in  large  amount.  Gly- 
curonates may  be  distinguished  from  glucose  in  the  urine  (1)  because 
they  are  levorotatory,  and  (2)  because  they  do  not  ferment.  The  free 
acid  itself,  however,  is  dextrorotatory. 


CHAPTER  LXXIV 

URIC  ACID  AND  THE  PURINE  BODIES 

Introductory. — The  participation  by  highly  trained  organic  chemists 
in  the  investigation  of  biochemical  problems  has  brought  our  knowledge 
of  the  history  of  the  purine  substances  in  the  animal  body  from  a  state 
of  chaos  and  guesswork  to  one  of  system  and  scientific  accuracy.  The 
peculiar  solubility  reactions  of  uric  acid  and  its  salts  and  the  discovery 
of  urates  in  gouty  deposits  served  to  make  uric  acid  metabolism  one  of 
the  earliest  research  problems  in  both  the  medical  clinic  and  the  bio- 
chemical laboratory,  but  the  earlier  results  were  practically  valueless, 
partly  because  they  were  inaccurate  and  partly  because  their  interpretation 
was  impossible  in  the  absence  of  even  the  most  elementary  facts  concerning 
the  chemistry  of  uric  acid. 

Before  any  real  progress  was  possible,  a  clean  sweep  had  to  be  made 
of  all  the  old  speculations  and  hypotheses,  such  as  that  dignified  by  the 
high-sounding  name  of  " uric-acid  diathesis,"  and  a  foundation  of  ac- 
curate chemical  knowledge  established.  This  foundation  is  now  wonder- 
fully complete,  and  a  superstructure  of  biochemical  fact  is  already 
beginning  to  grow  upon  it.  In  the  present  chapter  we  shall  examine 
some  of  the  most  important  contributions  that  have  made  this  progress 
possible, 

As  in  the  study  of  any  other  problem  of  metabolism,  we  must,  however, 
make  ourselves  familiar  with  the  main  facts  concerning  the  chemistry 
of  the  purine  bodies  and  of  the  tissue  constituents  into  the  composition 
of  which  they  enter,  before  proceeding  to  the  more  strictly  biological 
aspect  of  the  subject. 

The  Chemical  Nature  of  the  Purines 

By  an  examination  of  the  empirical  formulas  of  the  purines  of  biochemical  interest, 
it  will  be  observed  that  they  are  all  derivatives  of  a  substance  purine,  which  although 
in  itself  of  no  importance  is  interesting,  since  it  serves  as  the  basic  substance  from 
which  the  others  are  derived.  The  list  is  as  follows: 

Purine         .  C6H4N4 

Hypoxanthine  C5H4N4O  Monoxypurine         f 

Adenine       .  C5H3N4.NH2      Ammo-purine         I  Purine 

Xanthine     .  C5H4N4O2  Dioxypurine  1  bases. 

Guanine       .  C5H3N4O.NH2  Amino-oxypurine  1     ' 

Uric  acid    .  C5H4N4O3  Trioxypurine 

The  first  oxidation  product  of  purine  is  hypoxanthine,  which  has  long  been  known 
as  a  constituent  of  meat  extract.  Adenine,  the  amino  derivative  qf  hypoxanthine, 

667 


668 


METABOLISM 


occurs  iii  combination  with  other  substances  in  the  nuclear  material.  The  second  oxi- 
dation product  is  xanthine  and  its  amino  derivative,  guanine.  They  occur  in  the  same 
places  as  hypoxanthine  and  adenine.  The  highest  oxidation  product  of  all  is  the  well- 
known  urinary  constituent,  uric  acid,  which  may  therefore  be  chemically  designated  as 
trioxypurine.  In  addition  to  the  purines  of  animal  origin,  there  are  also  certain  ones  of 
vegetable  origin — the  methyl  purines,  which  exist  as  the  alkaloids  of  tea  and  coffee — 
namely,  caffeine,  theobromine,  and  theine. 

To  understand  the  chemical  structure  of  this  group  of  substances,  it  is  perhaps 
simplest  to  start  with  that  of  uric  acid.  This  consists  essentially  of  two  urea  molecules 
linked  together  by  a  central  chain  of  three  carbon  atoms,  as  will  be  evident  from  the 
accompanying  structural  formula : 


HN-CO 

-NH 


I      I!        \ 

CO 

HN-C-NH 

(urea)       (urea) 

(central  chain) 

This  structure  can  be  shown  by  methods  both  of  decomposition  and  of  synthesis. 
When  uric  acid  is  decomposed  by  oxidizing  it  with  nitric  acid,  it  yields  urea  and  a 
residue  called  alloxan;  or  it  can  be  synthetized  from  urea  and  trichlorlactamide,  a 
derivative  of  lactic  acid,  w^hich  it  will  be  remembered  contains  three  carbon  atoms. 
The  changes  involved  in  this  synthesis  will  be  made  clear  by  examination  of  the  ac- 
companying structural  formula,  in  which  the  manner  of  production  of  the  by-products 
of  the  reaction  (NH  ,  HoO  and  HC1)  are  shown  by  dotted  lines: 


NH.    !  H  NH..  :  -  C  =  O 


CO 
\ 


\ 


\ 
\ 

(urea)     NH.         H  Cl    I 


-C       |   OH  H       NH 


\ 

CO 


C-    ;    Cl  H          NH     (urea) 


(trichlorlactamide) 


By  milder  oxidation  by  means  of  potassium  permanganate  in  the  cold,  uric  acid  be- 
comes quantitatively  converted  to  allantoine: 


CSH4N403  +  H20  +  O  :=C4H6N403  +  CO2 
(uric  acid)  (allantoine) 

The  importance  of  this  transformation  lies  in  the  fact  that  in  most  animals,  man  and 
the  higher  apes  being  exceptions,  uric  acid  is  thus  decomposed  in  the  animal  body. 
The  structural  formulas  for  the  other  purine  bodies  in  relationship  with  those  of 
pnrine  and  uric  acid  are  given  below. 


URIC    ACID    AND    THE    PURINE    BODIES 


Purine  itself  has  the  following  structural  formula: 


H2  - 


H 


S  -  NH? 


\ 


1- 


C8-H 


(  For  convenience  of  description  the  atoms  in  purine  are  numbered  as  shown.) 


HN-C=O 

I       I 
H-C     C-NH 


HN-C=O 
0=0      C-NH 


\ 

/ 


C-H 


N-C-     N 
(hypoxanthine)        (6-oxypurine) 

N  =  C-NH2 


I 

HN-C- 
(xanthine) 


\ 

/ 


C-H 


(2-6-oxypurine) 


I       I 
H-C     C-NH 

I 


HN-C=0 

I        I 
H,N  =  0      C-NH 


C-H 


N-C  -     X 


/ 


N-C  -    N 


\ 
/ 


C-H 


(adenine)      (6-amino-purine)      (guanine)       (2-amino-6-oxypurine) 
HN-CO 


00 

I 


C-NH 


\ 


CO 


HN-  C  -NH 

Uric  acid  (2-6-8-trioxypurine) 

The  substances  with  which  the  purine  bases  are  most  closely  related  are  the  pyrir 
inidine  bases.     Three  of  these  are  known: 


thymine     (NH-CO 

CO     C.CH8 

I      !! 

NH-CH 


cytosine  (  N  =  C-NH2 

I 
CO     CH 

I        II- 
NH-CH)  ; 


and   uracil    (NH-CO 

I          I 
CO     .CH 


NH-CH). 


From  an  examination  of  the  structural  formulas,  it  will  be  seen  that  they  are  more 
or  less  related  to  purine  (having  one  of  the  urea  radicles  omitted),  although  it  can 
scarcely  be  doubted  that  they  exist  as  separate  constituents  of  the  nucleic  acid  group 
in  the  animal  body,  and  are  not  derived  from  purine.  They  are  primary  products. 

The  Chemical  Nature  of  the  Substances  in  Which  Purine  and 
Pyrimidine  Bases  Exist  in  the  Animal  Body. — In  general  it  may  be  said 
that  the  amino  purines — adenine  and  guanine — together  with  the 
pyrimidine  bases — thymine  and  cytosine — occur  combined  with  phos- 
phoric acid  and  a  carbohydrate  in  the  various  nucleic  acids,  each  of  which 


670  METABOLISM 

is  again  combined  with  some  simple  protein  to  form  nuclein,  the  essen- 
tial constituent  of  the  chromatin  of  the  nucleus.  One  of  the  oxypurines, 
hypoxanthine,  may  also  exist  combined  with  phosphoric  acid  and  carbo- 
hydrate to  form  a  substance  present  in  muscle  and  known  as  inosinic 
acid. 

The  simplest  form  of  nucleic  acid  is  that  known  as  guanylic,  which  is 
found  in  certain  organs  (liver,  pancreas,  etc.)  side  by  side  with  the  more 
complex  variety.     It  consists  of  phosphoric  acid,  a  pentose   (5  C-  atom 
sugar)    and    the    amino    purine,    guanine.      The    pentose    which    can    be 
detected  in  these   organs  is  apparently  derived   solely   from   guanylic 
acid.    The  more  complex  form  of  nucleic  acid,  and  probably  that  present 
in  all  nuclei,  is  composed  of  phosphoric  acid,  a  hexose  (in  animal  cells) 
or  a  pentose  (in  vegetable  cells),  the  two  amino  purines,  adenine  and 
guanine,  and  the  two  pyrimidine  bases,  cytosine  and  thymine. 
I.    Nucleic  acid  may  therefore  be  considered  as  a  compound  of  polyphos- 
Vbhoric  acid,  containing  carbohydrate  groups,  which  serve  to  link  the  phos- 
phoric acid  molecules  to  those  of  purine  and  pyrimidine. 

It  has  been  found  necessary  to  introduce  certain  terms  to  designate 
the  different  parts  of  the  nucleic  acid  molecule ;  thus,  the  whole  molecule 
is  called  a  tetranucleotide,  composed  of  four  mononucleotide  molecules, 
each  of  which  consists  of  a  phosphoric  acid  molecule  plus  a  micleosidey 
which  again  is  composed  of  a  purine  or  pyrimidine  nucleus  attached  to 
pentose  or  hexose.  The  nucleoside  is  so  named  because  it  is  similar  in 
structure  to  a  glucoside. 

Apart  from  differences  in  the  carbohydrate  group,  it  appears  that 
there  is  a  close  similarity  in  the  structures  of  nucleic  acids  from  dif- 
ferent cells.  This  would  indicate  a  common  function  for  them  all,  which 
may  be  either  of  a  structural  or  of  a  physiological  nature ;  that  is,  nucleic 
acid  may  have  to  do  with  the  sustentacular  material  that  builds  the 
nucleus,  or  it  may  have  to  do  with  some  physiological  function  common 
to  all  cells,  such  as  irritability,  or  growth,  or  respiration.  If  nucleic 
acid  is  merely  a  sustentacular  material,  then  the  study  of  the  behavior 
of  chromosomes  and  chromatine  in  cells  can  not  have  the  significance 
that  it  would  have  were  nucleic  acid  concerned  in  the  more  vital  activ- 
ities of  the  nucleus.  All  the  so-called  nuclear  stains  owe  their  specific 
staining  properties  to  the  fact  that  they  are  of  a  basic  nature  and  com- 
bine with  nucleic  acid.  Until  we  know  more  definitely  what  the  exact 
function  of  nucleic  acid  may  be,  it  is  unwise  to  place  too  much  weight 
on  the  behavior  of  the  chromosomes  in  cytologic  researches. 

By  studying  the  behavior  of  cells  (ameba)  from  which  the  nucleus 
was  removed,  it  has  been  found  that  the  process  of  reproduction  and 
growth  alone  are  affected.  The  other  functions  proceed  normally.  In 


URIC   ACID   AND   THE   PURINE   BODIES  671 

this  connection  it  is  interesting  to  note  that  much  evidence  is  accumulat- 
ing to  show  that  the  respiratory  functions  of  cells  are  linked  up  with 
the  presence  in  the  cytoplasm  of  bodies  called  mitochondria  composed  of 
phospholipin  and  protein.  (Lynch.61) 

The  History  of  Nucleic  Acid  in  the  Animal  Body.—  We  shall  first 
of  all  study  the  manner  in  which  nucleic  acid  may  be  broken  down.  As 
is  to  be  expected  from  its  complex  structure,  various  types  of  enzymes 
are  concerned  in  this  process.  The  first  to  act  are  known  as  the  nucle- 
ases.  They  split  the  tetranucleotide  molecule  into  two  dinucleotides, 
which  immediately  afterward  split  further  into  mononucleotides.  Four 
nucleotides,  two  of  purine  and  two  of  pyrimidine,  are  thus  formed  from 
each  molecule  of  nucleic  acid.  Each  nucleotide  molecule  may  now  un- 
dergo decomposition  in  one  of  two  w^ays:  (1)  either  by  the  splitting  off 
of  phosphoric  acid,  leaving  a  nucleoside  (guanosine  or  adenosine),  or 
(2)  by  the  splitting  off  of  both  phosphoric  acid  and  carbohydrate,  leaving 
free  purine  bases.  Nucleases  have  been  found  which  specifically  effect 
either  of  these  decompositions,  and  they  have  been  called  phospho- 
nucleases*  (1),  and  purine-nucleases  (2),  respectively.  In  the  decompo- 
sition of  nucleic  acid  all  of  the  four  purine  compounds  —  guanine,  guano- 
sine,  adenosine  and  adenine  —  may  be  formed.  This  is  illustrated  in  the 
accompanying  schema,  in  which  the  nucleic  acid  is  represented  as  a 
purine  nucleotide: 


NudeicAcid  (without  the  pyrimidine  group) 

W^  *(2) 
ases)  \ 

\  \ 

denosine  8—  >  Adeni 


(1) 
(Action  of  nucteases) 


Guanine  4-(7)  Guanosine  Adenosine  (8)—  >  Adenine 

(4)  (5)  (6) 

(Action  of  deaminiaing  enzymes) 

>Jr  ^ 

Xanthosine  Inosine 

(9)  (Action  of  hydrolyzing  enzymes)  (10) 
"*i£  . 

Uric  Acid*-  (  11  )  Xanthine  <  -  (  11  )  —  -  -  -+  Hypoxanthine 

(Action  of  xanthine  oxidase) 

(Jones.) 

The  next  step  in  the  disintegration  process  is  that  the  amino  group 

is  removed  and  the  corresponding  oxypurine  is  produced.    To  bring  this 

|  about,  there  exists  a  specific  deaminizing  enzyme  for  each  of  the  above 

•amino  compounds,  and  each  enzyme  is  named  according  to  the  exact 

amino  purine  upon  which  it  acts;  thus,  guanase  (3),  guanosine-deaminase 

(4),  adenosine-deaminase  (5),  and  adenase  (6)  have  all  been  identified. 

*The  numbers  refer  to  the  enzymes  indicated  in  the  schema. 


672  METABOLISM 

The  free  base  may  then  be  split  off  from  the  nucleosides  by  specific 
hydrolyzing  enzymes  (7)  (8)  (91)  (10). 

The  joint  action  of  these  enzymes  leads  to  the  formation  of  oxypurines, 
xanthine  and  hypoxanthine,  which  are  oxidized  to  uric  acid  by  xanthine- 
oxidase  (11). 

In  man  and  the  anthropoid  apes  uric  acid  is  the  end  product  of  the 
above  changes,  but  in  other  mammals  most  of  the  uric  acid  is  further 
oxidized  into  allantoine.  It  has  also  been  found,  except  in  man  and  the 
chimpanzee,  that  extracts  of  organs  such  as  the  liver,  are  capable  of 
decomposing  uric  acid  into  allantoine.  The  identification  of  these  specific 
enzymes  is  sought  by  a  determination  of  the  free  amino-purine  bases 
and  the  phosphoric  acid  produced  by  allowing  an  aqueous  extract  of 
the  tissue  in  question  to  act  on  nucleic  acid  (of  yeast)*  at  body  tempera- 
ture. Another  portion  of  the  digested  mixture  is  then  hydrolyzed  by 
means  of  boiling  sulphuric  acid  and  the  constituents  again  determined. 
From  the  results  it  is  often  possible  to  draw  conclusions  as  to  the  exact 
nature  of  the  enzymes  present. 

The  most  remarkable  outcome  of  this  work  has  been  to  show  that 
the  distribution  of  the  enzymes  is  not  the  same  in  the  tissues  and  organs 
of  different  animals.  Very  briefly,  some  of  the  most  important  results 
that  have  so  far  been  obtained  are  as  follows:  Gastric  and  pancreatic 
juices  do  not  contain  a  trace  of  any  of  the  enzymes.  Intestinal  juice, 
on  the  other  hand,  contains  a  nuclease  capable  of  splitting  the  poly- 
nucleotides  into  mononucleotides.  The  two  pyrimidiiie  nucleotides  split 
off  do  not  undergo  further  change,  but  the  purine  nucleotides  are  con- 
verted into  nucleosides  (the  enzyme  being  designated  "nucleotidase"). 
Extract  of  the  intestinal  mucosa,  besides  having  the  same  action  as  the 
intestinal  juice,  can  also  decompose  the  purine,  but  not  the  pyrimidine 
nucleosides,  into  carbohydrate  and  purine  groups  (specific  action  of 
"nucleosidase").  A  similar  action  is  produced  by  extracts  of  kidney, 
heart  muscle,  and  liver.  Blood  serum,  hemolyzed  blood,  and  extract  of 
pancreas,  on  the  other  hand,  are  capable  of  carrying  the  decomposition 
only  as  far  as  the  mononucleotides. 

Regarding  the  other  enzymes  mentioned  in  the  above  list,  it  is  im- 
portant to  note  that  they  appear  at  different  stages  in  embryonic  develop- 
ment, and  that  their  distribution  varies  considerably  in  different  species 
of  adult  animal,  the  spleen,  liver,  thymus,  and  pancreas  containing  them 
most  abundantly.  The  distribution  of  enzymes  in  the  organs  of  the 
monkey  resembles  that  in  the  lower  animals  considerably  more  than  it 
does  that  in  man.  Some  remarkable  facts  have  come  to  light  regarding 
guanase  and  adenase,  particularly  that  guanase  is  deficient  in  the  organs 

*Yeast  nucleic  acid  is  used  because  it  is  less  resistant  to  disintegration  than  thymic  nucleic  acid. 


URIC    ACID   AND    THE    PURINE   BODIES  673 

of  the  pig,  in  the  urine  of  which  animal  it  has  also  been  found  that  the 
purine  bases  are  in  excess  of  the  uric  acid.  This  absence  of  guanase 
no  doubt  accounts  for  the  fact  that  deposits  of  guanine  may  occur  in  the 
muscles,  and  that  these  may  be  so  large  as  to  constitute  the  condition 
known  as  guanine  gout  found  in  this  animal.  Adenase,  on  the  other 
hand,  is  absent  from  the  organs  of  the  rat,  which  again  corresponds  with 
the  fact  that,  when  adenine  is  injected  subcutaneously  into  these  ani- 
mals, it  undergoes  oxidation  without  the  removal  of  its  amino  group. 
In  the  human  organism,  adenase  appears  to  be  absent  from  all  of  the 
organs,  whereas  guanase  is  present  in  the  kidney,  lung  and  liver,  but 
not  in  the  pancreas  or  spleen.  Xanthine-oxidase  exists  only  in  the  liver. 

The  distribution  of  uricase  is  perhaps  the  most  interesting.  It  is  pres- 
ent in  most  of  the  lower  animals.  On  account  of  its  presence  extracts 
of  the  liver,  spleen,  etc.,  in  all  breeds  of  dogs,  with  the  exception  of 
Dalmatians,  rapidly  destroy  uric  acid;  and  practically  no  uric  acid 
when  injected  subcutaneously  can  be  recovered  unchanged  in  the  urine, 
but  appears  as  allantoine.  Uricase,  however,  is  absent  in  man.  This  has 
been  demonstrated  by  finding  (1)  that  when  uric  acid  is  injected  sub- 
cutaneously, nearly  all  of  it  reappears  in  the  urine,  and  (2)  that  uric  acid 
is  not  destroyed  when  extracts  of  the  organs  are  incubated  with  uric 
acid  or  its  precursors  at  body  temperature.  It  must  of  course  be  kept 
in  mind  that,  although  the  uric  acid  is  thus  shown  not  to  be  destroyed 
in  vitro,  it  may  nevertheless  be  destroyed  in  the  living  animal. 

The  importance  of  the  above  described  results  rests  in  the  fact  that 
from  them  we  may  hope  to  be  able,  ultimately,  to  state  exactly  in  what 
rgans  and  tissues  the  intermediary  metabolic  processes  concerned  in 
ucleic  acid  metabolism  occur.    The  work  at  the  present  time  is  of  spe- 
cial significance,  since  it  represents  one  type  of  evidence  which  we  must 
have  before  we  can  trace  exactly  every  step  in  the  metabolism  of  any 
ther  biochemical  substance. 

The  absence  of  uricase  from  the  tissues  of  man  places  him  in  a  unique 
osition  with  regard  to  the  metabolism  of  nucleic  acid,  and  renders  the 
vestigation  of  the  problem  particularly  difficult,  since  investigations 
n  the  usual  laboratory  animals  are  useless.     Recently,  however,  S.  R. 
enedict  has  discovered  that  the  Dalmatian  breed  of  dog — also  known 
as  the  carriage  dog,  and  having  a  spotted  or  mottled  skin — has  a  purine 
metabolism  like  that  of  man.4    When  fed  on  food  containing  no  purine 
substances,  a  dog  of  this  breed  excretes  large  quantities  of  uric  acid,  and 
when  the  latter  substance  is  injected  subcutaneously,  it  is  eliminated 
quantitatively  as  such  in  the  urine.    We  shall  see  later  how  experiments 
on  this  animal  have  been  made  use  of  in  the  investigations  of  problems 
of  purine  metabolism  as  applied  to  man.    In  all  other  animals  most  of  the 


674  METABOLISM 

uric  acid  is  oxidized  to  allantoine  before  being  excreted.  The  degree  to 
which  this  occurs  varies  between  79  and  98  per  cent  of  the  uric  acid  in 
different  species.  This  has  been  called  the  uricolytic  index  (Hunter  and 
Givens42) . 

The  Balance  between  Intake  and  Output  of  Purine  Substances  under 
Various  Physiological  and  Pathological  Conditions. — The  main  purine  ex- 
cretory product  in  man  is  uric  acid,  but  there  is  also  a  certain  amount 
of  purine  bases.  The  presence  of  uric  acid  in  urine  has  attracted  at- 
tention for  decades  in  medical  investigation,  because  of  the  relative 
ease  with  which  it  can  approximately  be  determined  quantitatively,  and 
because  of  the  well-known  fact  that  it  may  be  responsible  for  certain 
diseases,  such  as  gout,  when  it  accumulates  in  the  tissues  in  an  insoluble 
form.  On  a  diet  containing  meat,  or  more  particularly  on  one  con- 
taining glandular  substances,  the  total  daily  excretion  of  uric  acid  is 
very  considerably  greater  than  wrhen  the  diet  contains  no  such  food 
stuffs.  The  conclusion  which  Burian  and  Schur43  drew  from  this  ob- 
servation is  that  purine.  must  be  partly  of  exogenous  and  partly  of 
endogenous  origin.  In  other  words,  some  of  it  is  derived  more  or  less 
directly  from  preformed  purine  substances  in  the  food,  and  the  remain- 
der from  the  purine  constituents  of  the  animal's  own  tissues. 

Endogenous  Purines. — It  was  thought  that  a  definite  proportion  of 
each  of  the  administered  purines  could  be  invariably  recovered  from 
the  urine.  Although  this  has  not  been  found  to  be  exactly  true,  there 
is  nevertheless  a  certain  constancy  in  the  proportion  of  administered 
purine  that  is  excreted.  Thus,  Mendel  and  Lyman  have  found  recently 
ithat  about  60  per  cent  of  injected  hypoxanthine,  50  per  cent  of  xan- 
thine,  19-30  per  cent  of  guanosine,  and  30-37  per  cent  of  adenine  are 
eliminated  in  the  urine  as  uric  acid.  When  combined  purines — i.  e.,  nu- 
clear material — are  given,  only  a  small  proportion  of  the  purine  thus 
reappears.  There  is,  therefore,  a  general  parallelism  between  the  purine 
content  of  the  food  and  that  of  the  urine,  wrhich  indicates  that  purine- 
rich  food  ought  to  be  eliminated  from  the  diet  of  patients  who  are 
suffering  from  deposition  of  insoluble  urate  in  the  tissues,  as  in  gout. 
The  fate  of  the  purine  that  disappears  in  the  body  is  unknown;  some  of 
it  may  be  decomposed  in  the  intestine,  but  why  so  much  of  the  remainder 
should  disappear,  after  absorption  by  the  blood,  is  a  mystery,  since  no 
uricase  can  be  discovered  in  any  of  the  organs  or  tissues.  The  destroyed 
purines  can  not  be  shown  to  influence  any  of  the  other  well-known 
nitrogenous  metabolites  of  the  urine. 

The  following  table  of  experiments  by  Taylor  and  Eose45  may  serve 

/to  illustrate  these  points.    The  subject  was  placed  on  a  purine-free  diet 

consisting  of  milk,  eggs,  starch  and  sugar,  for  three  days.     After  this 


URIC    ACID    AND    THE    PURINE    BODIES  675 

period  a  part  of  the  total  nitrogen  (3  grams)  was  supplied  as  sweet- 
breads— thynms  gland,  etc.— containing  a  high  percentage  (0.482)  of 
purine  nitrogen;  for  another  period  of  four  days  still  more  of  the  nitro- 
gen (6  grams)  was  replaced  by  sweetbread  nitrogen;  and  this  was  fol- 
lowed by  a  final  period  in  which  the  original  diet  of  milk,  etc.,  without 
purine  substances,  was  restored.  The  following  table  gives  the  results: 


1ST  PERIOD 
PURINE-FREE 
DIET 

2ND  PERIOD 

3RD  PERIOD 

4TH  PERIOD 
PURINE-FREE 
DIET 

Total  urinary  1ST 
Urea  N  and  NH2 
Creatinine 
Purine  N  (total) 
Uric  acid  N 
Eemainder  N 

8.9 

7.3 
0.58 
0.11 
0.09 
0.91 

8.7 
7.1 
0.55 
0.17 
0.14 
0.88 

9.1 
7.1 

0.56 
0.26 
0.24 
1.18 

8.8 

7.05 
0.47 
0.10 
0.07 
1.18 

The  increase  of  uric  acid  accounted  for  less  than  half  of  the  purine 
nitrogen  ingested.  This  appeared  as  uric  acid,  the  excretion  of  purine 
bases  being  practically  unchanged. 


CHAPTER  LXXV 

URIC  ACID  AND  THE  PURINE  BODIES  (Cont'd) 
SOURCE  OF  ENDOGENOUS  PURINES 

Even  after  the  entire  elimination  of  all  purine  substances  from  the 
food  in  the  case  of  man,  purine  continues  to  be  excreted  in  the  urine 
as  uric  acid.  This,  as  above  remarked,  is  called  endogenous  excretion. 
At  first  it  was  thought  by  Burian  and  Schur  that  the  total  nitrogen  of 
the  purine-free  diet  could  be  considerably  varied  without  causing  any 
alteration  in  the  amount  of  the  endogenous  purine  excretion,  but  a  rep- 
etition of  the  work  has  shown  that,  when  these  changes  are  of  consider- 
able magnitude,  the  endogenous  moiety  does  not  remain  constant.  This 
has  already  been  demonstrated  in  the  table  on  Folin's  results  (see  page 
648),  and  is  still  better  illustrated  in  the  accompanying  table,  which 
shows  the  excretion  of  uric  acid  and  coincidently  of  urea  from  hour  to 
hour  in  the  urine  after  taking  food  which  is  free  from  nuclein  or  purine 
substances.  After  a  fast  of  six  hours,  a  diet  consisting  of  bread  and 
potatoes  was  taken  at  1:30,  and  the  urea  and  uric  acid  measured  in  the 
urine  each  hour  thereafter. 


TIME 

UREA 
GM. 

URIC  ACID 
MG. 

AMOUNT  OF  URINE 
C.C. 

10-11 

1.07 

26 

175 

11-12 

1.13 

27 

118 

12-1    P.M. 

1.07 

24 

164 

1-2   (meal) 

0.64 

21 

60 

2-3 

1.12 

22 

43 

3-4 

1.16 

38 

41 

4-5 

0.84 

40 

53 

5-6 

1.16 

56 

59 

6-7 

1.20 

39 

56 

7-8 

1.37 

30 

95 

8-9 

1.47 

33 

183 

9-10 

1.33 

24 

155 

10-11 

1.33 

23 

180 

(Hopkins  and  Hope.)46 

A  postprandial  increase  of  endogenous  purine  excretion  is  very  dis- 
tinct, and  it  indicates  that  during  the  process  of  assimilation  something 
must  be  occurring  in  the  organism  which  entails  the  production  of  purine 
from  the  organism  itself.  As  to  what  this  may  be,  it  is  impossible  to 
say.  It  may  be  associated  with  the  work  of  the  gastric  and  intestinal 
glands,  which  recalls  the  interesting  suggestion,  originally  made  by 

676 


URIC   ACID   AND   THE   PURINE   BODIES  677 

Horbaczewski,  that  ingested  substances  increase  the  excretion  of  uric 
acid  by  causing  a  leucocytosis,  the  purine  being  derived  from  the  nucleic 
acid  set  free  when  the  leucocytes  become  broken  down.  That  this  is 
not  the  correct  explanation,  however,  is  indicated  by  the  fact  that  in- 
gested substances  that  give  rise  to  an  increased  number  of  leucocytes 
affect  the  excretion  of  uric  acid  during  the  period  the  leucocytes  are 
present  in  the  blood,  and  not  after  they  have  disappeared,  which  would  be 
expected  to  be  the  case  were  the  uric  acid  a  product  of  purine  substances 
liberated  by  their  breakdown.  This  would  indicate  that  the  purine  sub- 
stance is  a  metabolic  product  of  the  living  leucocytes  and  not  a  break- 
down product  of  those  that  are  dead.  It  should  be  noted  that  the  increase 
in  the  postprandial  uric-acid  excretion  occurs  earlier  than  that  of  urea. 

The  most  pressing  question  concerns  the  origin  of  the  endogenous 
purines.  Uric  acid  is  the  purine  with  which  we  are  most  concerned  in 
the  case  of  man,  and  chemistry  shows  us  that  it  may  be  produced  either 
by  a  synthesis  of  two  urea  molecules  with  a  carbon  residue  containing 
three  carbon  atoms,  or  by  the  oxidation  of  the  lower  purines — namely, 
of  those  which  are  the  constituent  parts  of  the  nucleic-acid  molecule. 
There  are  consequently  two  sources  from  which  the  endogenous  purine 
excretion  in  man  may  be  derived  :  (1)  synthesis  of  two  urea  molecules, 
and  (2)  oxidation  of  the  lower  purines. 

We  will  consider  first  the  possibility  of  synthesis.  In  birds  and 
reptiles  practically  all  the  nitrogen  is  excreted  in  the  form  of  uric  acid, 
and  it  is  easy  to  show  that  this  has  been  produced  in  the  organism 
mainly  in  the  liver  by  the  synthesis  of  urea  with  carbon-rich  resi- 
dues. Minkowski  found  that  by  removing  the  liver  from  geese,  which 
is  a  comparatively  simple  operation  on  account  of  an  anastomotic  vein 
between  the  portal  and  the  renal  veins,  the  uric  acid  in  the  urine  became 
very  markedly  decreased  and  ammonium  lactate  took  its  place  (page 
651).  Since  we  know  that  ammonium  in  the  animal  body  is  ordinarily 
converted  into  urea,  we  may  conclude  from  this  observation  that  some- 
thing has  occurred  to  prevent  the  synthesis  of  urea  into  uric  acid.  In 
confirmation  of  this  conclusion  it  was  subsequently  found  that,  if  am- 
monium lactate  was  added  to  the  blood  perfused  through  the  isolated 
liver  of  the  goose,  uric  acid  accumulated  in  the  perfusion  fluid.  Fur- 
thermore, when  birds  and  reptiles  are  fed  with  ammonium  salts  or 
with  the  degradation  products  of  protein,  there  is  an  increase  in  the  ex- 
cretion of  uric  acid  instead  of  urea.  Everything  which  in  a  mammal 
tends  to  cause  an  increase  in  urea  excretion  causes  in  birds  and  reptiles 
a  similar  increase  in  the  excretion  of  uric  acid.* 

*The  reason  for  the  formation  of  this  relatively  insoluble  metabolite  in  place  of  the  soluble  urea 
is  connected  in  some  way  with  the  fact  that  birds  and  reptiles  do  not  take  such  large  quantities 
of  water  with  their  food  as  other  animals. 


678  METABOLISM 

In  the  early  days  of  research  in  the  uric-acid  problem,  not  inconsid- 
erable mistakes  were  made  on  account  of  failure  to  recognize  the  essen- 
tial difference  in  the  metabolism  of  uric  acid  in  birds  and  mammals, 
and  the  tendency  for  some  time  after  the  exact  state  of  affairs  was 
discovered  was  to  consider  that  in  mammals  none  of  this  synthetic  proc- 
ess occurs.  The  latter  view,  however,  is  surely  incorrect,  for  a  cer- 
tain amount  not  only  of  uric  acid  itself  but  of  the  lower  purine  bodies 
can  be  produced  by  synthesis  in  the  mammalian  body.  Thus,  Ascoli  and 
Izar47  discovered  that  uric  acid  could  be  made  either  to  disappear  or 
to  be  formed  when  a  minced  preparation  of  liver  was  incubated,  the  ex- 
act result  depending  upon  whether  the  incubation  was  conducted  in  the 
presence  of  oxygen  or  of  carbon  dioxide.  With  oxygen  uric  acid  disap- 
peared, whereas  with  carbon  dioxide  uric  acid  accumulated,  indicating 
that  in  the  presence  of  this  gas  the  destroyed  uric  acid  became  reformed 
from  the  disintegration  products  of  the  oxygenation  process.  As  similar 
results  were  obtained  from  the  livers  of  birds,  it  is  clear  that  no  essential 
difference  exists  between  the  purine  metabolic  processes  occurring  in 
the  livers  of  birds  and  of  mammals.  The  difference  is  a  quantitative  not 
a  qualitative  one. 

Eegarding  the  chemical  nature  of  the  product  into  which  uric  acid  is 
broken  down  and  from  which  it  may  be  resynthetized,  it  has  been  pos- 
sible so  far  to  identify  but  one  substance — namely,  dialuric  acid.  This 
is  a  perplexing  result,  for  from  all  other  investigations  it  would  appear 
that  in  mammals,  with  the  exception  of  man  and  the  anthropoid  apes, 
uricase  splits  uric  acid  into  allantoine  (see  page  673),  which  substance, 
however,  when  added  to  liver  extract  does  not  cause  any  uric  acid  to  be 
formed;  nor  do  any  of  the  other  known  decomposition  products  of  uric 
acid  have  such  a  result.  The  chemical  reaction  involved  in  the  produc- 
tion of  uric  acid  from  dialuric  acid  and  urea  is  indicated  as  follows: 

NH  —  C  = 

/  \ 


O  =  C  C I  —  H.OH  H    !  NH 

\  4  0  =  0 

NH  — c;  =  o  H  i  NH 

(dialuric  acid )  ( urea ) 

The  synthesis  of  uric  acid  is  brought  about  by  the  combined  action 
of  a  thermolabile  enzyme  in  the  blood  and  a  thermostable  body  in  the 
tissues.  An  aqueous  extract  of  blood-free  liver  of  the  dog  can  destroy 
uric  acid  only  in  the  presence  of  oxygen;  it  can  not  reform  it  even  in 


URIC    ACID    AND    THE    PURINE    BODIES  679 

the  presence  of  carbon  dioxide.  On  the  other  hand,  blood  serum  can 
not  reform  uric  acid,  whereas  a  mixture  of  the  bloodless  liver  extract 
and  blood  serum  produces  uric  acid  readily  under  suitable  conditions. 
Boiling  of  the  liver  extract  does  not  affect  the  result,  but  boiling  of  the 
blood  serum  renders  it  incapable  of  exerting  its  joint  action  with  the 
bloodless  liver  extract. 

These  experiments  with  dog's  liver  serve  only  as  circumstantial  evi- 
dence that  uric-acid  synthesis  occurs  in  mammals  as  well  as  in  birds. 
More  direct  proof  that  purine  synthesis  occurs  in  mammals  is  as  follows: 
(1)  It  was  discovered  long  ago  by  Miescher  that  salmon,  after  leaving 
the  sea  to  ascend  the  rivers  in  order  to  spawn,  have  a  well-developed  muscu- 
lar system,  but  that  in  the  upper  reaches  of  the  stream  the  muscular  system 
becomes  considerably  atrophied  and  the  testes  enormously  developed.  As 
the  fish  takes  no  food  during  the  migration,  there  must  be  conversion  of 
the  protein  of  the  muscles  into  the  cellular  tissue  of  the  sexual  glands, 
and  nucleic  acid  must  be  produced.  (2)  A  hen's  egg  before  its  incuba- 
tion contains  practically  no  nucleic  acid,  whereas  after  development  has 
well  started  nucleic  acid  increases  by  leaps  and  bounds.  Similarly  the 
eggs  of  insects  increase  in  purine  content  very  markedly  as  development 
proceeds.  (3)  Milk  contains  practically  no  purine  derivative,  and  yet 
when  it  is  fed  to  young  growing  animals,  the  organs  lay  on  purine  sub- 
stances abundantly.  In  general,  indeed,  it  may  be  said  that  the  combined 
purine  increase  is  in  proportion  to  the  increase  in  body  weight  on  the 
milk  diet.  (4)  In  Osborne  and  Mendel's  experiments  already  alluded 
to,  it  has  been  shown  that  adequate  growth  depends  primarily  on  the 
nature  of  the  protein  building  stones,  and  not  upon  the  purine  content 
of  the  food.  (5)  An  objection  might  be  raised  to  these  results  on  the 
score  that  they  do  not  apply  to  the  adult  mammal.  Investigation  of 
the  problem  has  hitherto  been  seriously  impeded  by  the  fact  that  no  or- 
dinary laboratory  animals  were  known  in  which  uric  acid  is  excreted  in 
the  urine.  The  discovery  that  this  occurs  in  the  Dalmatian  dog  has, 
however,  made  it  possible  for  S.  E.  Benedict41  to  show,  not  only  that 
after  increasing  the  amount  of  nonpurine  food  there  was  a  very  distinct 
increase  in  the  uric-acid  excretion,  but  also  that  when  the  animal  was 
kept  for  a  year  on  such  foods  there  was  excreted  a  total  amount  of  uric 
acid  which  was  at  least  ten  times  greater  than  could  have  come  from  the 
traces  unavoidablv  included  in  the  food. 


Eegarding  the  chemical  nature  of  the  substance  from  which  the  purine  is  synthe- 
tized,  we  know  at  present  practically  nothing.  No  doubt  some  of  the  protein  build- 
ing stones  functionate  in  this  capacity,  pyrimidine  being  probably  the  product  that  is 
first  formed.  Thus,  pyrimidine  may  be  produced  as  a  result  of  the  combination  of 
amino-malonic  acid  with  urea,  the  amino-malonic  acid  being  produced  by  condensa- 
tion of  hydrocyanic-acid  molecules: 


080  METABOLISM 

3  HCN  -^  H2N  -  CH  ( CN)  2  +  CO  ( NH )  2  -»  NH  -  CO 

CO     CNH2 

!        II 

NH  -  CNH2 

(hydrocyanic      (amino-malonic      (urea)      (oxy-diamino-pyrimidine) 
acid)  nitrile) 

Another  possible   source   of  pyrimidine  is  the  oxidation  of  arginine  to   guanidine-pro- 
pionic  acid,  which  then  condenses  to  form  amino  pyrimidine. 

Purine  synthesis  undoubtedly  occurs  in  the  mammalian  body,  but  it 
is  not  easy  to  recognize  for  its  occurrence  is  difficult  to  detect  in  metab- 
olism investigations;  it  is  a  slow,  continuous  process.  The  probabil- 
ity of  its  occurrence,  however,  is  indicated  by  such  results  as  those 
described  on  page  648,  in  which  increase  in  purine  excretion  is  observed 
after  varying  the  intake  of  food,  even  when  this  is  itself  entirely  free 
from  purine  substances.  Whether  or  not  changes  in  the  activity  of 
purine  synthesis  occur  in  conditions  of  disease  is  a  question  which  awaits 
investigation. 

The  Influence  of  Various  Physiological  Conditions,  of  Drugs,  and  of 
Disease  on  the  Endogenous  Uric-acid  Excretion. — Muscular  exercise  was 
thought  by  Burian  to  cause  an  increased  excretion  of  uric  acid,  from 
which  he  drew  the  conclusion  that  the  hypoxanthine  present  in  compara- 
tively large  amount  in  muscular  extract,  or  its  precursor,  inosinic  acid, 
must  be  an  important  source  of  endogenous  uric  acid.  Other  observers 
(Leathes,62  etc.)  have  found  that  strenuous  exercise  causes  a  distinct  in- 
crease in  uric-acid  excretion,  which,  however,  is  much  less  marked  on 
repetition  of  the  same  kind  of  exercise  on  the  next  day.  If  some  new 
kind  of  muscular  work  is  performed,  another  increase  in  uric  acid  will 
result.  There  are  still  other  investigators  who  deny  that  muscular  work 
has  any  influence  on  uric-acid  excretion. 

It  has  been  observed  by  several  investigators  that  the  endogenous 
purine  excretion  is  distinctly  higher  during  the  waking  hours  than  during 
sleep.  This  can  not  be  shown  to  depend  on  variations  in  the  urinary 
function,  and  since  it  is  decidedly  doubtful  whether  ordinary  muscular 
activity  has  any  influence,  the  diurnal  variation  is  most  difficult  to 
account  for.  The  endogenous  excretion  in  man  is  not  the  same  for 
different  individuals,  even  when  calculated  for  the  same  body  weight;  it 
varies  between  0.12  and  0.20  per  cent  purine  nitrogen  in  an  adult  man. 
It  remains  remarkably  constant  for  a  given  individual  from  time  to 
time,  being  unaffected  by  moderate  degrees  of  variation  in  the  amount 
of  food  taken,  provided  this  be  purine-free;  when,  however,  the  amounts 
are  extremely  variable,  changes  are  produced  (see  page  648). 

In  disease,  fever  causes  an  increased  excretion.  This  has  been  most 
clearly  shown  by  Leathes,62  who  took  a  large  enough  dose  of  antityphoid 


URIC    ACID   AND    THE    PURINE   BODIES  681 

serum  to  produce  a  distinct  degree  of  fever  (103°  F.),  and  found  that 
an  increase  in  uric-acid  excretion  occurred.  That  increased  combustion 
processes  occurring  in  the  tissues  were  responsible  for  the  uric  acid, 
was  shown  by  the  same  author,  who  caused  a  similar  increase  by  sub- 
jecting himself  to  cold  baths  for  a  considerable  period  of  time.  The  in- 
creased loss  of  heat  thus  induced  stimulated  the  combustion  processes  in 
the  body  so  as  to  maintain  the  body  temperature,  and  as  a  result  there 
was  an  increase  in  uric-acid  excretion.  It  has  long  been  known  that  an 
excessive  amount  of  uric  acid  is  excreted  in  leucemia.  The  nuclein 
of  disintegrated  leucocytes  is  commonly  held  responsible  for  the  increase. 
Naturally,  much  work  has  been  done  on  the  endogenous  and  exogenous 
purine  excretion  in  gout.  No  very  striking  anomalies  of  excretion  have, 
however,  been  brought  to  light,  except  perhaps  that  after  the  ingestion 
of  purine-rich  foodstuffs  it  takes  longer  for  the  resulting  exogenous  ex- 
cretion to  develop  and  pass  away. 

Certain  drugs  affect  the  excretion  of  uric  acid.  Salicylic  acid  is  said 
to  cause  an  increased  excretion,  and  citrates  certainly  have  this  effect.63 
In  both  cases  the  increase  is  followed  by  a  compensatory  fall,  which 
indicates  that  these  drugs  act  by  facilitating  the  excretion  rather  than 
by  influencing  the  metabolic  processes  that  are  the  source  of  the  uric 
acid.  The  effect  of  caffeine  has  been  very  carefully  investigated.  Given 
to  the  Dalmatian  dog,  referred  to  above,  S.  R.  Benedict  found  that  a 
small  dose  caused  a  slight  decrease,  but  that  a  larger  dose  had  practically 
no  effect,  although  there  was  a  notable  retention  of  nitrogen.  On  man, 
however,  different  results  were  secured,  for  it  was  found  that  when  1 
gram  of  caffeine  was  given  daily  for  several  days,  a  slight  but  definite 
progressive  increase  in  the  endogenous  uric-acid  excretion  occurred,  and 
it  lasted  for  10  days  after  the  caffeine  administration  was  discontinued. 
Liberal  allowance  of  this  alkaloid  may,  therefore,  not  be  quite  so  innocu- 
ous as  it  is  assumed  to  be. 

Uric  Acid  of  Blood. — In  all  of  the  investigations  considered  above, 
the  behavior  of  uric  acid  is  judged  from  the  amount  of  it  excreted  in 
the  urine.  Valuable  though  such  results  must  be,  their  interpretation  is 
always  difficult,  since  two  factors  that  are  quite  independent  of  each 
other  have  to  be  kept  in  mind — namely,  the  production  of  the  uric  acid 
in  the  organs  and  tissues  and  its  excretion  by  the  kidneys.  In  connection 
with  the  latter  factor,  we  must  also  consider  the  method  of  transporta- 
tion of  uric  acid  by  the  blood  from  its  place  of  production  (or  absorp- 
tion) to  the  kidneys.  These  problems  have  recently  been  very  consider- 
ably simplified  by  the  elaboration  of  an  accurate  method  for  the  estima- 
tion of  the  uric-acid  content  of  Hood. 

By  observing  changes  in  the  amount  of  uric  acid  in  the  blood  rather 


682 


METABOLISM 


than  in  the  urine,  the  excretory  factor  is  partly  controlled,  and  it  can 
be  completely  so  if  urine  and  blood  are  both  investigated.  Thanks  to 
the  work  of  Folin,  it  is  now  possible  to  determine  with  an  extreme  de- 
gree of  accuracy  the  uric  acid  in  as  little  as  10  c.c.  of  blood.  The  impor- 
tance of  this  achievement  will  be  appreciated  when  we  state  that  prior 
to  Folin 's  work  no  method  existed  by  which  uric  acid  could  be  approx- 
imately measured  even  when  large  quantities  of  blood  were  available. 
Much  of  the  work  that  has  been  done  by  the  use  of  this  new  method 
has  so  far  applied  to  the  amount  of  uric  acid  in  the  blood  of  man  in 
various  diseases.  We  shall  refer  to  these  results  immediately,  but 
meanwhile  it  is  important  to  call  attention  to  some  very  suggestive 
observations  concerning  the  condition  of  uric  acid  in  the  blood.  For 
many  years  there  have  been  investigators  who  have  thought  that  uric 
acid  can  not  be  simply  dissolved  in  the  blood  plasma,  like  sugar  or  some 
inorganic  salt.  It  is  believed  by  many  that  at  least  a  portion  of  the  uric 
acid  circulates  in  combination  with  nucleic  (thymic)  acid  (see  page  669), 
which  would  account  for  the  fact  that  some  purines  are  catabolized  in 
the  body  when  they  are  given  in  a  combined  state,  as  thymic  acid,  but 
are  excreted  unchanged  when  ingested  in  a  free  state.  When  given  freely, 
certain  purines — adenine,  for  example — may  moreover  cause  inflamma- 
tion and  calculus  formation  in  the  kidneys  of  dogs,  a  result  not  obtained 
when  thymic  acid  is  fed. 

Other  observers  have  concluded  that  uric  acid  exists  as  two  isomeric  varieties,  lac- 
tam  and  lactim,  the  monosodium  salts  of  which  are  of  unequal  stability.  The 
less  stable  a-salt  is  much  more  soluble  in  the  blood  serum  than  the  stable 
(3-salt.  It  is  the  a-salt  that  becomes  increased  in  the  blood  in  gout,  the  deposition 
of  urates  in  the  tissues,  which  is  the  most  characteristic  symptom  of  this  disease, 
being  caused  by  conversion  of  the  o-salts  into  /3-salts.  The  structural  formulas  of  the 
two  isomers  are  as  follows: 


H.N-C  :  O 

I     ! 

O : C     C - NH 

I     !! 


CO 


H.N  -  C  -  NH 

[lactam  modification  forming 
unstable  a-urates] 
(relatively  soluble) 


N-C.OH 

HO.C    C-NH 

I      I  \ 

C.OH 

I       I  / 

N  =  C-N 

[lactim  modification  forming 
stable  /3-urates] 
(relatively  insoluble) 


The  most  recent  work  of  S.  R.  Benedict  has  shown  that  uric  acid  ex- 
ists, chiefly  in  combination  in  the  blood  of  most  mammals  but  not  in 
that  of  the  bird.  It  was  found,  for  example,  that  fresh  ox-blood  exam- 
ined by  the  Folin  method  contains  only  0.0005  gm.  free  uric  acid  per  100 
gm.  of  blood;  after  boiling  the  protein-free  blood  filtrate  with  hydro- 
chloric acid,  however,  the  uric  acid  increased  by  about  ten  times.  This 


URIC    ACID    AND    THE    PURINE   BODIES 


683 


larger  amount  was  also  found  present  in  whole  blood  that  had  been 
allowed  to  stand  for  some  time,  indicating  that  the  uric-acid  compound 
can  be  split  by  means  of  an  enzyme.  The  compound  exists  in  the  cor- 
puscles and  not  in  the  plasma.  It  is  of  some  significance  that  after  thus 
setting  free  the  uric  acid,  there  should  be  about  50  per  cent  more  of  it 
present  in  the  blood  of  the  ox  than  in  that  of  the  bird,  where  most  exists 
in  a  free  state  in  the  serum,  although  the  urine  of  the  ox  contains  only 
the  smallest  trace  of  uric  acid,  and  that  of  the  bird  is  loaded  with  it. 
Investigation  of  the  condition  of  uric  acid  in  human  blood  is  at  present 
in  progress. 

Uricemia  in  Gout  and  Nephritis 

The  practical  application  of  these  observations  is  particularly  impor- 
tant in  connection  with  the  etiology  of  gout.  In  typical  cases  of  this  dis- 
ease, the  uric  acid  of  the  blood  increases  from  its  normal  value  of  1  to 
3  mg.  per  cent  to  nearly  10  mg.,  indicating  a  considerable  degree  of 

URIC  ACID,  UREA  N  AND  CREATININE  OF  BLOOD  IN  GOUT  AND  EARLY  AND  LATE  NEPHRITIS 


UREA  N           CREATININE        SYSTOLIC 
ACID 

DIAGNOSIS 

MG.  TO  100   C.C. 

BLOOD                                            PRESSURE 

Typical  Cases  of  Gout 

9.5 

13                    1.1 

230 

8.4 

12                   2.2 

164 

7.2 

17                    2.4 

200 

6.8 

14          1          1.7 

Typical  Early  Interstitial  Nephritis 

9.5 
8.0 

25 

37 

2.5 

2.7 

185 
150 

5.0 

37 

3.9 

130 

7.1 

16 

2.0 

6.6 

24 

3.3 

185 

6.3 

18 

2.1 

8.7 

20                   3.6 

100 

7.0 

33                   2.6 

117 

6.3 

31                   2.1 

6.3 

23 

2.4 

150 

Chronic    Diffuse    and    Chronic    Inter- 

8.0                    80 

4.8 

240 

stitial  Nephritis 

4.9 
8.3 

17 

72 

2.9 
3.2 

170 
238 

5.3 

21 

1.9 

145 

9.5                    44 

3.5 

210 

2.5                    19 

1.9 

120 

7.7                     67 

3.1 

6.7                     17 

1.6 

165 

8.3                     39 

2.9 

6.5                     24 

3.0 

200 

Typical  Fatal  Chronic  Interstitial 

22.4                   236 

16.7 

210 

Nephritis 

15.0 

240 

20.5 

225 

14.3 

263 

22.2 

220 

13.0 

90 

11.1 

265 

8.7 

144 

11.0 

225 

(Myers  and    Fine:      Arch.   Int.   Med.,   1916.) 


684 


METABOLISM 


renal  insufficiency.  This  uricemia  can  not  in  itself,  however,  be  the  cause 
of  the  deposition  of  urates  in  the  joints,  because  it  also  occurs  in  other 
diseases  with  renal  retention,  such  as  nephritis.  Moreover,  the  blood 
serum  is  capable  of  dissolving  much  larger  quantities  of  uric  acid  than 
are  ever  found  present  in  it  in  gout.  The  real  cause  for  the  gouty  deposits 
must  depend  on  some  change  affecting  the  blood  so  as  to  alter  the  form 
in  which  uric  acid  exists  therein,  with  the  result  that  it  passes  into  the 
joints  and  is  deposited  there. 

Other  diseases  showing  uricemia  are  lead  poisoning  and  nephritis.  In 
the  latter  disease  the  damaged  excretory  function  of  the  kidney  is 
manifested  first  of  all  by  an  increase  in  the  uric-acid  content  of  the 
blood,  accompanied  later  by  a  retention  of  urea  and  later  still  by  one 
of  creatinine.  The  severity  of  the  renal  involvement  may  therefore  be 
gauged  by  determining  the  percentage  of  these  three  metabolites.  On 
account  of  the  importance  of  these  facts  from  a  clinical  standpoint,  we 
append  a  table  containing  results  secured  by  Myers  and  Fine,  in  which 
the  behavior  of  the  metabolites  in  the  blood  is  shown  in  relationship 
to  the  severity  of  the  case  as  gauged  by  the  blood  pressure. 

Lastly,  regarding  the  influence  of  drugs  on.  the  blood  uric  acid  in  dis- 
ease, it  has  been  found  by  Fine  that  both  atophan  and  salicylates  cause 
a  pronounced  decrease  in  the  amount,  but  that  it  gradually  rises  to  the 
old  level  even  while  administration  of  the  drugs  is  being  continued. 

Important  contributions  to  the  behavior  of  uric  acid  in  blood  are 
constantly  appearing  at  present,  mainly  from  the  laboratories  of  Foli] 
in  Boston,  of  S.  R.  Benedict,  and  of  Myers  and  Fine  in  New  York. 


CHAPTER  LXXVI 
THE  METABOLISM  OF  THE  CARBOHYDRATES 

The  healthy  animal  organism  is  capable  of  rapidly  oxidizing  large 
quantities  of  carbohydrate,  as  is  evident  from  the  following  facts:  If 
carbohydrate  is  given  to  a  starving  animal,  (1)  the  energy  output  very 
shortly  afterward  increases;  (2)  the  respiratory  quotient  also  increases, 
indicating  that,  relatively  to  oxygen  intake,  more  carbon  dioxide  is  being 
excreted  (see  page  582)  ;  and  (3)  none  of  the  ingested  carbohydrate 
makes  its  appearance  in  the  excreta.  Indeed,  of  the  three  proximate 
principles  of  food,  carbohydrate  is  the  most  available  for  combustion 
in  the  animal  body.  It  may  therefore  be  considered  as  the  quickly 
available  fuel  for  the  body  furnaces. 

CAPACITY   OF  THE  BODY  TO   ASSIMILATE   CARBOHYDRATES 

Assimilation  Limits. — When  the  limit  to  the  amount  of  carbohydrate 
that  the  organism  can  metabolize  is  overstepped,  some  of  it  appears  in 
the  urine.  The  amount  that  can  be  tolerated  without  causing  glycosuria 
is  commonly  called  the  assimilation  or  saturation  limit.  The  use  of  the 
term  " limit"  is,  however,  very  unfortunate,  for  it  implies  that  beyond 
this  point  the  organism  is  capable  of  dealing  with  no  more  carbohy- 
drate, which  is  far  from  being  the  case,  for  if  a  larger  amount  is  taken, 
only  a  small  trace  of  the  excess  will  appear  in  the  urine.  When  the 
urine  is  allowed  to  collect  for  twenty-four  hours,  the  mixed  specimen 
shows  no  trace  of  glucose  in  the  majority  of  healthy  individuals  after 
the  ingestion  of  200  gm. ;  after  300  gm.  a  somewhat  higher  percentage 
of  cases  develop  a  mild  glycosuria,  but  frequently  none  is  evident  even 
after  500  gm.  Beyond  the  last  mentioned  amounts  the  limit  of  ingestion 
is  reached,  on  account  of  nausea,  etc.,  and  it  is  improbable  even  if 
larger  amounts  could  be  tolerated,  that  any  more  of  the  glucose  would 
be  absorbed  than  with  300  or  400  gm.  The  testing  of  the  so-called  as- 
similation limit  has  been  considered  an  important  aid  in  the  diagnosis 
of  early  cases  of  diabetes. 

It  has  been  found  that  to  make  the  results  of  any  value,  certain 
conditions  must  be  fulfilled  in  applying  the  assimilation  test.  The  most 
important  of  these  concerns  the  activities  of  the  gastrointestinal  appa- 
ratus at  the  time  the  sugar  is  given,  for  it  has  been  found  that  if  other 

685 


686  METABOLISM 

foodstuffs  are  being  absorbed  at  the  same  time  as  the  sugar,  more  of 
the  latter  can  be  tolerated  than  when  the  sugar  alone  is  being  absorbed. 
It  has  therefore  been  customary  to  give  the  sugar  dissolved  in  water, 
or  in  weak  coffee,  the  first  thing  in  the  morning  after  the  patient  awakes ; 
i.  e.,  at  least  twelve  to  sixteen  hours  after  the  last  meal  was  taken.  In 
making  these  tests  the  urine  voided  before  the  sugar  is  administered  should 
of  course  itself  be  thoroughly  examined  for  reducing  substances,  and 
specimens  should  be  collected  about  every  ninety  minutes  and  examined 
by  a  reliable  test  (Benedict's  or  Nylander's).* 

Although  a  limit  is  set  to  the  ability  of  the  organism  for  retaining 
sugar  (mono-  or  di-saccharides),  this  is  usually  considered  not  to  apply,  in 
healthy  individuals  at  least,  when  starches  (polysaccharides)  are  ingested. 
Thus,  it  is  a  well-known  fact  that  people  can  eat  enormous  quantities  of  po- 
tatoes or  of  bread  without  the  appearance  of  any  trace  of  reducing  sub- 
stances in  the  twenty-four-hour  urine.  It  should  be  pointed  out,  however, 
that  urine  collected  and  examined  at  short  intervals  (every  half  hour) 
after  taking  large  quantities  of  polysaccharide-rich  food  has  frequently 
been  found  to  contain  traces  of  reducing  substances  in  apparently 
healthy  persons. 

For  practical  purposes  it  has  been  considered  that  an  individual  who  developes  glycos- 
uria  after  taking  100  gm.  of  glucose  must  be  considered  as  at  least  a  potential  diabetic. 
In  the  light  of  the  above  results  and  for  many  other  reasons,  there  is,  however,  con- 
siderable doubt  as  to  the  value  of  the  assimilation  test.  Thus,  when  a  solution  of 
glucose  is  given  orally,  its  rate  of  absorption  will  depend  very  largely  on  the  motility 
of  the  stomach.  If  this  is  normal,  the  solution  will  very  quickly  find  its  way  past  the 
pyloric  sphincter  into  the  intestine,  where  it  will  be  rapidly  absorbed.  If,  on  the  other 
hand,  the  pyloric  sphincter  does  not  open  freely,  the  passage  of  the  glucose  into  the 
intestine  may  be  so  delayed  that  no  more  is  present  in  this  place  at  one  time  than 
would  be  the  case  after  an  ordinary  diet  of  polysaccharide.  And  even  after  the  sugar 
solution  enters  the  small  intestine,  differences  in  the  amount  of  the  intestinal  contents 
with  which  it  becomes  mixed,  in  the  extent  of  bacterial  growth,  and  in  the  absorption 
process,  may  very  materially  affect  the  rate  at  which  the  glucose  gains  entry  to  the 
blood. 

Although  often  of  doubtful  diagnostic  value,  determination  of  the 
assimilation  limit  is  of  considerable  aid  in  controlling  the  treatment  of 
diabetes.  For  this  purpose  the  patient  should  first  of  all  be  instructed 
to  follow  his  usual  diet,  so  that,  by  examination  of  the  amount  of  sugar 
excreted  in  the  urine,  an  opinion  may  be  formed  of  the  severity  of  the 
case.  The  diet  should  then  be  changed  so  as  to  consist  of  a  part  that 
contains  no  carbohydrates  and  another  composed  entirely  of  starchy 


•Examination  of  normal  individuals  has  shown  that  the  assimilation  limit  for  different  sugars 
varies  somewhat;  for  glucose  it  appears  to  be  from  about  150  to  250  gm. ;  for  leyulose,  which,  it 
will  be  remembered,  is  the  monosaccharide  associated  with  glucose  in  the  construction  of  the  cane- 
sugar  molecule,  the  assimilation  limit  is  from  100  to  150  gm. ;  for  cane  sugar  or  saccharose  itself 
the  figures  seem  to  vary  considerably,  but  are  given  as  between  50  and  200  gm. ;  for  lactose,  another 
disaccharide,  and  the  sugar  present  in  milk,  the  assimilation  limit  is  distinctly  lower — namely,  100  gm. 


THE    METABOLISM    OF    THE    CARBOHYDRATES  687 

food.  The  former  is  made  up  of  eggs,  fish,  green  vegetables,  fat,  etc., 
and  the  latter,  to  start  with,  should  consist  of  100  grams  of  bread,  dis- 
tributed between  the  two  main  meals  of  the  day,  one  of  which  is  break- 
fast. This  diet  should  be  continued  until  the  glycosuria  either  disappears 
or  attains  a  constant  level.  If  it  disappears,  the  case  is  classified  as  a 
mild  one  of  diabetes,  and  the  daily  allowance  of  bread  may  be  increased, 
by  50  grams  a  day,  until  the  sugar  again  makes  its  appearance  in  the 
urine,  indicating  that  the  assimilation  limit  has  been  reached.  For 
therapeutic  purposes,  the  patient  should  now  be  instructed  to  take  about 
three  fourths  of  this  amount  of  carbohydrate  in  his  daily  ration,  and 
he  should  be  supplied  with  explicit  instructions  in  the  shape  of  diet 
tables  as  to  what  variety  and  quantities  of  the  various  carbohydrate 
materials  his  food  may  contain.  His  urine  should  be  examined  at  fre- 
quent intervals — once  a  week — and  he  should  be  instructed  as  to  the 
nature  of  his  disease  and  the  importance  of  his  remaining  aglycosuric. 
By  further  treatment  such  so-called  latent  cases  of  diabetes  may  be 
kept  in  perfect  health  for  many  years. 

When,  on  the  other  hand,  the  glycosuria  persists  with  100  grams  of 
bread  in  the  daily  ration,  this  must  be  reduced  to  50  grams,  and  if  after 
some  days  the  first  reduction  does  not  suffice  to  render  the  urine  free 
from  sugar,  carbohydrates  must  be  withheld  entirely  from  the  diet. 
If  the  glycosuria  does  not  now  disappear,  the  case  is  to  be  considered 
severe,  and  it  may  be  necessary  to  undertake  the  starvation  treatment, 
which  has  recently  been  developed  in  this  country  by  Allen18  and  Joslin19 
with  apparent  success.  By  the  reduction  of  carbohydrate,  or  by  the 
starvation  treatment,  it  is  usually  possible  to  make  even  the  severest 
cases  of  diabetes  aglycosuric.  When  this  has  been  attained,  the  amount 
of  protein  or  carbohydrate  food  may  be  cautiously  increased  until  just 
short  of  the  assimilation  limit. 

To  avoid  error  caused  by  irregular  absorption  from  the  intestines,  some  investigators 
have  recommended  the  determination  of  the  assimilation  limit  after  intravenous  or 
subcutaneous  injections  of  sugar.  But'  even  this  refinement  in  technic  has  not,  as  a 
rule,  had  the  effect  of  rendering  the  results  of  any  very  evident  value  as  a  criterion 
of  the  utilization  of  glucose  in  the  animal  body.  The  reason  for  the  unreliability  of 
this  method  is  mainly  that  the  period  of  injection  of  the  glucose  solution  usually  oc- 
cupies only  a  few  minutes,  so  that  it  causes  a  sudden  instead  of  a  very  gradual  in- 
crease in  the  sugar  concentration  of  the  blood,  the  conditions  being  therefore  quite 
unlike  that  which  exists  during  the  normal  absorption  of  glucose  from  the  intestine. 
The  mechanism  by  which  the  body  ordinarily  disposes  of  excessive  amounts  of  glucose 
absorbed  into  the  portal  blood,  is  not  adjusted  to  operate  when  the  systemic  blood 
is  suddenly  overcharged  with  this  substance.  In  the  one  case  the  glucose  is  a  food- 
stuff; in  the  other,  because  of  its  excessive  concentration  in  the  blood,  it  is  more  or 
less  of  a  poison.  Such  results,  in  other  words,  merely  show  us  how  much  glucose  can 
be  added  at  one  time  to  the  organism  without  any  overflow  into  the  urine,  but  they 


688  METABOLISM 

furnish  us  with  no  information  regarding  the  power  of  the  organism  to  utilize  a  con- 
stant though  moderate  excess  of  this  substance.  In  the  one  case  it  is  the  "satura- 
tion limit,"  in  the  other  the  "utilization  limit"  of  the  organism  for  glucose,  that  we 
are  really  measuring. 

The  Tolerance  of  the  Body  for  Glucose. — Consideration  of  these  prin- 
ciples has  led  Woodyatt,  Sansum  and  Wilder20  to  undertake  a  thorough 
reinvestigation  of  the  whole  problem  of  the  utilization  or,  as  they  prefer 
to  call  it,  the  tolerance  of  the  body  for  glucose.  They  emphasize  the  obvi- 
ous fact  that  the  ability  of  the  organism  to  utilize  glucose  ' '  must  de- 
pend on  the  rate  at  which  the  tissues  are  able  to  abstract  it  from  the 
blood  by  their  combined  powers,  to  burn  it,  to  reduce  it  into  fat  or  to 
polymerize  it  into  glycogen. "  To  form  any  estimate  of  the  combined 
effect  of  these  processes,  we  must  take  into  account  not  only  the  amount 
of  glucose  per  unit  of  body  weight  (grams  per  kilogram),  but  also  the 
rate  of  injection,  for  "tolerance  must  be  regarded  as  a  velocity,  not  as 
a  weight." 

Briefly  summarized,  the  conclusions  which  Woodyatt,  etc.,  have  so  far 
drawn  from  their  investigations  are  as  follows:  In  a  normal  rabbit,  dog, 
or  man,  0.8-0.9  gm.  of  glucose  per  kilogram  body  weight  and  per  hour  can 
be  utilized  by  the  organism  for  an  indefinite  time  without  causing  gly- 
cosuria.  When  between  0.8  and  2  gm.  are  injected,  a  part  of  the  excess 
appears  in  the  urine,  steadily  increasing  until  a  maximum  is  reached, 
after  which  the  excreted  fraction  remains  constant  (at  about  one-tenth). 
If  more  than  about  2  grams  per  kilogram  an  hour  are  injected,  "a  large 
percentage  of  all  glucose  in  excess  of  the  2  gm.  per  kilogram  an  hour 
appears  in  the  urine  when  constant  conditions  are  once  established." 

The  fact  that  so  much  glucose  injected  intravenously  can  be  used 
without  the  appearance  of  any  of  it  in  the  urine,  indicates  a  method  by 
which  foodstuffs  may  be  supplied  to  the  tissues  in  cases  where,  on  account 
of  gastrointestinal  disturbances,  it  is  impossible  to  have  food  absorbed 
by  the  usual  pathways.  The  possible  value  of  such  a  method  of  treat- 
ment in  cases  of  extreme  weakness  has  been  tested  on  laboratory  animals 
by  Allen,  who  states  that  such  injection  seems  to  have  a  valuable  nutri- 
tive and  strengthening  effect.  He  found;  for  example,  that  in  cats 
starved  to  extreme  weakness  the  injection  of  a  fraction  of  a  gram  per 
kilogram  of  glucose  had  an  unmistakable  strengthening  effect,  and 
sometimes  appeared  to  save  life.  Such  results  would  seem  to  indicate  that 
in  certain  cases  where  blood  transfusion  is  impracticable,  glucose  in- 
fusions should  be  tried.  Subcutaneous  injection  of  sugar,  either  for  the 
purpose  of  determining  the  assimilation  limit  or  with  the  object  of  sup- 
plying foodstuffs  parenterally,  is  impracticable  because  of  the  pain  and 
sometimes  sloughing  produced  at  the  point  of  injection. 


THE    METABOLISM    OF    THE    CARBOHYDRATES  689 

We  may  now  turn  our  attention  to  a  closer  analysis  of  the  changes  that 
take  place  in  carbohydrates  during  their  passage  through  the  animal 
body  and  to  the  more  recently  introduced  methods  of  diagnosis  in  which 
the  blood  sugar  is  measured. 

DIGESTION  AND  ABSORPTION 

Digestion. — All  digestible  carbohydrate  taken  with  the  food  is  con- 
verted by  the  digestive  agencies  into  the  monosaccharides,  glucose  and 
levulose,  as  which  it  is  absorbed  into  the  blood  of  the  portal  system. 
To  bring  about  this  resolution  of  carbohydrate  into  monosaccharides, 
several  enzymes  are  employed.  The  first  of  these  is  the  ptyalin  of  saliva. 
It  is  not  a  very  powerful  enzyme,  being  capable  of  acting  only  on  starches 
that  are  in  a  free  state,  i.  e.,  not  surrounded  by  a  cellulose  envelope ; 
but  even  on  free  starch,  ptyalin  displays  little  of  its  activity  during  the 
time  the  food  is  in  the  mouth.  After  the  food  is  swallowed  and  becomes 
deposited  in  the  fundus  of  the  stomach,  there  is  an  interval  of  time — 
lasting  until  hydrochloric  acid  has  been  secreted  to  such  an  extent  as  to 
permit  some  of  the  acid  to  exist  in  a  free  state — during  which  the  ptyalin 
acts  on  the  starch  of  the  swallowed  food.  During  this  time  the  activity 
of  the  ptyalin  is  actually  assisted  on  account  of  the  fact  that  a  slight 
increase  in  hydrogen-ion  concentration  of  the  digestive  mixture  accel- 
erates the  action  of  ptyalin. 

The  product  of  ptyalin  digestion  is  maltose,  a  disaccharide  composed 
of  two  molecules  of  glucose.  On  entering  the  intestine,  the  carbohydrates 
therefore  exist  partly  as  undigested  starch,  partly  as  glucose,  and  partly 
as  maltose.  In  the  favorable  environment  of  the  duodenum  a  much 
stronger  diastatic  enzyme  called  amylopsin  very  quickly  hydrolyzes  the 
starch  through  dextrine  into  maltose.  The  maltose  derived  from  the 
starch  and  the  unchanged  sugars,  such  as  cane  sugar,  maltose  and  lac- 
tose, which  have  been  taken  with  the  food,  unless  they  are  present  in  very 
high  concentration  in  the  intestinal  contents,  are  not  immediately  ab- 
sorbed into  the  blood,  but  become  subject  to  the  action  of  other  enzymes 
contributed  by  the  intestinal  juice — namely,  the  inverting  enzymes,  one 
of  which  exists  for  each  of  the  disaccharides.  By  their  action  maltose 
is  converted  into  two  molecules  of  glucose  by  the  enzyme  maltase;  lac- 
tose, into  galactose  and  glucose  by  lactase;  and  cane  sugar,  into  levu- 
lose and  glucose  by  invertase.  It  is  interesting  to  note  that  in  animals 
whose  food  does  not  contain  one  or  other  of  those  disaccharides,  the  cor- 
responding inverting  enzyme  is  absent  from  the  intestinal  juice.  The  her- 
bivorous animals,  for  example,  do  not  take  any  lactose  in  their  food,  and  the 


690  METABOLISM 

intestinal  juice  contains  therefore  no  lactase,  although  it  is  present  in 
that  of  the  young  animals  while  still  suckling. 

A  certain  amount  of  carbohydrate  becomes  attacked  by  the  intestinal 
bacteria.  These  split  the  monosaccharides  into  lower  fatty  acids  and 
gases,  such  as  methane  and  carbon  dioxide.  Besides  this  obviously  de- 
structive process,  bacteria  also  perform  a  useful  function  in  the  digestion 
of  carbohydrates,  in  that  certain  strains  of  them  are  able  to  digest  cellu- 
lose, for  which  no  special  enzyme  is  provided.  Bacterial  digestion  is  con- 
sequently essential  in  herbivorous  animals;  it  takes  place  in  the  cecum, 
which  is  enormously  developed  for  this  purpose  (page  497). 

Absorption. — The  glucose  and  levulose  produced  by  digestion  are 
absorbed  into  the  blood  of  the  portal  system.  When  a  very  large  quan- 
tity of  a  disaccharide,  such  as  cane  sugar,  is  present  in  the  food,  a  certain 
amount  of  the  sugar  is  absorbed  unchanged — that  is  to  say,  as  cane  sugar 
— and  appears  in  the  blood,  from  which,  since  it  is  an  abnormal  con- 
stituent, it  is  excreted  unchanged  in  the  urine.  This  alimentary  glyco- 
suria  is  particularly  evident  when  the  sugar  is  taken  without  any  other 
food;  thus,  after  taking  cane  sugar  in  an  amount  corresponding  to  5 
grams  per  kilogram  body  weight,  it  was  found  in  one  and  a  half  hours 
afterward  that  the  urine  of  ten  out  of  seventeen  healthy  individuals  con- 
tained cane  sugar.  The  urine  of  three  of  these  men,  however,  also  con- 
tained invert  sugar — that  is,  dextrose  and  levulose.  Cane  sugar  con- 
tinued to  be  excreted  for  from  six  to  seven  hours. 

The  Sugur  Level  in  the  Blood. — "While  no  absorption  of  sugar  is  going 
on,  the  percentage  of  this  substance  in  the  blood  of  the  portal  vein  is  the 
same  as  that  in  the  systemic  circulation.  During  absorption  the  former 
becomes  perceptibly  raised — to  what  extent  we  can  not  say — and  in  the 
latter  a  less  marked  increase  of  sugar  concentration  is  usually  detectable. 
Evidently,  then,  between  the  point  at  which  the  sugar  is  absorbed  and 
the  blood  of  the  systemic  circulation,  some  barrier  exists  which  holds 
back  some  of  the  excess  of  absorbed  sugar.  We  have  very  inaccurate 
information  as  to  how  efficiently  these  barriers  hold  back  the  excess  of 
absorbed  glucose  because  of  the  technical  difficulty  in  collecting  blood 
from  the  portal  vein  without  serious  disturbance  to  the  animal.  Indeed, 
the  only  way  by  which  the  problem  can  be  studied  is  by  comparing  the 
blood  of  the  portal  circulation  with  that  of  the  systemic  circulation  dur- 
ing the  injection  of  a  solution  of  glucose  into  one  of  the  smaller  branches 
of  the  portal  vein.21 

In  such  experiments  it  has  been  found  that  the  percentage  of  sugar  is  a  little  less 
in  the  blood  of  the  abdominal  vena  cava  than  in  that  of  the  portal  vein,  and  is  still 
less  in  the  blood  of  the  systemic  veins,  such  as  the  femoral — results  which  justify  the 
conclusion  that  the  barriers  responsible  for  taking  out  some  of  the  absorbed  sugar 
from  the  blood  exist  in  the  liver  and  in  the  muscles.  The  curve  in  Fig.  190  will  illus- 
trate to  what  extent  the  mechanism  operates. 


THE    METABOLISM    OF    THE    CARBOHYDRATES 


691 


It  will  be  observed  that,  so  far  as  can  be  judged  from  changes  in  the  concentration 
of  sugar  in  the  blood,  the  sugar-retaining  power  of  the  liver  is  about  equal  to  that  of 
the  muscles.  One  objection  which  may  properly  be  raised  to  these  observations  is 
that  the  animals  on  which  they  were  made  were  under  anesthesia,  and  that  the  anesthetic 
may  have*  had  a  paralyzing  effect  on  the  sugar-retaining  power  of  the  liver.  In  view  of 
this  criticism  it  is  important  to  examine  the  results  obtained  on  animals  that  are  not 
under  the  influence  of  anesthesia.  By  collecting  blood  from  the  ear  veins  of  rabbits,  it 
has  been  found,  after  giving  from  two  to  ten  grams  of  glucose  by  stomach,  that  the 
glucose  concentration  of  the  systemic  blood  begins  to  vise  in  fifteen  minutes,  attaining  a 
maximum  in  about  an  hour  and  then  returning  to  the  normal  level  in  about  three  hours. 

Similar  results  have  been  obtained  by  examination  of  the  venous  blood 
in  man.  After  giving  100  grams  of  glucose  by  mouth,  for  example,  there 
is  commonly  an  increase  in  blood  sugar  amounting  to  from  30  to  34  per 
cent  of  the  normal  and  lasting  for  from  one  to  four  hours.  The  existence 
of  this  postprandial  hyperglycemia,  as  we  may  call  it,  indicates  that  the 


/    /    / 


Fig.  190. — Curves  showing  the  percentage  of  glucose  in  blood  after  a  constant  injection  of 
an  18  per  cent  solution  into  a  mesenteric  vein.  V.C.,  vena  cava,  continuous  line;  P.O.,  pan- 
creaticoduodenal  vein,  broken  line;  I,  iliac,  dotted  line. 

sugar-retaining  powers  of  the  liver  and  muscles  are  not  sufficiently  de- 
veloped to  prevent  the  accumulation  of  some  of  the  absorbed  sugar  in  the 
systemic  blood.  Whenever  this  increase  exceeds  a  certain  limit,  some  of 
the  sugar  begins  to  escape  through  the  kidney  into  the  urine,  producing 
glycosuria — postprandial  glycosuria.  The  concentration  to  which  blood 
sugar  must  rise  before  glycosuria  occurs  in  the  case  of  man  is  about 
0.17  gm.  per  cent.  After  damage  to  the  kidney,  as  in  nephritis,  or 
in  long-standing  cases  of  mild  diabetes,  the  percentage  may  probably 
rise  considerably  higher  in  the  blood  without  evidence  of  glycosuria. 

Value  of  Blood  Examination.!!!  Diagnosis  of  Diabetes. — The  determina- 
tion of  the  amount  of  ingested  carbohydrate  required  to  bring  about  post- 
prandial glycosuria  constitutes,  as  we  have  already  seen,  the  so-called 


692  METABOLISM 

assimilation  limit  for  sugar,  which  is  often  taken  as  an  index  of  the  sugar- 
metabolizing  power  of  the  organism.  It  is  evident,  however,  that  the  time 
of  onset,  and  the  extent  and  duration  of  postprandial  hyperglycemia  must 
serve  as  a  more  certain  index  of  the  efficiency  of  sugar  metabolism.  It 
is  now  the  usual  practice  to  determine  the  sugar  in  samples  of  venous 
blood  removed  immediately  before  and  at  half  hour  intervals  following 
the  administration  by  mouth  of  100  gm.  glucose  dissolved  in  water.  This 
is  done  on  an  empty  stomach.  In  a  healthy  person  the  curve  of  blood 
sugar  rises  within  an  hour  to  not  above  0.15  per  cent  and  the  normal  is 
regained  in  two  hours.  In  early  diabetes  the  curve  rises  higher,  stays 
up  for  a  longer  time  and  does  not  return  to  normal  for  several  hours. 
Slight  deviations  from  the  normal  must  not  be  given  too  much  weight  in 
diagnosis  since  they  may  occur  in  other  diseases  or  even  in  perfectly 
normal  persons. 

In  no  disease,  probably  not  even  in  tuberculosis,  is  it  more  important 
than  in  diabetes  that  an  early  diagnosis  should  be  made.  Thus,  if  we  find 
that  the  postprandial  hyperglycemia  after  a  certain  amount  of  carbo- 
hydrate develops  to  an  unusually  high  degree  and  persists  for  an  unusual 
length  of  time,  we  are  justified  in  curtailing  the  carbohydrate  supply  so  as 
to  hold  these  values  down  to  the  level  they  attain  in  normal  individuals. 
It  is  almost  certain  that  the  earliest  sign  of  diabetes  is  an  unusual  degree 
and  duration  of  postprandial  hyperglycemia.  At  first  the  excess  of  sugar 
leads  to  no  damage  and  it  is  insufficient  to  cause  any  evident  glycosuria,  al- 
though it  is  quite  likely  that  if  the  urine  in  such  individuals  were  collected 
at  very  frequent  intervals  after  eating  carbohydrate-rich  food,  glucose  would 
be  found  present  in  at  least  some  of  the  specimens.  In  incipient  diabetes, 
however,  the  condition  progresses,  until  the  postprandial  hyperglycemia 
after  one  meal  has  not  become  entirely  replaced  before  the  next  is  taken, 
so  that  the  increase  in  sugar  produced  by  the  second  meal  becomes  super- 
added  on  that  following  the  first  meal.  The  curve  of  blood  sugar  rises 
ever  higher  and  higher,  until  at  last  permanent  hyperglycemia  is  estab- 
lished, or  rather  the  normal  level  from  which  the  postprandial  rise  occurs 
has  become  permanently  raised,  so  that  in  blood  collected  at  any  time  a 
higher  percentage  of  sugar  is  found. 

The  Relationship  Between  the  Sugar  Concentration  of  the  Blood  and 
the  Occurrence  of  Glycosuria. — Claude  Bernard  first  pointed  out  that  the 
percentage  of  sugar  in  the  blood  may  rise  considerably  above  its  normal 
level  without  the  appearance  of  any  of  the  sugar  in  the  urine,  or  at  least 
without  a  sufficient  amount  appearing  to  give  the  usual  tests  for  sugar. 
Thus  in  man  the  blood  sugar  may  rise  to  0.17  per  cent  before  sugar  can 
be  detected  in  the  urine.  This  has  been  called  the  renal  threshold.  Even 
when  the  threshold  has  been  overstepped,  however,  the  sugar  which 
appears  is  not  all  of  the  excess  but  only  a  small  part  of  it. 


THE    METABOLISM    OF    THE    CARBOHYDRATES  693 

Strong  support  has  been  lent  to  the  idea  of  the  renal  threshold  by 
the  recent  work  of  Woodyatt  and  his  collaborators,  who  have  shown  by 
continuous  intravenous  glucose  injections  that  as  much  as  0.8  gm.  of 
glucose  per  kilo  body  weight  can  be  injected  during  an  hour  into  an 
animal  without  any  glycosuria,  although  under  such  conditions  a  very 
distinct  increase  occurs  in  the  percentage  of  sugar  in  the  blood. 

To  explain  the  failure  of  glucose  to  pass  into  the  urine  under  normal  conditions, 
it  has  been  supposed  by  several  investigators  that  the  glucose  exists  in  some  form  of 
chemical  combination  in  the  blood.  This  compound  is  believed  to  behave  like  a 
colloid.  One  of  the  recent  supporters  of  this  view  is  Allen,  who  has  observed  that, 
when  glucose  is  injected  intravenously,  it  causes  diuresis  as  well  as  glycosuria;  whereas 
glucose  injected  subcutaneously  or  taken  by  mouth  causes  neither  of  these  conditions  to 
become  developed;  indeed  it  causes  for  some  time  after  its  administration  a  dimin- 
ished urinary  flow.  To  explain  these  differences  in  behavior  between  glucose  ad- 
ministered intravenously  and  that  taken  in  other  ways,  it  is  supposed  that  the  glucose 
molecule  in  passing  through  the  intervening  wall  of  the  capillaries  combines  with  some 
substance  to  form  a  compound  which  becomes  available  for  incorporation  into  and 
utilization  by  the  tissues,  glucose  in  a  free  state  being  incapable  of  utilization.  This 
compound  is  supposed  to  be  of  a  colloidal  nature,  and  the  substance  which  combines 
with  glucose  to  form  it  is  believed  to  be  related  to  the  internal  secretion  of  the  pan- 
creas (see  page  710). 

The  difficulty  in  explaining  why  the  glucose  of  the  blood  does  not  constantly  leak 
into  the  kidney  is,  however,  the  only  evidence  upon  which  the  hypothesis  of  a  blood 
sugar  compound  rests.  No  chemical  evidence  can  be  offered  in  support  of  such  a  view. 
On  the  contrary,  all  experimental  work  indicates  that  the  sugar  exists  in  a  free  state; 
but  unfortunately  even  this  evidence  is  not  convincing.  Thus,  it  has  been  found  that, 
when  specimens  of  perfectly  fresh  blood  are  placed  in  a  series  of  dialyzer  sacs  sus- 
pended in  isotonic  saline  solutions,  each  solution  containing  a  slightly  different  per- 
centage of  glucose,  diffusion  of  glucose,  in  one  or  other  direction,  occurs  in  all  of  them 
save  one — namely,  that  in  which  the  percentage  of  glucose  in  the  fluid  outside  the 
dialyzer  is  exactly  equal  to  the  total  sugar  content  of  the  blood.  Such  a  result  can 
be  explained  only  by  assuming  that  all  of  the  sugar  in  the  blood  exists  in  a  freely 
diffusible  state.  In  its  general  nature  this  experiment  is  analogous  to  that  by  which 
the  tension  or  partial  pressure  of  CO2  is  determined  in  blood  (see  page  355). 

It  has  been  shown  that  glycosuria  may  sometimes  become  developed 
because  the  kidney  fails  to  hold  back  the  blood  sugar  even  when  the 
percentage  is  not  above  the  normal — so-called  renal  diabetes.  For  the 
diagnosis  of  this  condition  a  comparison  must  be  made  between  the 
sugar  concentration  of  the  blood  and  that  of  the  urine.  In  order  to 
do  this  at  least  two  samples  of  blood  must  be  taken,  one  of  them  at  the 
beginning  and  the  other  at  the  end  of  a  period  during  which  urine  is  being 
collected.  Merely  to  find  that  one  sample  of  blood  collected  before  or  after 
or  during  the  period  of  urine  collection  contains  a  normal  percentage  of 
sugar,  does  not  necessarily  indicate  that  at  some  other  period  while  the 
urine  was  being  produced  a  temporary  hyperglycemia  may  not  have  ex- 
isted. Recent  contributions  have  shown  that  this  condition  is  of  more 
frequent  occurrence  than  it  was  previously  thought  to  be.26 


CHAPTER  LXXVII 
THE  METABOLISM  OF  THE  CARBOHYDRATES  (Cont'd) 

FATE  OF  ABSORBED  GLUCOSE.     GLUCONEOGENESIS 

We  may  now  consider  what  becomes  of  the  sugar  that  is  retained  by 
the  liver  and  muscles.  Two  things  may  happen  to  it:  It  may  become 
stored,  or  it  may  become  oxidized  or  split  up.  Of  these  processes,  storage 
occurs  in  both  the  liver  and  muscles,  whereas  oxidation  occurs  mainly  if 
not  entirely  in  the  muscles,  although  a  certain  amount  of  splitting  of  the 
glucose  molecule  may  also  occur  in  the  liver. 

Storage  of  Sugar. — For  the  present  we  shall  consider  the  process  of 
storage  of  sugar  and  defer  a  consideration  of  its  utilization  until  after  we 
have  studied,  not  only  the  nature  of  the  process  by  which  the  storage 
occurs,  but  also  the  immediate  destiny  of  the  stored  sugar.  The  storage 
of  sugar  by  the  liver  is  brought  about  by  its  conversion  into  a  polysac- 
charide  called  glycogen.  After  an  animal  has  been  absorbing  large  quan- 
tities of  glucose,  an  acidified  watery  extract  of  a  portion  of  liver  made 
immediately  after  death  will  be  found  to  contain  no  more  sugar  than  that 
of  a  normal  liver.  On  the  other  hand,  it  will  be  observed  that  the  extract 
is  highly  opalescent  and  yields  on  the  addition  of  alcohol  a  copious  precip- 
itate, which  on  further  purification  can  readily  be  shown  to  consist  of  a 
polysaccharide — that  is  to  say,  of  a  starch-like  substance  which  on  hydrol- 
ysis with  mineral  acid  becomes  entirely  converted  into  sugar.  If  instead 
of  examining  the  liver  immediately  after  death,  it  is  allowed  to  stand  for 
some  time,  the  yield  of  glycogen  will  greatly  diminish,  and  in  its  place 
will  appear  large  quantities  of  glucose,  indicating  that  some  enzyme  must 
exist  which  attacks  the  glycogen  after  death  and  converts  it  into  sugar, 
This  enzyme  is  called  glycogenase.  The  existence  of  postmortem  glyco- 
genolysis,  as  it  is  called,  would  seem  to  indicate  that  during  life  a  con- 
stant tendency  for  the  glycogen  in  the  liver  to  be  attacked  by  glycogenase 
is  held  in  check  by  conditions  which  depend  on  the  vital  integrity  of 
the  liver  cell.  It  is  evident  that  if  anything  should  happen  during  life 
to  interfere  with  this  inhibiting  influence,  the  glycogen  will  become  con- 
verted into  glucose,  which  on  escaping  into  the  blood  will  produce  hyper- 
glycemia  and  glycosuria. 

Sources  of  Glycogen. — In  studying  the  sources  of  sugar  in  the  animal 
bod}*  it  is  of  great  importance  that  we  should  first  of  all  know  exactly  the 

694 


THE    METABOLISM    OF    THE    CARBOHYDRATES  695 

conditions  under  which  glycogen  may  be  formed  in  the  liver;  that  is, 
whether  it  is  formed  exclusively  from  absorbed  sugar,  or  whether  other 
substances,  such  as  protein  and  fat  may  also  form  it.  The  importance  of 
such  knowledge  rests  in  the  fact  that  in  severe  diabetes,  sugar  continues 
to  be  added  to  the  blood,  although  no  sugar  is  being  taken  with  the  food. 
To  check  the  hyperglycemia  in  such  cases  it  becomes  necessary,  therefore, 
to  curtail  the  diet  not  only  with  regard  to  its  carbohydrate  content,  but 
also  with  regard  to  whatever  other  foodstuffs  may  be  capable  of  causing 
glycogen  formation.  The  practical  question  therefore  is,  What  are  these 
foodstuffs?  There  are  two  methods  by  which  the  problem  may  be  investi- 
gated. The  first,  which  we  may  call  the  direct  method,  consists  in  rendering 
the  liver  free  of  glycogen  and  then  feeding  the  animal  with  the  food- 
stuff in  question,  afterward  killing  it  and  immediately  examining  the  liver 
for  glycogen.  The  other,  which  we  may  call  the  indirect  method,  con- 
sists in  first  of  all  rendering  the  animal  incapable  of  oxidizing  glucose — 
that  is,  making  it  diabetic — and  then  proceeding  to  see  whether  the  in- 
gestion  of  a  given  foodstuff  causes  an  increase  in  the  sugar  excretion  in 
the  urine.  The  methods  for  rendering  an  animal  experimentally  diabetic 
will  be  considered  later;  for  the  present  it  is  important  to  note  that,  if 
a  diabetic  animal  excretes  more  glucose  while  fed  on  a  given  foodstuff, 
we  may  infer  that  the  normal  animal  would  convert  it  into  glycogen. 

The  results  of  the  direct  method  are  much  less  reliable  than  those  of 
the  indirect  for  the  reason  that  it  is  extremely  difficult  to  remove  all 
traces  of  glycogen  from  the  liver.  The  methods  employed  for  this  pur- 
pose have-xjonsisted  in:  (1)  starvation  of  the  animal;  (2)  muscular  ex- 
ercise; (3)  exercise  and  starvation  combined;  and  (4)  the  production  of 
certain  forms  of  experimental  diabetes — for  example,  that  produced  by 
phlorhizin.  Starvation  alone  is  unsatisfactory,  for  it  has  been  found 
that,  although  at  certain  stages  of  this  condition  the  liver  may  become  al- 
most entirely  free  from  any  trace  of  glycogen,  at  a  later  stage  glycogen 
may  again  make  its  appearance.  It  is  therefore  most  difficult  to  decide 
at  what  stage  in  starvation  the  animal  should  be  considered  as  glycogen- 
free. 

If  the  starving  animal  is  made  to  perform  muscular  exercise,  complete 
removal  of  glycogen  from  the  liver  can  be  depended  upon.  The  exercise 
may  be  produced  by  the  administration  of  strychnine  in  such  dosage  as 
just  to  produce  convulsions  of  the  voluntary  muscles  without  permanent 
contraction  of  those  of  respiration.  The  most  useful  method,  however, 
consists  in  starving  the  animal  for  a  few  days  and  then  placing  it  in  a 
cold,  damp  room,  after  giving  it  a  cold  bath.  The  evaporation  of  mois- 
ture from  the  surface  so  cools  the  body  down  that  the  stores  of  glycogen 
a.ll  become  used  up  in  the  attempt  to  supply  fuel  for  the  production  of 


696  METABOLISM 

sufficient  heat  to  maintain  the  body  temperature.  This  method  can  be 
rendered  still  more  certain  in  effecting  a  removal  of  all  carbohydrate 
from  the  body  by  giving  the  animal  phlorhizin  every  eight  hours.  Phlor- 
hizin,  as  we  shall  see,  renders  the  animal  diabetic. 

After  removing  the  glycogen,  further  deposition  in  the  liver  can  be 
readily  shown  to  occur  when  any  of  the  ordinary  sugars  or  starches  are 
given  as  food.  It  does  not  occur,  however,  when  chemical  substances 
closely  related  to  ordinary  sugar,  such  as  the  wood  sugars  (pentoses) 
or  the  alcohols  and  acids  corresponding  to  dextrose,  are  contained  in  the 
diet.  Nor  does  it  occur  with  cellulose  or  with  inulin,  a  polysaccharide 
built  up  from  pentose  sugar.  When  proteins  are  fed  the  results  are  not 
so  definite,  although  many  observers  have  claimed  that  glycogen  is 
formed.  With  fat,  on  the  other  hand,  no  glycogen  formation  can  be 
shown  to  occur,  although  we  know  that  a  trace  of  carbohydrate  must  be 
formed  out  of  the  glycerine  of  the  fat  molecule. 

The  results  of.  the  direct  method,  even  when  the  conditions  are  per- 
fectly controlled,  are  very  unreliable,  especially  when  they  are  of  a  nega- 
tive character,  because  any  new  sugar  that  may  be  produced  by  the  in- 
gested substance  instead  of  being  stored  as  glycogen  is  likely  to  be  used 
by  the  tissues  as  it  is  formed.  Where  only  a  slight  degree  of  gluconeo- 
genesis,  as  the  process  of  sugar  formation  is  called,  is  occurring,  it  is  not 
probable  that  any  of  the  glucose  will  be  retained  in  the  body  as  glycogen. 

The  methods  employed  for  producing  experimental  diabetes  in  investi- 
gation of  these  problems  by  the  indirect  method  are  (1)  the  entire  removal 
of  the  pancreas,  and  (2)  the  continuous  administration  of  the  drug 
phlorhizin.  The  animal  rendered  diabetic  by  either  of  these  methods  is 
first  of  all  observed  for  several  days  to  determine  the  normal  daily  ex- 
cretion of  sugar.  At  the  same  time  the  nitrogen  excretion  for  the  day 
is  determined,  the  ratio  between  the  total  nitrogen  and  the  glucose — 
known  as  G  to  N  ratio — being  about  3'.65  to  1  when  complete  diabetes 
has  become  established.  The  foodstuff  in  question  is  then  fed  to  the 
animal,  and  the  amount  of  extra  glucose  excreted  thereby  is  taken  to 
represent  that  which  has  been  derived  from  the  ingested  food.  By  this 
method  it  has  been  possible  to  show  that,  not  only  the  above  mentioned 
carbohydrates,  but  protein  as  well  produce  a  very  considerable  quan- 
tity of  glucose  in  the  animal  body.  Fats,  however,  yield  only  negative 
results. 

The  indirect  method  has  another  great  advantage  over  the  direct  in 
that  the  results  are  much  more  quantitative  in  character;  for  example, 
Lusk  and  his  pupils  have  been  able  to  determine  the  amount  of  glucose 
which  can  be  produced  by  feeding  certain  of  the  building  stones  of  the 
protein  molecule.  The  great  practical  importance  of  such  results  in 


THE    METABOLISM    OF    THE    CARBOHYDRATES  697 

the  therapy  of  diabetes  makes  it  advisable  for  us  to  go  into  the  subject 
a  little  more  in  detail  here. 

After  a  cold  bath  and  exposure  in  a  cold  room,  dogs  are  rendered 
diabetic  by  phlorhizin.  When  all  of  the  original  glycogen  in  the  body 
has  been  got  rid  of,  as  evidenced  by  the  constancy  of  the  G  to  N 
ratio  in  the  daily  quantities  of  urine  excreted,  the  substance  under  in- 
vestigation is  fed.  If  this  substance  contains  no  nitrogen  and  causes  no 
change  in  the  nitrogen  excretion,  any  increase  in  that  of  glucose  must 
obviously  represent  the  extent  to  which  the  substance  has  become  con- 
verted into  this  sugar.  On  the  other  hand,  if  the  substance  itself  con- 
tains nitrogen,  or  if  it  causes  a  change  in  the  excretion  of  nitrogen,  it 
becomes  necessary  to  calculate  how  much  of  the  excreted  glucose  may 
have  been  derived  from  the  body  protein,  assuming  that  this  can  form 
glucose,  and  how  much  from  the  administered  substance.* 

From  the  results  of  this  method  it  has  been  an  easy  matter  to  show 
that  the  following  substances  are  converted  in  the  animal  body  into 
glucose:  (1)  Glycol  aldehyde  (CH2OH-CHO).  By  placing  three  mol- 
ecules of  this  substance  together,  a  hexose  molecule  results,  a  synthesis 
which  can  be  accomplished  in  the  chemical  laboratory.  The  hexose  formed 
in  the  animal  body  is  glucose.  Glycol  aldehyde  may  be  formed  in  normal 
metabolism  out  of  glycocoll  (CH2NH2COOH). 

(2)  Glycerol   (CH2OH-  CHOH-  CH2OH)    may   also   readily   be    con- 
verted into  hexose  in  the  laboratory,  the  possible  intermediary  products 
being    dioxyacetone     (CH2OH  -  CO  -  CH2OH)     and    glyceric    aldehyde 
(CH2OH-CHOH-CHO).     Two  molecules   of  either   of  these   may  be 
polymerized  to  form  a  hexose  molecule,  and  when  this  process  occurs 
in  the  animal  body,  the  hexose  formed  is  glucose. 

(3)  Lactic  acid  (CH3CHOH  -  COOH)   is  completely  converted  to  glu- 
cose in  the  diabetic  animal,  and  the  process  must  involve  both  a  re- 
arrangement of  the  molecule  and  subsequent  polymerization.    The  related 
substance,  propyl  alcohol    (CH3  -  CH2  -  CH2OH)    is  also  converted  into 
glucose  in  the  phlorhizinized  dog.  As  to  the  exact  nature  of  the  chemical 
changes  which  occur  as  intermediary  stages  in  the  conversion  of  these 
substances   into    glucose,   we   are   not   as   yet   certain,   but   a   clue   has 
been   afforded  by   the   discovery  that   a   substance   called   methylglyoxal 
(CHgCOCHO)  can  be  obtained  from  lactic  acid  and  also  from  glucose,  and 
that  this  substance  is  converted  into  glucose  when  it  is  administered  to  phlor- 
hizinized dogs.     We  shall  find  later  an  important  role  for  this  substance 
in  fat  metabolism.     It  can  also  readily  be  produced  during  the  interme- 

*This  calculation^  made  as  follows:  The  amount  of  nitrogen  in  the  administered  substance  is 
deducted  from  the  nitrogen  excretion,  and  the  difference,  which  must  represent  the  nitrogen  of  the 
body  protein,  is  multiplied  by  the  G  to  N  ratio  which  prevailed  on  the  day  previous  to  that  on 
which  the  substance  was  fed.  We  obtain  in  this  way  the  glucose  derived  from  the  body.  The 
glucose  coming  from  the  administered  substance  can  then  be  ascertained  by  deducting  that  derived 
from  the  body  protein  from  the  total  glucose  excretion. 


698  METABOLISM 

diary  breakdown  of  certain   of  the   protein   building-stones,   such   for 
example  as  alanine  (CH3CHNH2COOH). 

These  chemical  possibilities  regarding  the  nature  of  the  substances 
that  serve  as  stepping  stones  between  the  above  sugar-forming  sub- 
stances and  sugar  itself  may  be  considered  as  probabilities  on  account 
of  the  discovery  that  enzymes  exist  in  various  tissues  which  are  capable 
of  converting  methylglyoxal  into  lactic  acid : 

CH3  CH3 

|  I 

CO          +  H2-»HCOH 

I  Q<-    J 
CHO  COOH 

(methylglyoxal)         (lactic  acid) 

These  enzymes  are  called  glyoxalases,  and  since  the  reactions  which 
they  mediate  are  undoubtedly  reversible  in  character,  it  is  probable  that 
the  conversion  into  sugar  of  lactic  acid  and  alanine — to  take  those  two 
as  among  the  commonest  of  the  sugar  precursors  of  the  animal  body- 
occurs  according  to  the  following  equation: 

CH3CHNH2COOH  v. 

(alanine)  CHXOCHO  — >  C6H12O6 

CH,CHOHCOOH   /* 

(lactic  acid)          (methylglyoxal)    (hexose) 

The  unique  position  of  methylglyoxal,  besides  explaining  the  known 
resolutions  of  protein  and  fat  and  carbohydrate  in  intermediary  metab- 
olism, is  also  of  importance  in  explaining  the  synthetic  production  of 
glucose  from  fructose  (or  levulose).  Fructose  will  first  of  all  become 
converted  into  methylglyoxal  radicles,  and  these  will  then  become  syn- 
thetized  into  glucose. 

The  hypothesis  of  the  conversion  of  glucose  into  lactic  acid  as  a  stepping 
stone  in  the  metabolism  of  carbohydrate  is  difficult  to  test  by  direct  ex- 
periment because  the  lactic  acid  does  not  accumulate  in  the  organism, 
except  in  cases  where  there  is  oxygen  deficiency  or  excess  of  alkali  in  the 
tissue  fluids. 

Coming  now  to  the  amino  acids,  which,  it  will  be  remembered  repre- 
sent the  building  stones  of  the  protein  molecule,  it  has  been  found  that 
glycocoll,  alanine,  and  aspartic  and  glutamic  acids  increase  the  glucose 
excretion  when  given  to  phlorhizinized  dogs,  whereas  leucine  and  tyro- 
sine  have  no  such  action.  By  the  method  described  above,  it  is  possible 
to  determine  the  exact  proportion  of  the  carbon  of  each  of  those  amino 
acids  which  becomes  converted  to  glucose.  This  is  shown  in  the  accom- 
panying table. 

It  is  of  further  interest  to  point  out  that  these  four  amino  acids 
constitute  about  26  per  cent  of  all  the  amino  acids  in  flesh  protein,  and 


THE    METABOLISM    OF    THE    CARBOHYDRATES 


699 


TWENTY  GRAMS  OF  THE  VARIOUS  AMINO  BODIES  WERE  GIVEN  TO 
PHLORHIZIN-DIABETIC  DOGS 


ACID  AND  FORMULA 

AVERAGE  AMOUNT 
OF  GLUCOSE  PRO- 
DUCED  IN  BODY 

PROBABLE                  GLUCOSE  THAT 
CHANGE                     WOULD  BE  PRO- 
DUCED BY  CHANGE 

Glycocoll 
CH2NH2COOH 

i.  alanine 
CH3CHNH2COOH 

Aspartic  acid 

13.43     (five     dogs, 
one  gave  15.77) 

18.77   (two  dogs) 
12.42    (four   dogs) 

All  C  converted             16.00 
to  glucose 

"                          20.22 
Three  of  the  four         13.52 

COOH— CH2—  CHNH,— COOH 


Glutamic  acid 
COOH 

CH2         . 
CHa— CHNHa 
COOH 


13.31 


C  atoms  converted 
to  glucose 

Three  of  the  five 
C  atoms  converted 
to  glucose 


12.24 


that  the  total  yield  of  glucose  from  them  could  be  26.3  grams;  thus 
accounting  for  nearly  one  half  of  the  66  grams  which  a  diabetic  animal 
produces  from  100  grams  of  flesh. 

Gluconeogenesis  in  Normal  Animals. — Although  it  has  been  clearly 
shown  by  the  indirect  method  that  not  only  protein  but  its  decomposi- 
tion products  as  well,  can  be  readily  converted  into  glucose,  yet  this  does 
not  necessarily  indicate  that  a  similar  conversion  occurs  in  the  nondia- 
betic  animal.  That  such  is  the  case,  however,  can  be  shown  in  various 
ways.  Thus,  at  the  end  of  a  period  of  long  starvation  considerable 
quantities  of  glycogen  are  quite  commonly  found  in  the  body,  and  the 
blood  sugar,  although  lower  than  normal,  never  entirely  disappears. 
Now,  since  no  carbohydrate  is  being  ingested,  and  the  body  stores  of  this 
foodstuff  become  exhausted  early  during  starvation  (cf.  page  695),  it 
is  evident  that  the  carbohydrate  must  be  produced  from  the  protein  of 
the  animal's  body.  A  still  more  convincing  experiment  can  be  con- 
ducted by  producing  strychnine  convulsions  in  a  starving  animal.  If 
the  animal  is  killed  after  the  convulsions  have  lasted  for  a  certain  time, 
the  tissues  will  be  found  almost,  if  not  entirely,  free  of  glycogen, 
but  if  the  convulsions  are  made  to  disappear  by  giving  chloral  and  the 
animal  allowed  to  sleep  for  some  time  before  killing  it,  glycogen  again 
accumulates  in  the  body.  This  glycogen  must  have  been  manufactured 
out  of  noncarbohydrate  material. 

Corroborative  evidence  of  a  somewhat  different  nature  is  furnished  by 
an  examination  of  the  respiratory  quotient,  which,  it  will  be  remem- 
bered (page  582),  varies  according  to  the  nature  of  the  foodstuff  or  body 


700 


METABOLISM 


constituent  that  is  undergoing  metabolism  at  the  time,  being  about  1 
with  carbohydrate  and  about  0.8  with  protein.  If  the  quotient  is 
observed  during  starvation,  it  will  often  be  found  to  fall  below  0.7,  a 
figure  which  can  be  explained  only  by  assuming  that  oxygen  has  been 
retained  in  the  body  beyond  the  quantity  which  is  necessary  for  imme- 
diate purposes  of  oxidation  (cf.  equations  on  page  583). 

Since  it  is  known  that  this  retained  oxygen  can  not  exist  in  the  body 
in  a  free  state  it  must  be  concluded  that  it  has  become  incorporated 
into  substances  having  a  high  oxygen  content.  Such  would  be  the  case 
if  protein  or  fat,  which  contains  only  from  12  to  20  per  cent  of  oxygen, 
were  converted  to  carbohydrate,  which  contains  about  53  per  cent. 
Utilization  of  inhaled  oxygen  for  this  purpose,  as  we  have  seen,  becomes 
very  striking  in  the  case  of  hibernating  animals  during  the  winter  sleep. 


CHAPTER  LXXVIII 

THE  METABOLISM  OF  THE  CARBOHYDRATES  (Cont'd) 
FATE  OF  GLYCOGEN 

Having  become  familiar  with  the  sources  from  which  glycogen  may 
be  derived,  we  may  now  proceed  to  study  the  fate  of  the  glycogen  found 
in  the  liver  cells  and  in  the  muscles.  For  the  present  we  shall  confine  our 
attention  to  the  glycogen  of  the  liver.  If  a  portion  of  liver  removed 
from  a  well-fed  animal  is  examined  microscopically  after  staining  either 
with  iodine  or  with  carmine  by  Best's  method,  it  will  be  found  that  the 
cells  of  the  lobules  are  filled  with  glycogen  except  for  the  nuclei,  which 
are  free  from  this  substance.  If,  on  the  other  hand,  the  liver  is  from  an 
animal  that  has  not  been  recently  fed,  the  lobules  will  contain  no  glyco- 
gen except  in  an  area  bordering  on  the  central  vein  and  perhaps  a 
narrow  strip  at  the  periphery  of  the  lobule.  When  it  is  present  the  rela- 
tive amount  of  glycogen  in  different  lobules,  as  determined  chemically, 
is  the  same  over  the  entire,  liver — that  is  to  say,  no  one  lobe  is  richer  in 
this  substance  than  another.  Nothing  definite  is  known  as  to  how  the 
glycogen  is  held  in  the  protoplasm  of  the  cells,  although  some  histolo- 
gists  suggest  that  it  is  combined  with  a  sustentacular  material  especially 
provided  for  this  purpose. 

The  glycogen  stored  in  the  liver  is  gradually  given  up  to  the  blood  of 
the  hepatic  vein  at  such  a  rate  as  to  maintain  in  the  blood  of  the  sys- 
temic circulation  a  more  or  less  constant  percentage  of  glucose.  Under 
ordinary  conditions  this  process  of  glycogenolysis  is  relatively  slow,  but 
when  the  requirements  of  the  organism  for  fuel  become  increased,  as 
during  muscular  exercise,  it  becomes  very  rapid.  The  glycogenic  func- 
tion of  the  liver  appears  therefore  to  exist,  in  part  at  least,  for  the 
purpose  of  preventing  the  flooding  of  the  blood  of  the  systemic  circu- 
lation with  excess  of  sugar  during  absorption  from  the  intestine  and  of 
maintaining  the  normal  percentage  at  other  times.  This  function  is 
analogous  to  that  occurring  in  plants,  in  which  the  sugar  produced  in 
the  leaves,  if  not  immediately  required,  is  transported  to  various  parts 
of  the  plant  and  there  converted  into  starch,  which,  when  the  plant 
requires  it,  as  during  new  growth,  may  again  become  transformed  into 
glucose. 

The  agency  converting  the  glycogen  into  glucose  is  the  diastatic 

701 


702  METABOLISM 

enzyme  glycogenase,  which  is  present,  not  only  in  the  liver  cell,  but 
also  in  the  blood  and  lymph.  It  is  a  difficult  matter  to  explain"  why 
glycogen  should  be  able  to  exist  at  all  in  the  liver  cells  in  the  presence 
of  this  powerful  enzyme.  The  following  possibilities  may  be  considered: 
(1)  That  glycogenase  does  not  really  exist  in  the  living  liver  cells,  but 
is  a  postmortem  product;  (2)  that,  although  present,  glycogenase  is  pre- 
vented from  acting  on  the  glycogen  in  the  living  liver  cell  on  account  of 
the  latter  being  protected  from  its  influence  by  combination  with  a 
sustentacular  substance;  or  (3)  that  some  chemical  substance  in  the  liver 
cell  prevents  the  glycogenase  from  acting  on  the  glycogen — an  anti- 
glycogenase.  Since  the  removal  of  any  one  of  these  inhibiting  influ- 
ences would  cause  glycogenolysis  to  become  excessive,  and  so  bring 
about  hyperglycemia,  it  is  important,  in  searching  for  the  possible 
causes  of  this  condition,  to  examine  the  evidence  that  has  been  brought 
forward  in  support  of  each  of  these  views. 

Against  the  first  of  the  above-mentioned  possibilities,  namely,  that  glycogenase  is  a 
post-mortem  product,  may  be  cited  the  very  rapid  conversion  into  glucose  that  occurs 
when  glycogen  is  added  to  living  blood,  as  by  injecting  some  into  a  vein.  On  account  of 
the  active  glycogenolytic  action  of  blood,  it  has  been  suggested  that  during  life  glycogen 
does  not  become  transformed  into  glucose  until  after  it  has  been  discharged  into  the 
blood  from  the  liver  cell.  When  increased  sugar  must  be  mobilized,  glycogen  passes 
unchanged,  or  perhaps  as  some  dextrine,  into  the  blood  and  lymph  of  the  liver  capillaries 
and  lymphatics,  the  glycogenase  of  which  converts  it  into  glucose,  the  conversion  being 
so  rapid  that,  by  the  time  the  blood  has  traveled  from  the  liver  through  the  heart 
and  pulmonary  vessels  to  the  arteries,  all  the  glycogen  has  already  become  transformed 
into  glucose.  Postmortem  glycogenolysis,  according  to  this  view,  is  due  to  the  opposite 
occurrence — the  transference  of  glycogenase  from  the  blood  into  the  liver  cell.  Some 
facts  supporting  this  view  are  as  follows:  (1)  It  has  been  found  that  the  amount  of 
free  glucose  in  the  blood  of  the  vena  cava  is  sometimes  less  than  in  that  collected  simul- 
taneously from  the  carotid  artery.  (2)  After  giving  certain  substances,  such  as  phos- 
phorus or  peptone,  there  is  distinct  diminution  in  the  amount  of  glycogen  in  the  liver, 
accompanied,  it  is  said,  by  no  increase  in  the  amount  of  glucose  in  the  blood.  And 
(3)  if  the  liver  of  an  animal  that  has  been  rendered  diabetic  by  stimulation  of  the 
splanchnic  nerve  or  by  puncture  of  the  floor  of  the  fourth  ventricle  is  examined  micro- 
scopically, after  staining  by  the  carmine  method,  masses  of  stained  glycogen  can  be 
found  present  in  the  capillaries  (sinusoids)  that  lie  between  the  liver  cells. 

According  to  the  second  view,  the  glycogen  is  removed  from  the  influence  of  the  in- 
trahepatic  glycogenase  on  account  of  its  combination  with  a  sustentacular  material. 
By  disrupting  this  combination  and  thus  exposing  the  glycogen  to  the  action  of  glyco- 
genase, glycogenolysis  will  occur.  We  may  call  this  the  mechanical  hypothesis  and 
it  deserves  serious  consideration,  for  it  has  been  shown  that  very  little  postmortem 
glycogenolysis  occurs  in  the  intact  liver  of  frogs  in  winter, — even  though  at  this  time 
the  organ  contains  an  excess  of  glycogen, — but  becomes  marked  when  the  liver  is  broken 
down  by  mechanical  means. 

The  third  view  depends  on  the  well-known  fact  that  enzyme  activities  becomes  most 
markedly  altered  by  slight  changes  in  the  chemical  nature  of  the  environment  in  which 
they  act.'  Diastatic  enzymes  are  particularly  susceptible  to  the  reaction  (CH)  of  their 
environment,  a  very  slight  degree  of  acidity  favoring  and  a  trace  of  alkalinity  mark- 


THE    METABOLISM    OF    THE    CARBOHYDRATES  703 

edly  depressing  their  activities.  That  a  tendency  to  increasing  acidity  in  the  liver 
cells  may  accelerate  the  breakdown  of  glycogen  is  suggested  by  the  depressing  effect 
produced  on  the  assimilation  limit  of  sugars  by  administering  acids,  and  by  the  ob- 
servation that  postmortem  glycogenolysis  becomes  marked  in  proportion  as  the  dying 
liver  becomes  acid  in  reaction.  It  might  be  thought  then  that  glycogenolysis  in  the 
liver  cell  could  be  set  up  by  the  local  production  of  a  certain  amount  of  acid.  Such 
a  liberation  of  free  acid  could  be  brought  about  by  a  curtailment  in  the  arterial  blood 
supply  of  the  hepatic  cell,  producing  a  local  accumulation  either  of  carbonic  or  of  other 
less  completely  oxidized  acids  (e.  g.,  lactic).  It  may  be  that  asphyxia  causes  hyper- 
glycemia  by  such  a  mechanism.  Vasoeonstriction  and  consequent  curtailment  of  ar- 
terial blood  supply  occurs  in  the  liver  when  the  hepatic  nerves  are  stimulated,  and 
it  is  possible  that  the  glycogenolysis  which  is  also  set  up  by  such  stimulation  is  due  to 
the  appearance  of  acids.  The  accelerating  effect  of  epinephrine  on  glycogenolysis  might 
also  be  explained  as  due  to  limitation  of  blood  supply  on  account  of  vasoconstriction 
and  local  asphyxia. 

THE  REGULATION  OF  THE  BLOOD  SUGAR  LEVEL 

The  level  at  which  the  concentration  of  sugar  in  the  systemic  blood 
is  maintained  represents  the  balance  between  two  opposing  factors:  (1) 
the  consumption  of  glucose  bv  the  tissues,  and  (2)  the  production  of 
glucose  by  the  liver.  Since  this  is  the  most  readily  oxidizable  of  all 
the  proximate  principles  of  food  (page  685),  muscular  activity  causes 
large  quantities  of  it  to  be  consumed,  so  that  its  concentration  in  the 
blood  tends  to  fall  below  the  physiological  level,  a  tendency  which  is 
immediately  met  by  an  increased  discharge  of  glucose  from  the  liver. 
The  question  therefore  arises  as  to  how  the  muscles  or  other  tissues 
transmit  their  requirements  for  glucose  to  the  liver.  There  are  two 
possible  ways  by  which  this  could  be  done:  (1)  by  means  of  a  nervous 
reflex,  or  (2)  by  changes  in  the  composition  of  the  blood,  either  with 
regard  to  the  percentage  of  sugar  itself  or  because  of  the  appearance  in 
it  of  decomposition  products  of  glucose  or  of  some  special  exciting 
agent  or  hormone. 

In  order  to  ascertain  the  relative  importance  of  these  methods  of 
correlation  between  the  places  of  supply  and  demand  of  glucose  in  the 
normal  animal,  it  is  necessary  to  investigate  the  conditions  under  which 
an  excessive  discharge  of  glucose  occurs  either  because  of  overstimulation 
of  the  nervous  control,  or  because  of  the  presence  of  exciting  substances 
(hormones)  in  the  blood.  The  glycogenolytic  function  can  be  excited  through 
the  nervous  system  in  a  variety  of  ways  so  as  to  cause  hyperglycemia 
and  glycosuria.  This  constitutes  one  form  of  experimental  diabetes.  In 
laboratory  animals  mechanical  irritation  of  the  medulla  oblongata  and 
stimulation  of  the  great  splanchnic  nerves  act  in  this  way.  Similar  stimula- 
tion may  also  occur  under  certain  conditions  in  man.  Excitation  as  a  result 
of  changes  in  the  composition  of  the  blood  can  be  produced  experimen- 
tally by  certain  drugs  (phlorhizin),  or  by  the  removal  of  certain  of  the 


704  METABOLISM 

ductless  glands  or  the  injection  of  extracts  prepared  from  them,  such 
as  epinephrine. 

Nerve  Control  and  the  Nervous  Forms  of  Experimental  Diabetes. — 

The  simplest  experimental  condition  which  illustrates  the  relationship 
between  the  nervous  system  and  the  blood  sugar  is  electrical  stimulation 
of  the  great  splanchnic  nerve  in  animals  in  which,  by  previous  feeding 
with  carbohydrates,  a  large  amount  of  glycogen  has  been  deposited  in 
the  liver.  By  examination  of  the  blood  as  it  is  discharged  into  the  vena 
cava  from  the  hepatic  veins,  the  increase  in  blood  sugar  is  very  evident 
in  from  five  to  ten  minutes  after  the  first  application  of  the  stimulus; 
but  it  is  not  until  later  that  a  general  hyperglycemia  becomes  estab- 
lished. The  conclusion  which  we  may  draw  from  these  results  is  that 
the  splanchnic  nerve  contains  efferent  fibers  controlling  the  rate  at 
which  glycogen  becomes  converted  to  glucose  in  the  liver.  The  center 
from  which  these  fibers  originate  is  situated  somewhere  in  the  medulla 
oblongata,  for  the  irritation  that  is  set  up  by  puncturing  this  portion  of 
the  nervous  system  with  a  needle  yields  results  similar  to  those  which 
follow  splanchnic  stimulation.  This  "  glyco  genie"  or  diabetic  center,  as 
it  has  been  called,  must  be  provided  with  afferent  impulses.  Such  im- 
pulses have  indeed  been  described  in  the  vagus  nerves,  but  their  dem- 
onstration is  by  no  means  an  easy  matter  on  account  of  the  disturbance 
in  the  respiratory  movements  coincidently  produced  by  the  stimulation. 
The  changes  that  such  disturbances  bring  about  in  the  aeration  of  the 
blood  may  in  themselves  be  responsible  for  the  hyperglycemia  (see  page 
348).  It  can  at  least  be  said  that  when  the  respiratory  disturbances  are 
guarded  against,  as  by  intratracheal  insufflation  of  oxygen,  vagal  hyper- 
glycemia is  much  less  marked,  if  not  entirely  absent.  But  this  question 
awaits  more  thorough  investigation. 

The  increased  glycogenolysis  which  results  from  stimulation  of  the 
efferent  fibers  in  the  splanchnic  nerves  may  depend  either  on  a  direct 
control  exercised  over  the  glycogenic  functions  of  the  hepatic  cells,  or 
on  the  discharge  into  the  blood  of  some  hormone  which  excites  the 
glycogenolytic  process.  It  must  furthermore  not  be  lost  sight  of  that 
the  glycogenolysis  may  be  secondary  to  local  asphyxial  conditions  in 
the  liver  cells  resulting  from  vasoconstriction.  From  their  anatomic 
position,  the  adrenals  are  to  be  thought  of  as  the  source  of  the  hormone, 
and  evidence  that  splanchnic  hyperglycemia  is  entirely  due  to  hyper- 
secretion  from  these  glands  has  seemed  to  be  furnished  by  the  fact  that 
soon  after  they  are  extirpated  splanchnic  stimulation  no  longer  pro- 
duces hyperglycemia.  There  is  also  no  doubt  that  the  nervous  system, 
acting  by  way  of  the  splanchnic  nerves,  does  exercise  a  control  over  the 
discharge  of  the  internal  secretion  of  the  adrenal  glands  and  that  extracts 
of  the  gland,  which  we  must  suppose  act  in  the  same  way  as  the  internal 


THE    METABOLISM    OF    THE    CARBOHYDRATES  705 

secretion,  cause  hyperglycemia  when  injected  intravenously  (epinephrine 
hyperglycemia  and  glycosuria)  (page  776). 

There  are,  however,  several  experimental  facts  which  do  not  conform 
with  such  a  view.  Thus,  after  complete  severance  of  the  hepatic  plexus 
of  nerves,  stimulation  of  the  splanchnic  nerve  does  not  cause  the  usual 
degree  of  hyperglycemia,  whereas  electric  stimulation  of  the  peripheral 
end  of  the  cut  plexus  does  cause  it.  On  the  one  hand,  therefore,  there 
is  evidence  that  stimulation  of  the  efferent  nerve  path  above  the  level  of 
the  adrenals  has  no  effect  on  the  sugar  production  of  the  liver  in  the 
absence  of  these  glands ;  and  on  the  other,  we  see  that  when  the  glands  are 
present,  stimulation  of  the  nerve  supply  of  the  liver  is  effective,  even 
though  the  point  of  stimulation  is  beyond  them.  There  is  but  one  con- 
clusion that  we  may  draw — namely,  that  the  functional  integrity  of  the 
efferent  nerve-fibers  that  control  the  glycogenolytic  process  of  the  liver 
depends  on  the  presence  of  the  adrenals,  very  probably  because  of  the 
hormone  which  the  glands  secrete  into  the  blood.  This  conclusion  is 
corroborated  by  the  fact  that  stimulation  of  the  hepatic  plexus,  even 
with  a  strong  electric  current,  some  time  after  complete  removal  of 
both  adrenals,  is  not  followed  by  the  usual  degree  of  excitement  of  the 
glycogenolytic  process. 

These  experiments  demonstrate  a  possible  relationship  between 
the  nervous  control,  and  at  least  one  form  of  hormone  control,  of  the 
sugar  output  of  the  liver.  They  indicate  that  when  a  sudden  increase 
of  blood  sugar  is  required,  the  glycogenic  center  sends  out  impulses 
which  not  only  directly  excite  the  breakdown  of  glycogen  in  the  he- 
patic cells,  but  also  simultaneously  influence  the  adrenals  in  such  a  man- 
ner as  to  produce  more  epinephrine  in  the  blood  and  so  augment  the  ac- 
tion of  the  nerve  impulse.  It  must  be  pointed  out  that  the  less  marked 
hyperglycemia,  following  piqure  and  splanchnic  stimulation  in  adrenal- 
ectomized  animals  may  be  due  to  the  moribund  condition  of  the  animal, 
for  Stewart  and  Rogoff  have  shown  that  piqure  causes  the  usual  degree 
of  hyperglycemia  when  it  is  performed  on  cats  some  time  after  removal 
of  one  adrenal  and  complete  denervation  of  the  other.  At  the  time  of  the 
piqure  the  animals  were  well  nourished  and  apparently  normal  in  every 
way  (cf.  page  787). 

We  are  as  yet  quite  in  the  dark  as  to  the  mechanism  by  which  the  nerve  impulses  or 
the  hormone  brings  about  increased  glycogenolysis.  It  must  consist  of  a  removal  of  the 
influence  that  prevents  glycogenolysis  from  occurring  in  the  normal  liver,  for  it  has 
been  shown  by  direct  observation  that  there  is  no  increase  in  the  amount  of  glycogenase 
present  in  extracts  of  the  liver  removed  from  diabetic  animals  over  that  present  in 
extracts  of  the  liver  of  normal  animals.  The  possible  nature  of  this  influence  has 
already  been  discussed  (page  702).  The  change  may  consist  either  in  a  loosening  of 
the  combination  between  the  glycogen  and  the  protoplasm  of  the  liver  cell,  or  in  a 
removal  of  the  chemical  influence  that  ordinarily  prevents  the  glycogenase  from  at- 


706  METABOLISM 

tacking  the  glyeogen.  In  the  former  case  the  glycogen  liberated  from  its  union  with 
the  sustentacular  substances  would  either  become  attacked  by  the  glycogenase  present 
in  the  liver  cell  itself  or  it  would  first  of  all  migrate,  as  glyeogen,  into  the  blood  capil- 
laries and  there  be  attacked  by  the  blood  glycogenase.  Evidence  for  the  possibility  of 
the  occurrence  of  such  a  process  has  already  been  given  (page  702).  The  chemical 
change  referred  to  under  the  second  possibility  might  consist  in  an  alteration  in  the 
hydrogen-ion  concentration  of  the  liver  cell,  a  change,  however,  which  for  obvious  reasons 
it  is  impossible  to  investigate. 

Nervous  Diabetes  in  Man.— The  main  interest  attaching  to  the  inves- 
tigation of  these  nervous  forms  of  experimental  diabetes  depends  on  the 
insight  which  they  afford  us  into  the  nature  of  the  mechanism  by  which 
a  prompt  mobilization  of  glucose  may  be  brought  about  in  the  normal 
animal.  There  is  also  some  evidence  that  a  relationship  may  exist  be- 
tween certain  of  the  clinical  varieties  of  the  disease  in  man  and  repeated 
excitation  of  glycogenolysis  brought  about  by  nerve  stimulation.  In- 
creased glucose  output  from  the  liver  as  a  result  of  nerve  excitation 
may  be  a  normal  process,  but  there  is  reason  to  believe  that  frequent 
repetition  of  this  process  tends  to  induce  a  permanent  rise  in  the  glucose 
level  of  the  blood  and  therefore  a  tendency  to  diabetes.  There  have 
recently  been  collected  several  facts  which  lend  some  support  to  this 
view.  The  frequent  occurrence  of  diabetes  in  those  predisposed  by 
inheritance  to  neurotic  conditions,  or  in  those  whose  daily  habits  entail 
much  nerve  strain,  and  the  aggravation  of  the  symptoms  which  is  likely 
to  follow  when  a  diabetic  patient  experiences  some  nervous  shock,  all 
point  in  this  direction. 

Diabetes  is  common  in  locomotive  engineers  and  in  the  captains  of 
ocean  liners — that  is,  in  men  who  in  the  performance  of  their  daily  duties 
are  frequently  put  under  a  severe  nerve  strain.  It  is  apparently  in- 
creasing in  men  engaged  in  occupations  that  demand  mental  concentra- 
tion and  strain,  such  as  in  professional  and  business  work.  Cannon23 
found  glycosuria  in  four  out  of  nine  students  after  a  severe  examination, 
but  only  in  one  of  them  after  an  easier  examination.*  In  the  urines  of 
twenty-four  members  of  a  famous  football  squad,  sugar  was  found  pres- 
ent in  twelve  immediately  after  a  keenly  contested  game.  Anxiety  and 
excitement  must  have  been  responsible  for  its  appearance,  since  five  of 
the  twelve  players  were  substitutes  who  did  not  get  into  the  game. 

Although  these  nervous  conditions,  by  excitement  of  hepatic  glyco- 
genolysis, produce  at  first  nothing  more  than  an  excessive  discharge  of 
sugar  into  the  blood — a  condition  which  is  exactly  duplicated  in  our 
laboratory  experiments  by  stimulation  of  the  nerve  .supply  of  the  liver— 
their  repetition  may  gradually  lead  to  the  development  of  a  permanent 
form  of  hyperglycemia.  To  prevent  the  repetition  of  these  transient 

*We  have  been  unable  to  confirm  this  observation  even  though  the  examinations  were  made 
unusually  "nerve-racking." 


THE    METABOLISM    OF    THE    CARBOHYDRATES  707 

hyperglycemias  must  be  one  of  our  aims  in  the  treatment  of  early  stages 
of  the  disease. 

It  is  possible  that  the  relationship  of  nerve  strain  to  the  incidence  of 
diabetes  has  been  exaggerated,  for  it  has  been  stated  that  there  was  a 
marked  decrease  in  the  number  of  cases  of  this  disease  in  Berlin  during 
the  later  years  of  the  war.  During  this  period  the  nerve  strain  was  very 
great,  but  the  diet  was  greatly  restricted  and  it  may  be  in  light  of  the 
latter  fact  that  the  disease  is  related  more  to  dietetic  habits  than  to  con- 
ditions of  nerve  strain  (Magnus  Levy).  In  view  of  the  observations,  it 
is  significant  that  diabetes  is  said  to  be  increasing  in  frequency  in  the 
United  States  since  prohibition  came  into  effect.  The  excessive  consump- 
tion of  sugar  is  possibly  responsible  for  this  condition. 

Although  there  can  be  no  doubt  that  the  glycogenic  function  of  the 
liver  is  subject  to  nerve  control,  it  is  probable  that  its  control  by  hor- 
mones is  of  equal  if  not  greater  importance.  This  dual  control  of  a 
glandular  mechanism  is  by  no  means  unique  for  the  glycogenic  function, 
for  we  have  already  seen  it  to  exist  in  the  case  of  the  gastric  glands 
and  the  pancreas,  and  it  is  probable  that  it  also  exists  in  the  case  of 
the  thyroid.  It  may  well  be  that  the  nerve  control  of  the  glycogenic 
function  has  to  do  only  with  those  transitory  changes  in  sugar  produc- 
tion that  would  be  demanded  by  sudden  activities  of  muscle,  and  that 
the  hormone  control  has  to  do  with  the  more  permanent  process  of  build- 
ing up  and  breaking  down  of  glycogen  to  meet  the  general  metabolic 
requirements  of  the  tissues. 


HORMONE  CONTROL  AND  PERMANENT  DIABETES 

Nervous  excitation  can  explain  only  transitory  increases  in  blood  sugar, 
the  more  permanent  hyperglycemias  being  dependent  upon  some  dis- 
turbance in  the  hormone  control  of  carbohydrate  utilization.  This  dis- 
turbance is  a  much  more  serious  affair  than  that  produced  by  nervous 
excitation.  In  the  latter  case  the  hyperglycemia  ceases  whenever  all 
of  the  glycogen  stores  of  the  liver  have  been  exhausted;  whereas  a  dis- 
turbance in  the  hormone  control,  besides  causing  as  its  first  step  a 
breakdown  of  all  the  available  glycogen,  goes  on  to  cause  a  production 
of  sugar  out  of  protein.  A  process  of  gluconeogenesis  (new  formation 
of  glucose)  becomes  superadded  on  one  of  glycogenolysis. 

To  ascertain  the  nature  of  this  hormone  and  the  mechanism  of  its 
action  has  been  the  object  of  most  of  the  researches  on  those  forms  of 
diabetes  that  are  produced  by  changes  in  certain  of  the  ductless  glands. 
The  following  possibilities  may  be  considered:  (1)  that  the  controlling 
agency  is  the  concentration  of  glucose  in  the  blood;  (2)  that  it  is  the 


708  METABOLISM 

presence  in  the  blood  of  decomposition  products  of  glucose ;  (3)  that  it 
is  due  to  a  special  hormone  produced  from  some  ductless  gland.  Con- 
cerning the  first  of  these  possibilities,  it  is  supposed  that  the  mechanism 
involved  is  dependent  on  the  law  of  mass  action ;  namely,  that  glycogen  be- 
comes converted  into  glucose  whenever  the  blood  flowing  to  the  liver  con- 
tains less  than  its  normal  concentration  of  glucose,  and  conversely,  when  this 
blood  contains  an  excess  of  glucose,  as  during  absorption,  that  a  glycogen- 
building  process  occurs.  Although  there  can  be  little  doubt  that  the  process 
of  glycogen  formation  or  destruction  will  depend  to  a  certain  extent 
upon  the  amount  of  glucose  present  in  the  blood  flowing  to  the  liver 
cells,  yet  it  is  impossible  that  this  can  be  an  important  means  in  the 
control  that  exists  between  sugar  production  by  the  liver  and  sugar 
consumption  by  the  tissues,  because  the  sugar  that  is  added  to  the  portal 
blood  during  absorption  would  mask  any  depletion  caused  by  sugar 
consumption. 

The  second  possibility — that  the  hormone  is  some  decomposition  prod- 
uct of  glucose — would  appear  to  have  some  support,  if  we  consider  this 
hormone  to  be  an  acid  product  (carbon  dioxide  or  lactic  acid)  produced  by 
sugar  metabolism,  for  it  is  known  that  an  increase  in  the  hydrogen-ion 
concentration  of  the  blood  flowing  to  the  liver  cells  excites  a  glycogen- 
olysis.  As  we  have  already  seen,  however,  it  is  difficult  to  secure  ex- 
perimental evidence,  in  anesthetized  animals  at  least,  that  glycogen- 
olytic  activity  is  readily  excited  in  this  way. 

The  third  possibility — that  some  specific  hormone  may  exist  in  the 
blood  exciting  the  glycogenolytic  process — is  investigated  by  producing 
disturbances  involving  various  of  the  ductless  glands,  particularly  the 
pancreas,  the  adrenals,  the  parathyroids  and  the  pituitary.  The  influ- 
ence of  certain  of  these  glands  may  be  closely  bound  up  with  that 
exercised  through  the  nervous  control,  as  we  have  seen  to  be  the  case 
with  the  adrenal  gland.  Whether  it  is  by  the  production  of  hormones 
directly  necessary  for  proper  carbohydrate  metabolism,  or  by  the  re- 
moval from  the -blood  of  such  substances  as  interfere  with  this  process, 
that  the  ductless  glands  functionate,  is  one  of  the  main  problems  we 
have  to  consider.  , 

Utilization  of  Glucose  in  Tissues. — Although  the  experimental  diabetes 
induced  by  disturbances  in  the  function  of  the  ductless  glands  is  dependent 
in  the  first  instance  on  an  upset  of  the  glycogenic  function  and  later  on  glu- 
coneogenesis,  the  utilization  of  glucose  in  the  tissues  ultimately  becomes 
interfered  with.  It  is  therefore  important  that  we  should  digress  for  a 
moment  to  consider  briefly  what  is  known  regarding  the  process  by 
which  sugar  becomes  utilized  in  the  organism.  That  glucose  becomes 
used  up  by  active  muscle  there  can  be  no  doubt.  Thus,  if  the  muscles 


THE    METABOLISM    OF    THE    CARBOHYDRATES  709 

of  one  leg  in  the  frog  are  tetanized,  the  glycogen  content,  compared  with 
that  of  the  other  leg,  will  be  found  to  be  diminished. 

At  first  sight  it  might  appear  that  the  easiest  way  to  study  the  utiliza- 
tion of  glucose  in  the  muscles  would  be  to  compare  its  concentrations 
in  the  blood  flowing  to  and  coming  from  them.  The  muscle  that  has  been 
most  successfully  employed  in  studies  of  this  kind  has  been  the  heart. 
Some  years  ago  Starling  and  Knowlton24  sought  to  measure  the  consump- 
tion of  glucose  by  the  excised  mammalian  heart,  by  comparing  the  per- 
centage in  the  perfusion  fluid  at  various  periods  during  the  observation. 
Patterson  and  Starling25  showed  later,  however,  that  the  results  obtained 
by  such  a  method  can  furnish  no  criterion  of  the  actual  consumption  of 
glucose  by  the  tissue  on  account  of  the  fact  that  the  heart  itself  may 
store  away  large  quantities  of  carbohydrate  in  an  unused  state,  i.e.,  as 
glycogen.  After  allowing  for  the  glycogen  as  well  as  for  the  glucose 
consumption  by  the  lungs,  Cruikshank  and  Patterson64  computed  that 
the  heart  (of  the  cat)  uses  1.5  mg.  glucose  per  gram  per  hour. 

Other  investigators  have  thought  to  study  the  utilization  of  glucose 
by  observing  the  rate  at  which  it  disappears  from  drawn  blood  kept  in 
a  sterile  condition  at  body  temperature  for  some  hours  after  death. 
This  process  is  called  glycolysis,  and  it  has  been  assumed  that  the  process 
is  similar  to  that  which  occurs  in  the  tissues  themselves — an  assumption, 
however,  for  which  there  is  no  warranty.  Indeed,  it  may  readily  be 
shown  that  the  glycolysis  occurring  in  blood  has  very  little  if  anything 
to  do  with  the  utilization  of  glucose  in  the  tissues,  for  it  has  been  found 
that  glucose  disappears  from  drawn  blood  very  slowly  indeed  when 
compared  with  the  rate  at  which  it  disappears  from  the  blood  of  animals 
in  which  the  addition  of  glucose  from  the  liver  has  been  prevented  by 
removal  of  this  viscus  (Macleod).26 

A  third  method  for  studying  the  utilization  of  glucose  consists  in 
observing  the  respiratory  exchange  of  animals.  In  normal  animals  the 
injection  of  glucose  causes  an  increase  in  the  carbon-dioxide  excretion 
and  a  rise  in  the  respiratory  quotient,  which  it  will  be  remembered  is 
a  ratio  expressing  the  relationship  between  the  amount  of  carbon  dioxide 
excreted  and  of  the  oxygen  retained  in  the  organism.  When  carbohy- 
drate is  undergoing  combustion,  the  quotient  is  nearly  1,  whereas  with 
that  of  protein  it  is  about  0.7  (see  page  582).  By  observing  the  quotient 
under  given  conditions  one  can  compute  the  proportions  of  carbohydrate 
and  of  fat  and  protein  that  are  undergoing  metabolism.  In  the  hands 
of  Murlin  and  others,27  this  method  has  proved  of  some  value  in  settling 
certain  questions  concerning  the  utilization  of  glucose  in  normal  and 
diabetic  animals ;  but  the  results  must  be  interpreted  with  great  care  on 
account  of  the  fact  that  temporary  changes  in  the  blood  may  cause  a 


710  METABOLISM 

greater  or  a  less  expulsion  of  carbon  dioxide  from  it.  Thus,  if  acids 
appear  in  the  blood,  they  will  dislodge  carbon  dioxide,  and  apparently 
cause  the  respiratory  quotient  to  rise.  Alkalies,  on  the  other  hand,  ap- 
parently cause  the  quotient  temporarily  to  fall,  and  unless  the  observa- 
tions are  done  over  a  long  period  of  time  and  with  great  care,  faulty 
conclusions  are  very  apt  to  be  drawn  from  the  results.  Starling  and 
Evans65  have  measured  the  respiratory  exchange  in  the  heart  lung  prep- 
aration (see  page  163)  and  have  found  that  the  heart  uses  an  average  of 
3.2  c.c.  of  oxygen  per  gram  an  hour  when  doing  moderate  work,  the 
E.Q.  being  0.85.  This  corresponds  to  1.6  mg.  glucose  consumption  per 
gram  per  hour,  thus  corroborating  the  results  obtained  by  direct  estima- 
tion of  glucose. 

Diabetes  and  the  Ductless  Glands 

We  are  now  in  a  position  to  consider  the  forms  of  experimental  dia 
betes  produced  by  disturbances  in  the  ductless  glands. 

Relationship  of  the  Pancreas  to  Sugar  Metabolism. — In  no  other  of 
the  many  causes  of  diabetes  has  greater  interest  been  shown  than  in 
that  due  to  disturbance  in  the  pancreatic  function.  Many  of  the  earlier 
clinicians  who  followed  cases  of  diabetes  mellitus  into  the  postmortem 
room,  noted  that  definite  morbid  changes  in  the  pancreas  were  a  fre- 
quent accompaniment  of  the  disease.  Prompted  by  these  observations, 
several  investigators  attempted  experimental  extirpation  of  the  gland, 
but  did  not  succeed  in  producing  glycosuria  in  the  few  animals  that 
survived  the  operation.  Their  failure,  no  doubt,  was  due  to  incom- 
plete extirpation.  To  reduce  the  severity  of  the  operation,  Claude  Ber- 
nard injected  oil  into  the  pancreatic  duct,  and  tied  it;  but  he  succeeded 
in  keeping  only  two  dogs  alive  for  any  length  of  time,  and  these  did 
not  exhibit  glycosuria.  Neither  were  other  investigators  that  adopted 
similar  methods  any  more  successful.  It  looked  as  if  the  pancreas  had 
no  relationship  to  carbohydrate  metabolism.  In  the  year  1889  Minkowski 
and  von  Mering  in  Germany,  and  de  Dominicis  in  Italy,  by  thorough 
extirpation  of  the  gland,  succeeded  in  producing  in  dogs  a  marked  and 
persistent  glycosuria,  accompanied  by  many  of  the  other  symptoms  of 
diabetes.  The  first  two  authors  attributed  the  condition  to  removal  of 
an  internal  secretion. 

The  course  of  the  diabetes  produced  by  complete  pancreatectonry  is, 
however,  somewhat  different  from  that  usually  observed  in  man.  It  is 
extremely  acute  from  the  start,  the  G:N  ratio  being  3.6:1  (see  page 
696),  and  it  is  unaccompanied  by  any  of  the  classical  symptoms  seen  in 
the  clinical  condition.  Experimental  pancreatic  diabetes  can,  however, 
be  made  to  simulate  very  closely  the  disease  in  man.  This  was  first  of 


THE    METABOLISM    OF    THE    CARBOHYDRATES  711 

all  demonstrated  by  Sandemeyer,  who  found  that  if  the  greater  part  of 
the  pancreas  was  removed,  the  animals  for  some  months,  if  at  all,  were 
only  occasionally  glycosuric,  but  later  became  more  and  more  frequently 
so,  until  at  last  the  condition  typical  of  complete  pancreatectomy  super- 
vened. Similar  results  have  more  recently  been  obtained  by  Thiroloix 
and  Jacob,  in  France,  and  by  Allen  in  this  country.  These  investigators 
point  out  that  different  results  are  to  be  expected  according  to  whether 
the  portion  of  pancreas  which  is  left  does,  or  does  not,  remain  in  con- 
nection with  the  duodenal  duct.  When  this  duct  is  ligated,  atrophy  of 
any  remnant  of  pancreas  that  is  left  is  bound  to  occur,  and  this  is  asso- 
ciated with  rapid  emaciation  of  the  animal,  diabetes  and  death.  When 
the  remnant  surrounds  a  still  patent  duct,  a  condition  much  more  closely 
simulating  diabetes  in  man  is  likely  to  become  developed — one,  namely, 
in  which  there  is,  for  some  months  following  the  operation,  a  more  or 
less  mild  diabetes,  which,  however,  usually  passes  later  into  the  fatal 
type. 

It  is,  of  course,  difficult  to  state  accurately  what  proportion  of  the  pancreas  must  be 
left  in  order  that  the  above  described  condition  may  supervene.  Leaving  a  remnant 
amounting  to  from  one-fifth  to  one-eighth  of  the  entire  gland  is  commonly  followed 
by  a  mild  diabetes,  whereas  if  only  one-ninth  or  less  is  left,  a  rapidly  fatal  type  de- 
velops. As  in  clinical  experience,  the  distinguishing  feature  between  the  mild  and  the 
severe  types  of  experimental  pancreatic  diabetes  is  the  tolerance  toward  carbohydrates. 
In  the  mild  form,  no  glycosuria  develops  unless  carbohydrate  food  is  taken;  in  the 
severe  form,  it  is  present  when  the  diet  is  composed  entirely  of  flesh.  It  is  thus  shown 
that  "by  removal  of  a  suitable  proportion  of  the  pancreas,  it  is  possible  to  bring  an 
animal  to  the  verge  of  diabetes,  yet  to  know  that  the  animal  will  never  of  itself  become 
diabetic.  .  .  .  Such  animals,  therefore,  constitute  valuable  test  objects  for  judging 
the  effects  of  various  agencies  with  respect  to  diabetes'7 — (Allenis).  By  these  means 
it  becomes  theoretically  possible  to  investigate,  on  the  one  hand,  other  conditions  which 
will  have  an  influence  similar  to  removal  of  more  of  the  gland,  or,  on  the  other,  condi- 
tions which  might  prevent  the  incidence  of  diabetes,  even  though  this  extra  portion 
of  pancreas  is  removed. 

Allen  has  shown  that  the  continued  feeding  of  a  partially  depancreatized 
dog  with  excess  of  carbohydrate  food  will  surely  convert  a  mild  into  a 
?vere  case  of  diabetes,  and  in  one  experiment  he  succeeded  in  bringing 
ibout  the  same  transition  by  performing  puncture  of  the  medulla — that 
is,  by  creating  an  irritative  nervous  lesion.    By  none  of  the  other  means 
usually  employed  to  produce   experimental  glycosuria   could  the  mild 
case  be  made  severely  diabetic,  although  this  was  accomplished  in  one 
inimal  after  ligation  of  the  portal  vein.    To  the  clinical  worker  the  value 
)f  these  results  lies  in  the  fact  that  they  furnish  experimental  proof  that 
so-called  latent  case  of  diabetes — that  is,  one  that  has  a  low  tolerance 
*alue   for   carbohydrates — may  be  prevented   from   developing   into    a 
severe  case  by  proper  control  of  the  diet. 


712  METABOLISM 

The  Pathogenesis  of  Pancreatic  Diabetes 

The  certainty  with  which  diabetes  results  from  pancreatectomy  in  dogs, 
as  well  as  the  frequent  occurrence  of  demonstrable  lesions  of  the  pan- 
creas in  diabetes  in  man,  leaves  no  doubt  that  this  gland  must  be  in  some 
way  essential  in  the  physiological  breakdown  of  carbohydrates  in  the 
normal  animal,  but  how,  we  can  not  at  present  tell.  All  we  know  is 
that  the  first  change  to  occur  after  the  gland  is  removed  is  a  sweeping 
out  of  all  'but  a  trace  of  the  glycogen  of  the  liver,  although  the  glycogen  of 
the  muscles  may  remain ;  indeed,  in  the  cardiac  muscle  there  may  be  more 
than  the  usual  amount.28  Nor  can  any  glycogen  be  stored  in  the  liver  when 
excess  of  carbohydrates  is  fed.  After  the  glycogen  has  disappeared, 
gluconeogenesis  sets  in,  so  that  the  tissues  come  to  melt  away  into  sugar, 
and  all  the  symptoms  of  acute  starvation,  associated  with  certain  others 
that  are  possibly  due  to  a  toxic  action  of  the  excess  of  sugar  and  of  other 
abnormal  products  in  the  blood  such  as  ketone  bodies  make  their  appear- 
ance. 

Accompanying  the  gluconeogenesis  another  very  definite  abnormality  in 
metabolism  becomes  evident — namely,  an  inability  of  the  tissues  to  ~burn 
sugar.  This  fact  is  ascertained  by  observing  the  respiratory  quotient. 
When  glucose  is  added  to  the  blood  in  the  case  of  a  completely  diabetic 
animal,  no  change  occurs  in  the  quotient,  whereas  in  normal  animals 
under  such  conditions  it  rises  almost  to  1.0  (cf.  page  582). 

There  are,  therefore,  two  essential  disturbances  of  carbohydrate 
metabolism  in  pancreatic  diabetes — overproduction  of  sugar  and  aboli- 
tion of  the  ability  of  the  tissues  to  use  it.  It  becomes  important  for  UP 
to  see  whether  the  tissues  exhibit  this  inability  to  use  sugar  when  they 
are  isolated  from  the  animal ;  for  if  they  should,  a  much  more  searching 
investigation  of  the  essential  cause  of  their  inability  would  be  possible 
than  is  the  case  when  they  are  functioning  along  with  the  other  organs 
and  tissues. 

The  earlier  experiments,  of  Lepine  and  his  pupils,  which  seemed  to  show  that  diabetic 
blood  did  not  possess  the  glycolytic  power  of  normal  blood;  and  those  of  Cohnheim, 
from  which  it  was  concluded  that  mixtures  of  the  expressed  juices  of  muscle  and 
pancreas,  although  ordinarily  destroying  glucose,  failed  to  do  so  when  they  were  taken 
from  a  diabetic  animal,  are  now  known  to  be  erroneous.  The  failure  to  show  a  depres- 
sion of  glycolytic  power  by  these  methods  prompted  Knowlton  and  Starling2*  to 
investigate  the  question  whether  any  difference  is  evident  in  the  rate  with  which  glucose 
disappears  from  a  mixture  of  blood  and  saline  solution  used  to  perfuse  a  heart  outside 
the  body,  according  to  whether  the  heart  was  from  a  normal  or  a  diabetic  dog.  In 
the  first  series  of  observations  which  these  workers  made,  it  was  thought  that  the 
normal  heart  used  glucose  at  the  rate  of  about  4  mg.  per  gram  of  heart  substance 
per  hour;  whereas  that  of  a  diabetic  (depancreatized)  animal  used  less  than  1  mg. 
If  such  striking  differences  in  the  rate  of  sugar  consumption  could  make  themselves 
manifest  for  so  relatively  small  a  mass  of  muscular  tissue  as  that  of  the  heart,  it  is 


THE    METABOLISM    OF    THE    CARBOHYDRATES  713 

permissible  to  assume  that  a  much  more  striking  difference  could  be  demonstrated 
when  the  perfusion  fluid  is  made  to  traverse  all  or  practically  all  of  the  skeletal  muscles, 
as  well  as  the  heart.  For  this  purpose  an  eviscerated  animal  may  be  employed — that 
is,  one  in  which  the  abdominal  viscera  are  removed  after  ligation  of  the  celiac  axis 
and  mesenteric  arteries,  and  the  liver  is  eliminated  by  mass  ligation  of  its  lobes. 
Using  such  preparations,  E.  G.  Pearce  and  Macleod29  found  that  the  rate  at  which 
glucose  disappears  from  the  blood,  although  very  irregular,  is  in  no  way  different  in 
completely  diabetic  as  compared  with  normal  dogs.  They  were  thus  unable  to  confirm 
any  of  Knowlton  and  Starling's  earlier  conclusions.  As  has  already  been  stated 
Patterson  and  Starling  subsequently  pointed  out  that  a  serious  error  was  involved  in 
the  earlier  perfusion  experiments,  partly  on  account  of  a  remarkable  but  irregular 
disappearance  of  glucose  from  the  lungs,  and  partly  because  the  diabetic  heart  may 
contain  a  considerable  excess  of  glycogen,  from  which  its  demands  for  sugar  may  be 
met  without  calling  on  that  of  the  perfusion  fluid. 

More  recent  work  by  Starling  and  Evans,  in  which  the  respiratory  ex- 
change of  the  heart  in  heart  lung  preparations  from  diabetic  (pancreatic) 
dogs  was  determined,  has  revealed  a  low  R.Q.  (0.71)  although  the  oxygen 
consumption  was  normal.  These  workers  consider  that  their  results  indi- 
cate "a  depression  or  abolition  of  the  power  of  the  diabetic  tissue  to  utilize 
carbohydrate."  This  conclusion,  however,  awaits  confirmation  by  more 
direct  methods. 

Whatever  may  be  the  fundamental  cause  for  the  development  of  dia- 
betes following  pancreatectomy  it  is  important  to  know  whether  the 
condition  supervenes  because  of  the  absence  of  an  internal  secretion,  or 
hormone,  furnished  by  the  pancreas  or  merely  because  some  local  action 
of  the  gland  has  been  removed.  Attempts  have  been  made  (by  Hedon, 
Carlson  and  Drennan  and  others)  to  demonstrate  the  presence  of  such 
a  hormone  in  the  blood  of  normal  animals  but  with  doubtful  success. 

I  That  one  may  be  present  has  however  been  shown  by  A.  H.  Clark,65  who 
perfused  the  isolated  pancreas  of  a  dog  for  some  time  with  Locke's  solu- 
tion and  then  used  this  fluid  to  perfuse  the  isolated  heart  of  the  same 
animal.  He  found  under  these  conditions  (i.e.,  of  combined  perfusion) 
that  sugar  disappeared  much  more  rapidly  from  the  perfusion  fluid  than 
when  fresh  Locke's  solution  was  perfused  through  the  heart  from  the 
beginning.  This  indicates  that  the  pancreas  must  contribute  some  sub- 
stance which  is  carried  by  the  blood  to  the  heart,  and  presumably  other 
muscles,  where  it  enables  the  muscle  to  consume  sugar. 
Until  recently,  however,  no  constant  success  has  attended  the  injection 
of  pancreatic  extracts  in  reducing  the  hyperglycemia  or  other  symptoms  of 
diabetes.  Thinking  that  this  might  be  due  to  the  destruction  of  the  hor- 
mone by  the  trypsin  present  in  such  extracts,  Banting  and  Best,  working 
in  the  author's  laboratory,  made  extracts  either  from  the  residue  which 
remains  some  weeks  after  ligation  of  the  pancreatic  ducts  or  from  early 

» fetal  pancreas.  In  both  these  cases  trypsin  production  in  the  gland  is 
absent,  or  nearly  so,  but  it  is  believed  that  the  Isles  of  Langerhans  are 


714 


METABOLISM 


functioning.  Injected  subcutaneously  into  completely  depancreated  dogs, 
these  extracts  caused  a  marked  lowering  of  blood  sugar  with  great  re- 
duction in  the  sugar  excretion  by  the  urine  and  when  the  injections  were 
repeated  daily  the  animals  survived  the  operation  for  several  weeks 
longer  than  is  usually  the  case  and  were  in  excellent  condition.  Later, 
in  collaboration  with  Collip,  extracts  were  prepared  by  alcohol  from 


fcl.  15    16    17 

Fig.  190-A. — Curves  showing  effect  of  "insulin"  in  a  case  of  diabetes  mellitus.  I,  Daily 
excretion  of  glucose  in  urine  for  periods  before,  during  and  after  administration  of  Insulin;  //, 
Daily  excretion  of  total  ketone  bodies  before  and  during  administration  (from  Jan.  23rd  on);  ///, 
The  effect  of  one  injection  (4  c.c.  subcutaneously)  of  insulin  on  the  blood  sugar;  IV,  The  two 
hourly  excretion  of  glucose  for  several  days  during  administration. 


adult  beef  pancreas  and  their  effects  on  human  diabetes  observed  by 

Campbell  and  Fletcher.    The  results  as  shown  in  Fig.  190-A  justify  the 

ifiope  that  when  this  extract,  for  which  the  name  "insulin"  is  suggested, 

\is  given  subcutaneously  for  some  time  to  diabetic  patients,  the  pancreas 

may  reacquire  its  normal  function,  or  at  least,  with  control  of  the  diet, 


THE    METABOLISM    OF    THE    CARBOHYDRATES  715 

may  be  restored  sufficiently  to  effect  a  practical  cure.  In  any  case 
"insulin"  has  a  profound  effect  on  carbohydrate  metabolism  for  we  have 
found  (in  collaboration  with  Hepburn,  Latchford  and  Noble)  that  it 
causes  the  respiratory  quotient  to  rise  almost  to  unity  when  given  along 
with  sugar  to  diabetic  animals  (and  also  to  diabetic  patients),  in  which 
also  it  causes  large  amounts  of  glycogen  to  appear  in  the  liver.  Insulin 
also  greatly  reduces  the  blood  sugar  in  normal  rabbits  and  in  rabbits 
showing  hyperglycemia  as  a  result  of  piqure,  injection  of  adrenalin  or 
asphyxia. 


DIABETIC  ACIDOSIS  OR  KETOSIS 

Nature  and  Cause. — Much  confusion  has  existed  in  medical  literature 
over  the  correct  definition  of  acidosis,  mainly  because  the  term  was  first 
used  for  the  particular  variety  of  the  condition  observed  in  the  later 
stages  of  diabetes  mellitus.  The  acids  which  accumulate  in  the  tissue 
fluids  in  this  disease  are  acetoacetic  and  /3-oxybutyric,  which  are  re- 
lated to  acetone  and  are  derived  from  fatty  acids  by  a  faulty  metabolism 
(see  page  737).  The  essential  cause  of  the  acidosis  is  therefore  en- 
tirely different  from  that  in  nephritis;  in  diabetes  foreign  acids  are 
added  to  the  blood,  whereas  in  nephritis  the  acids  of  a  normal  metab- 
olism accumulate  because  of  faulty  excretion  through  the  kidneys. 
The  usual  signs  of  acidosis  exist  in  both  cases,  because  the  surplus  of 
acid  depletes  the  store  of  bicarbonate  and  causes  changes  in  the  alveolar 
C02,  in  the  C02-absorbing  power  of  the  blood,  in  the  reserve  alkalinity, 
and  in  the  acid  excretion  by  the  kidney.  It  is  important  to  recognize  the 
special  nature  of  diabetic  acidosis  by  a  separate  name — ketosis. 

The  chemical  processes  by  which  the  kQtone  bodies  are  produced  are 
discussed  elsewhere  (page  737).  It  remains  for  us  to  consider  the 
general  nature  of  the  metabolic  disturbance  responsible  for  the  appear- 
ance of  ketone  bodies  in  diabetes. 

For  the  thorough  combustion  of  fat  in  the  animal  body  a  certain 
amount  of  carbohydrate  must  be  simultaneously  burned.  Fat  evidently 
is  a  less  readily  oxidized  foodstuff  than  sugar;  it  needs  the  fire  of  the 
burning  sugar  to  consume  it.  If  the  carbohydrate  fires  do  not  burn 
briskly  enough,  the  fat  is  incompletely  consumed;  it  smokes,  as  it  were, 
and  the  smoke  is  represented  in  metabolism  by  the  ketones  and  derived 
acids.  Such  a  closing  down  of  the  carbohydrate  furnaces  may  be 
brought  about  either  by  curtailment  4of  the  intake  of  carbohydrates,  as 
in  starvation  (page  600),  or  by  some  fault  in  the  mechanism  of  the 
furnace  itself,  as  in  diabetes.  Besides  fat,  protein  may  also  contribute 
to  the  production  of  ketones  when  carbohydrate  combustion  is  de- 


716  METABOLISM 

pressed.  Fundamentally,  therefore  ketosis  in  diabetes  is  due  to  the 
same  cause  as  in  starvation — namely,  an  improper  adjustment  between 
the  metabolisms  of  fat  and  carbohydrate. 

Bearing  these  principles  in  mind,  it  is  easy  to  see  how  the  intensity 
of  acidosis  which  develops  during  starvation  will  depend  upon  the  re- 
lative metabolism  of  carbohydrate,  on  the  one  hand,  and  of  fat  and 
protein,  on  the  other;  it  will  therefore  depend  on  the  amounts  of  these 
foodstuffs  which  have  been  stored  in  the  organism,  and  this  again  will 
depend  on  the  nature  of  the  diet  previous  to  the  starvation  period.  For 
the  first  few  days  following  entire  abstinence  from  food  in  a  healthy, 
well-nourished  individual,  very  few  if  any  ketones  will  be  excreted  in 
the  urine,  because  the  carbohydrate  stored  in  the  body  as  glycogen  has 
sufficed  during  this  time  to  maintain  the  proper  proportion  between  fat 
and  carbohydrate.  Afterwards,  however,  their  appearance  is  to  be  ex- 
pected, because  the  glycogen  stores  become  exhausted  long  before  those 
of  fat.  If  starvation  is  still  further  prolonged,  a  stage  will  come  when 
the  fat,  as  well  as  the  carbohydrate,  is  used  up  so  that  the  organism  has 
now  to  subsist  on  protein  alone.  When  this  stage  arrives,  the  ketones 
will  diminish,  for,  although  they  might  be  derived  from  certain  of  the 
amino  acids,  yet  this  does  not  actually  occur,  because  a  large  part  of  the 
protein  molecule  (nearly  half)  also  becomes  changed  into  glucose,  which 
by  burning,  as  above  explained,  prevents  the  formation  of  ketones  from 
the  other  part  of  the  molecule.  For  the  same  reasons,  marked  acidosis 
will  not  be  expected  to  occur  during  any  stage  of  starvation  in  lean 
persons,  who  from  the  start  must  utilize  mainly  their  stored  protein  to 
supply  the  fuel  upon  which  to  live. 

In  diabetes  exactly  the  same  principles  apply,  but  to  an  organism  in 
which  the  ability  to  metabolize  carbohydrate  has  been  depressed,  so  that 
"the  maximum  rate  at  which  dextrose  can  be  oxidized  is  fixed  at  some 
level  which  is  absolutely  lower  than  in  health. '  '30  Therefore,  since  a  cer- 
tain proportionality  must  exist  between  the  rates  of  combustion  of  fat 
and  carbohydrate,  the  diabetic  can  thoroughly  oxidize  less  fat;  in  other 
words,  an  amount  of  fat  which  could  readily  be  burned  in  a  healthy  body 
is  improperly  burned  by  the  diabetic,  and  ketones  and  their  acids  ac- 
cumulate. 

Starvation  Treatment. — "In  order  to  check  a  diabetic  acidosis,  it  is 
necessary  to  restore  the  proper  ratio  of  fatty  acid  to  glucose  oxidation/' 
which  can  best  be  done  by  starvation,  rest  in  bed  and  warmth.  But  this 
treatment  may  not  at  first  suffice,  because  we  have  to  deal  not  only  with 
the  acidosis  bodies  derived  from  fat,  but  with  those  which  can  be  derived 
from  protein  on  account  of  the  diabetic  organism  having  lost  the  power 


THE    METABOLISM    OF    THE    CARBOHYDRATES  717 

even  of  burning  the  glucose  which  is  derived  from  this  foodstuff.  By 
persistence  in  the  starvation,  however,  the  ability  of  the  organism  to 
utilize  carbohydrate  usually  becomes  so  far  restored  that  enough  burns  to 
prevent  acidosis.  Every  case  of  diabetes  can  not,  therefore,  be  expected 
to  react  in  the  same  way  to  starvation,  the  determining  condition  being 
the  relation  between  the  quantities  of  glycogen  and  fat  stored  in  the  body 
at  the  outset  of  the  fasting  period.  This  relationship  depends  on  the 
nature  of  the  previous  diet. 

To  sum  up,  "fasting  will  lower  acidosis  either  in  health  or  in  diabetes, 
if  it  has  the  effect  of  stopping  a  one-sided  metabolism  and  throwing  the 
tissues  on  a  more  nearly  balanced  ratio  of  fatty  acids  and  glucose" — 
(Woodyatt).  A  practical  point  may  be  noted  here — namely,  that  there 
is  likely  to  be  more  danger  of  serious  acidosis  developing  during  starva- 
tion in  fat  than  in  lean  diabetics.  The  importance  of  our  appreciation  of 
these  facts  in  the  starvation  treatment  of  diabetes  will  be  self-evident. 

Insulin  Treatment. — As  already  pointed  out,  subcutaneous  injections 
of  properly  prepared  extracts  of  pancreas  remove  all  the  cardinal  symp- 
toms of  diabetes  both  in  man  and  laboratory  animals  and  also  cause  the 
ketone  bodies  to  disappear  from  the  urine.  Life  has  also  been  consider- 
ably prolonged  in  depancreated  dogs  by  such  injections  and  the  subjec- 
tive symptoms  and  muscular  vigor  of  diabetic  patients  markedly 
improved. 


CHAPTER  LXXIX 

FAT  METABOLISM 

Before  considering  the  physiology  of  fats,  a  few  of  the  most  essential 
points  regarding  their  chemistry  may  be  of  assistance. 

THE  CHEMISTRY  OF  FATTY  SUBSTANCES 

It  is  usual  to  classify  all  substances  that  are  soluble  in  ether  as  lipoids.  They  in- 
elude  fatty  acids,  neutral  fats,  cholesterols,  cholesterol  esters,  and  phospholipins. 

The  fatty  acids  belong  to  two  main  homologous  series,  which  differ  from  each  other 
with  regard  to  whether  they  are  saturated  or  unsaturated.  A  saturated  fatty  acid 
is  typified  by  palmitic,  whose  formula  is  CH3-CH2-CH2-CH2-CH2-CH2-CHo-  CH^-CH^CI^ 
CH2-CH2-CH2-CH2-CH2-COOH,  or  CH3-(CH2)14-COOH;  that  is  to2  say2  it  is2  a  MgheJ 
member  of  the  series  to  which  acetic  acid  (CH  -COOH)  belongs,  differing  from  the 
latter  in  having  fourteen  extra  methyl  radicles,  each  joined  to  its  neighbor  by  one 
bond  or  saturated  linking  on  either  side.  Another  member  of  this  series  is  stearic,  in 
which  there  are  sixteen  extra  CH2  groups  (CH3(CH2)i6-COOH).  An  unsaturated 
fatty  acid  is  oleic  (CH3(CH2)7  —  CHr=CH-(CH2)7-COOH).  Its  unsaturation  is  rep- 
resented in  the  formula  by  the  double  bond  or  unsaturated  linking,  which  it  will  be 
seen  occupies  a  position  in  the  middle  of  the  molecule,  the  other  methyl  radicles  being 
linked  together  by  single  bonds. 

The  fatty  acids  readily  combine  with  alkali  to  form  soaps;  thus, 

CH3(CH2)i4-COOH  +  KOH  =  CH3(CH2)i4-COOK  +  H20, 
(palmitic  acid)  (soap) 

the  reaction  being  analogous  to  that  by  which  acetic  acid  forms  an  acetate  with 
alkalies.  In  place  of  being  combined  with  alkali,  the  COOH  (carboxyl)  group  of  fatty 
acids  may  combine  with  alcohols  to  form  substances  called  esters.  Thus,  acetic  acid  and 
ethyl  alcohol  from  ethyl  acetate, 

CHCOO 


2o  = 

(acetic       (ethyl'  (ethyl  acetate) 

acid)       alcohol) 

When  the  alcohol  thus  united  with  fatty  acid  is  glycerol  (glycerine),  in  which  there 
are  three  OH  (hydroxyl)  groups,  the  resulting  ester  —  called  triglyceride  —  is  neutral  fat. 
Tripalmitin  has  the  formula: 

CH,-OOC-C15H31 

CH  -OOC-C]5H31 

CH2-OOC-C15H31. 

By  boiling  neutral  fats  with  alkali  the  fatty  acid  radicles  are  split  off  as  soaps, 
leaving  the  glycerol.     This  process  is  called  saponification,  and  it  may  be  effected  in 

718 


FAT    METABOLISM  719 

many  othor  ways,  as  for  example  by  heating  with  steam  or  by  the  action  of  special 
enzymes  called  Upases,  which  are  widely  distributed  in  plants  and  animals. 

The  natural  fats  are  usually  a  mixture  of  triglycerides,  and  their  differences  in 
properties  are  dependent  upon  the  relative  amounts  of  fatty  acids  present.  The  three 
most  important  in  animal  fats  are  tripalmitin,  tristearin  and  triolein.  It  is  essential  in 
the  study  of  fat  metabolism  that  we  should  know  the  most  important  methods  "by  which 
the  proportion  of  fatty  acids  present  in  a  mixed  fat  is  determined.  These  methods 
are  as  follows: 

1.  The  melting  point.     Olein  is  liquid  at  0°  C.;  palmitic  acid  melts  at  62.6°  C. ;  and 
stearic  at  69.3°  C.     The  solidity  of  animal  fats  depends  on  the   proportion  of  olein, 
palmitin  and  stearin  present.     Mutton  fat,  for  example,  is  much  stiffer  than  pig  fat 
because   it   contains   less   olein   and  more    stearin.     The   melting  points   of   fats   from 
different  parts  of  the  body  may  also  vary. 

2.  The  acid  number  indicates  the  amount  of  free  fatty  acid  mixed  with  the  fat, 
and  is  determined  by  titrating  a  solution  of  a  weighed  quantity  of  the  fat  in  alcohol  with 
a  N/10  alcoholic  solution  of  KOH,  phenolphthalein  being  used  as  indicator. 

3.  The  saponification  value  indicates  the  total  amount  of  fatty  acid  present,  both 
that  which  is  free  and  that  combined  with  glycerol.     It  is  determined  by  heating  a 
weighed  amount  of  fat  with  an  exactly  known  amount  of  alcoholic  KOH   (determined 
by  titration  with  standard  acid).     After   saponification  is   complete,   titration   of  the 
mixture  shows  how  much  alkali  has  been  used  to  combine  with  the  fatty  acid.     This 
is  the  saponification  value. 

4.  The  ester  value  indicates  the  amount  of  fatty  acid  combined  with  glycerol,  and 
is  obtained  by  subtracting  the  acid  value  from  the  saponifieation  value. 

Besides  these  there  are  two  values,  known  as  the  iodine  and  the  Beichert-Meissl  val- 
ues, that  are  of  importance  because  they  depend  on  certain  cliar  act  eristics  of  the  fatty- 
acid  radicles. 

5.  The  iodine  value  indicates  the  amount   of  unsaturated   fatty   acids  present,  or 
the   number  of   double   bonds.     It   depends   on  the  fact  that  iodine,   like   many  other 
substances,   is   capable   of   directly   attaching  itself   to   the   fatty-acid   chain   wherever 
double  bonds  exist. 

6.  The  Eeichert-Meissl  value  indicates  the  amount  of  volatile  soluble  acid  present 
in  the  fat.     It  is  determined  by  first  of  all  saponifying  the  fat,  then  decomposing  the 
soap  by  mixing  it  with  mineral  acid  and  distilling  the  liberated  fatty  acid,  the  distil- 
late being  collected  in  a  known  amount  of  standard  alkali  and  titrated.     It  is  a  value 
that  is  not  of  very  great  use  in  physiological  investigations,  but  it  is  so  in  connection 
with  food  chemistry.     Since  volatile   acids  are  present  in  butter,  the  Beichert-Meissl 
value  helps  us  to  distinguish  between  butter  and  margarine. 

Fat  is  insoluble  in  water  but  soap  is  soluble,   forming  a  colloidal  solution   which 
)resents  phenomenon  'of  surface  aggregation  of  molecules.     This  consists  in  the  con- 
centration of  the  soap  both  at  the  free  surface  of  the  liquid,  where  a  skin  may  form, 
id  at  the  interfaces  between  the  soap  solution  and  any  undissolved  particles  present  in 
it.     This  pellicle-formation  around  the  particles  prevents  them  from  running  together 
that  they  remain  suspended,  thus  forming  an  emulsion.     An  emulsion  may  there- 
fore be  formed  either  of  neutral  fat  of  any  other  physically  similar  substance.     When 
fat  itself  is  used,  there  is  usually  enough  free  fatty  acid  admixed  with  it  to  make  it 
unnecessary  in  forming  the  emulsion  to  do  more  than  shake  the  fat  with  weak  sodium- 
irbonate  solution.     With  other  substances  not  containing  any  free  fatty  acid,  some 
soap  should  be  added.    To  preserve  the  emulsion  it  is  often  useful  to  add  some  mucilage, 
the  emulsified  state,  neutral  fats  are  much  more  readily  attacked  by  lipases  than 
rtien  they  are  present  in  an  unemulsified  state.     Thus,  emulsified  fats  are  "digested" 


720 


METABOLISM 


by  the  relatively  small  amounts  of  lipase  present  in  the  stomach,  whereas  neutral  fats 
themselves  are  not  so. 

Fatty  acids  also  exist  in  nature  in  combination  not  only  with  the  triatomic  alcohol, 
glycerol,  but  also  with  monatomic  alcohols  such  as  cholesterol.  These  cholesterol  fats 
differ  from  the  glycerol  fats  in  being  very  resistant  towards  enzymes  and  microorgan- 
isms. They  are  therefore  used  for  protective  purposes  in  the  animal  economy;  for 
example,  they  occur  in  the  sebum,  the  secretion  of  the  sebaceous  glands,  where  they 
serve  to  moisten  the  hairs  and  skin.  They  are  also  present  in  cells,  in  which  it  is  prob- 
able they  take  an  important  part  in  forming  the  skeleton  of  the  cell.  Cholesterol  is 
absorbed  from  the  intestine;  it  is  always  present  in  the  blood  both  in  plasma  and  in 
corpuscles;  and  it  is  an  important  constituent  of  bile,  from  which  it  may  separate  out 
in  the  bile  passages  and  form  calculi  (gallstones). 

In  the  cells  themselves  the  lipoids  are  represented  mainly  by  compounds  of  a  some- 
what more  complex  structure  —  namely,  the  phospliolipins.  As  their  name  indicates, 
these  consist  chemically  of  phosphoric  acid  combined  with  neutral  fat  and  with  a  nitro- 
genous base,  cholin.  The  best  known  of  the  phospholipins  is  lecithin,  which  is  widely 
distributed  in  the  animal  body  (present  in  blood  and  bile  as  well  as  in  all  cells). 
Other  phospholipins  present  in  nervous  tissue  are  cephalin,  cuorin  and  sphyngomyelin. 
There  are  various  lecithins  distinguished  from  one  another  by  the  fatty-acid  radicles 
which  they  contain.  Distearyl-lecithin,  for  example,  has  the  formula: 

CH2-0-OC(CH2)14-CH3 

CH  -0-OC(CH2)14-CH3 
(stearic  acid) 
CH2-0          O 

(glycerol)       P 

OH  OCH2-CH2-N(CH3)2 

(phosphoric  I 

acid)  OH 

(choline) 

This  complex  molecule  can  readily  be  split  up  by  hydrolysis  (warming  with  baryta 
water)  into: 

glycero-phosphoric  acid,  CH2-OH 
CH  -OH 


CH2  -  O 


O 


\ 


;  choline,  N 


OH 


C2H4OH 

(CH3)3  (oxy-ethyl-ammonium 
OH 


hydroxide) ;    and   fatty   acids. 

With  hydrochloric  acid,  choline  forms  a  salt  which  readily  forms  a  double  salt 
with  plantinic  chloride.  Since  this  double  salt  forms  characteristic  crystals,  it  is 
used  to  identify  and  separate  lecithins.  For  quantitative  purposes,  however,  it  is 
more  suitable  to  determine  lecithin  indirectly  by  the  amount  of  phosphoric  acid 
present  in  an  ethereal  extract  of  the  organ  or  tissue. 

Evidence  is  constantly  accumulating  to  show  that  lecithin  is  an  extremely  impor- 
tant constituent  of  cells;  indeed,  it  seems  to  be  the  intermediate  stage  in  the  utiliza- 
tion of  neutral  fats  by  protoplasm.  Its  phosphorus  also  probably  serves  as  the  source 
of  this  element  for  the  construction  of  nucleie  acid  (see  page  669).  In  nervous  tissues 


FAT    METABOLISM  721 

it  is  often  associated  with  carbohydrate  molecules  (galactose),  forming  the  substance 
known  as  cerebrin.  It  may  therefore  have  some  role  to  play  in  carbohydrate  metabo- 
lism. Some  workers  also  attribute  to  lecithin  an  important  function  in  the  transference 
of  substances  through  cell  membranes.  When  mixed  with  water  it  swells  up  by  imbibi- 
tion, and  if  crystalloids  or  other  substances  are  dissolved  in  the  water,  a  means  is 
offered  for  bringing  water-soluble  and  fat-soluble  substances  into  intimate  contact. 


DIGESTION  OF  FATS 

A  certain  amount  of  fat,  especially  when  it  is  in  an  emulsified  condi- 
tion, can  be  digested  in  the  stomach  by  the  lipase  contained  in  the  gas- 
tric juice.  Most  of  it,  however,  is  digested  in  the  small  intestine,  into 
which  as  we  have  seen,  it  is  gradually  discharged  suspended  in  the  chyme. 
For  this  intestinal  digestion  of  fat  both  pancreatic  juice  and  bile  are  nec- 
essary. This  is  easily  shown  in  the  rabbit,  in  which  the  pancreatic  duct 
enters  the  intestine  at  a  considerable  distance  below  the  bile  duct.  If  the 
mesentery  is  inspected  during  the  absorption  of  fatty  food,  no  fat  in- 
jection of  the  lymphatics  will  be  noted  between  the  bile  and  the  pan- 
creatic ducts  but  only  below  the  latter.  In  the  dog,  in  which  both  the  bile 
and  the  main  pancreatic  ducts  enter  the  intestine  at  about  the  same  level, 
fat  injection  of  the  lymphatics  starts  at  this  point,  but  if  the  bile  duct 
(or  rather  the  gall  bladder)  is  transplanted  at  some  distance  down  the 
intestine,  it  will  be  found  that  the  injection  of  the  lymphatics  with  fat 
occurs  only  below  the  new  point  of  insertion  of  the  bile  duct. 

Removal  of  the  pancreas  interferes  very  materially  with  the  absorption 
of  fat.  In  man,  for  example,  absence  of  the  pancreatic  juice  alone  di- 
minishes the  absorption  of  fat  by  50  or  60  per  cent.  If  the  bile  is  also 
absent,  the  diminution  amounts  to  80  or  90  per  cent,  and  in  such  cases, 
as  is  well  known,  the  administration  of  bile  or  pancreas  powder  greatly 

tproves  fat  absorption.  This  interference  is  no  doubt  mainly  dependent 
>n  the  secretion  of  pancreatic  juice.  Pratt,  McClure  and  Vincent,48  for 
example,  found  that  completely  depancreated  dogs  could  still  absorb  con- 
siderable quantities  of  fat.  On  the  other  hand,  the  internal  secretion  of 
the  pancreas  has  a  considerable  influence  on  fat  metabolism  as  is  evi- 
denced by  the  fact,  observed  by  us,  that  there  is  usually  10-12  per  cent 
of  total  fatty  acid  in  the  livers  of  depancreated  animals  but  only  a  small 
amount  after  the  animals  have  been  treated  with  pancreatic  extract 
(insulin,  page  717). 

As  to  the  relative  roles  of  pancreatic  juice  and  bile  in  the  digestion  of 
fat,  we  know  of  course  that  in  the  pancreatic  juice  there  exists  a  lipolytic 
enzyme,  lipase,  which,  under  suitable  conditions  has  the  power  of  split- 
ting neutral  fat  into  fatty  acids  and  glycerol.  If  bile  is  examined,  no 
lipolytic  enzyme  will  be  found  in  it.  It  is  entirely  inactive  on  fat,  but 


722  METABOLISM 

if  we  mix  bile  with  fresh  pancreatic  juice,  which  by  itself  only  slowly 
digests  fat,  we  shall  find  that  the  bile  very  materially  increases  the  lipo- 
lytic  activity  of  the  pancreatic  juice.  It  has  been  found  that  the  salts 
of  cholalic  acid,  the  so-called  bile  salts,  are  the  constituents  of  bile 
that  are  responsible  for  this  activation  of  lipase,  this  fact  having  been 
demonstrated  with  bile  salts  prepared  in  such  a  way  that  there  was  no 
possible  chance  of  any  other  biliary  constituent  being  present  as  an 
impurity.  It  is  important  to  remember,  however,  that  lipase  itself  be- 
comes slowly  activated  on  standing,  which  explains  why  it  should  be 
that  bile  added  to  pancreatic  juice  that  has  stood  for  some  time,  has  a 
less  evident  activating  influence  than  bile  added  to  fresh  juice.  It  is 
probable  that  the  activating  influence  of  bile  salts  is  due  to  some  physico- 
chemical  change  induced  in  the  digestion  mixture. 

One  may  ask  how  it  happens  that,  when  bile  and  pancreatic  juice  are 
both  absent  from  the  intestine,  the  fat  which  appears  in  the  feces  is  not 
neutral  fat  but  fatty  acid.  The  reason  is  that  the  neutral  fat  that  has 
escaped  digestion  in  the  small  intestine  becomes  acted  on  by  the  intestinal 
bacteria,  particularly  in  the  large  intestine.  Under  these  conditions, 
however,  the  fatty  acid  that  is  split  off  is  not  absorbed,  because  the 
epithelium  of  the  lower  parts  on  the  intestinal  tract  can  not  perform  this 
function. 

Besides  assisting  the  action  of  lipase,  bile  facilitates  fat  digestion  in 
other  ways.  Thus,  by  its  containing  alkali  and  mucin-like  substances 
it  assists  in  the  emulsification  of  fat.  Although  emulsification  is  no  es- 
sential part  of  fat  absorption,  yet  it  greatly  facilitates  the  process  by 
breaking  up  the  fat  into  small  globules  on  which  the  lipase  can  act 
much  more  efficiently.  The  alkali  also  combines  with  the  fatty  acids, 
as  they  are  liberated  by  the  digestive  process,  to  form  water-soluble 
soaps,  which  are  readily  absorbed  by  the  epithelial  cells.  The  bile  salts 
further  assist  in  the  solution  of  the  fatty  acids,  and  they  lower  the  sur- 
face tension  of  fluids  in  which  they  are  contained  and  so  bring  the  fat 
and  lipase  into  closer  contact. 

ABSORPTION  OF  FATS 

After  its  digestion  fat  lies  in  contact  with  the  intestinal  border  of  the 
epithelial  cells  as  fatty  acid  and  glycerol.  The  fatty  acid  is  combined 
either  with  alkali  to  form  a  water-soluble  soap,  or  with  bile  salts  to 
form  a  compound,  which  is  also  soluble.  The  glycerol  and  the  dissolved 
fatty  acids  are  separately  absorbed  into  the  epithelial  cells  of  the  in- 
testine, in  the  protoplasm  of  which — after  the  fatty  acid  has  been  set 
free  from  the  alkali  or  bile  salt — they  become  united  or  resynthetized 


FAT    METABOLISM  723 

to  form  neutral  fat,  which  gradually  finds  its  way  by  the  central  lac- 
teals  into  the  lymphatics  and  then  to  the  thoracic  duct.  No  evidence 
can  be  obtained  that  any  of  the  fat  is  absorbed  into  the  portal  blood 
although  only  about  60  per  cent  of  ingested  fat  can  be  recovered  from 
the  thoracic  duct. 

The  chemical  explanation  of  the  absorption  of  fat  is  very  different  from 
that  formerly  held  by  histologists  who  maintained  that  the  fine  particles  of 
emulsified  fat  in  the  intestine  penetrate  by  a  mechanical  process  through 
the  striated  border  of  the  epithelial  cell  into  its  protoplasm.  The  histolog- 
ical  evidence  for  this  view  seemed  very  convincing,  for  fine  fat  globules  can 
readily  be  seen  in  the  epithelial  cells  of  the  intestine  after  fatty  food 
has  been  taken,  while  they  are  absent  during  starvation.  These  par- 
ticles seemed  to  have  passed  directly  from  the  intestinal  canal  into  the 
epithelial  cells  because,  when  the  fat  was  stained  with  characteristic  fat 
dyes  before  feeding  it  to  the  animal,  the  globules  in  the  epithelial  cells 
were  found  to  be  similarly  stained.  The  supporters  of  this  mechanistic 
view  of  fat  absorption  maintained  that  the  appearance  of  the  stained  fat 
globules  in  the  epithelial  cells  could  not  be  explained  in  any  other  way 
than  by  supposing  that  the  fat  globules  had  wandered  unbroken  into 
the  epithelial  cells.  Such  a  conclusion  is,  however,  unwarranted,  for  the 
stains  that  are  soluble  in  fat  are  also  soluble  in  soap,  so  that  when  the 
fat  splits  up,  the  stain  will  remain  attached  to  the  soap  and  be  carried 
along  with  it  into  the  intestinal  epithelium. 

Proof  that  the  chemical  theory  is  the  correct  one  has  been  supplied  by  a  large 
number  of  experiments.  The  following  may  be  cited:  (1)  When  the  lymph  flowing 
from  the  thoracic  duct  is  examined  after  feeding  with  fatty  acids  instead  of  neutral 
fat,  it  is  found  to  contain  only  neutral  fat,  indicating  that  a  synthesis  must  have 
occurred  between  glycerol  and  fatty  acid  during  the  absorption.  The  glycerol  for 
this  synthesis  is  furnished  from  sources  which  will  be  described  later.  (2)  When  an 
emulsion  made  partly  of  neutral  fats,  and  partly  of  some  hydrocarbon,  such  as  albo- 
lene,  is  fed  and  the  feces  are  examined  for  these  substances,  it  has  been  found  that 
all  the  fat  but  none  of  the  hydrocarbon  is  absorbed;  the  feces  contain  all  of  the  albo- 
lene  but  none  of  the  fat.  This  experiment  supplies  very  strong  evidence  against  the 
mechanistic  theory,  for  microscopic  examination  of  the  above  described  emulsion  shows 
the  particles  of  neutral  fat  and  hydrocarbon  to  be  of  exactly  the  same  size.  (3)  By 
examining  the  properties  of  the  fatty  substances  in  the  thoracic  lymph  collected 'during 
the  absorption  of  such  an  emulsion  as  that  described  above,  nothing  but  neutral  fat 
has  been  found  present.  (4)  Similar  results  are  obtained  when  wool  fat,  which  is  an 
ester  of  cholesterol  and  fatty  acid,  is  fed. 

We  may  conclude  that  fatty  substances  which  are  insoluble  in  water  or 
can  not  be  changed  by  digestion  into  substances  (soap)  that  are  soluble 
in  water,  are  not  absorbed,  however  like  fat  they  may  be  in  other  particulars. 

The  chemical  theory  of  fat  absorption  further  explains  why  there  should 
be  such  large  quantities  of  soapy  substances  in  the  intestinal  contents, 
and  also  why  the  globules  of  fat  present  in  the  epithelial  cells  of  the 


724  METABOLISM 

intestine  are  so  very  much  smaller  than  those  which  lie  on  the  surface  of 
the  epithelium. 

It  might  be  objected  to  the  conclusions  just  stated  that,  although  undetectable, 
there  is  really  some  essential  physical  difference  between  emulsified  fat  and  emulsified 
hydrocarbon.  In  order  entirely  to  prove  the  case  for  the  chemical  theory,  it  is  neces- 
sary to  feed  a  neutral  fat  possessing  some  characteristic  that  depends  on  the  manner  of 
union  existing  between  fatty  acid  and  glycerol,  and  then  to  see  whether  it  appears  in 
an  unchanged  condition  in  the  thoracic  duct.  If  it  does  so,  the  fat  must  have  been 
absorbed  through  the  intestinal  epithelium  in  an  unbroken,  unsaponified  condition,  for 
it  is  unlikely  that,  in  'the  resynthesis  which  occurs  in  the  intestinal  epithelium,  the  fatty- 
acid  molecules  would  recombine  with  the  glycerol  molecules  in  exactly  the  same  manner 
as  before. 

There  are,  however,  but  very  few  qualities  of  neutral  fats,  apart  from  those  of  the 
fatty  acids  which  compose  them,  by  which  they  can  be  characterized.  The  most  likely 
one  is  that  of  optical  activity.  None  of  the  ordinary  fats  is  optically  active,  although 
from  chemical  considerations  it  is  quite  conceivable  that  some  ought  to  be  so.  In 
order  to  obtain  such  a  fat  Bloor^  conducted  numerous  experiments  with  the  esters  of 
stearic  acid.*  In  a  series  of  experiments  Bloor  fed  isomannid-dilaurate — a  synthetic  fat 
of  dextrorotatory  power  and  as  readily  absorbed  as  natural  fats — and  by  examination 
of  the  neutral  fat  present  in  the  chyle  flowing  from  the  thoracic  duct,  found  no  evi- 
dence of  'the  dextrorotatory  fat.  This  result  confirms  previous  work  by  Frank,  who 
found  that  the  ethyl  esters  of  fatty  acids  are  not  absorbed  unchanged.  The  results  of 
both  workers  emphasize  the  probability  that  readily  saponifiable  fatty-acid  esters  do 
not  escape  saponification  under  the  favorable  conditions  of  the  normal  intestine.  In 
other  words,  had  the  fats  been  absorbed  unchanged,  as  would  be  required  by  the 
mechanistic  theory  of  fat  absorption,  they  would  have  appeared  in  the  chyle  in  optic- 
ally active  conditions. 

These  most  important  conclusions  lead  us  to  inquire  as  to  the  reason 
for  the  change  in  fat  during  its  absorption.  It  can  not  be  for  the  purpose 
of  preventing  the  absorption  of  undesirable  fatty  substances,  such  as  the 
petroleum  hydrocarbons  or  the  wool  fats,  because  such  substances  are 
so  rarely  present  in  our  food.  It  is  most  probable  that  the  breakdown 
and  resynthesis  of  neutral  fat  occurs  for  the  same  reason  that  similar 
processes  occur  during  the  absorption  and  assimilation  of  protein.  It 
will  be  remembered  that  protein  is  entirely  disintegrated  in  the  intestine 
into  its  so-called  building  stones.  These  are  absorbed  separately  into 
the  blood,  which  carries  them  to  the  tissues,  in  which  they  become  re- 
synthesized  to  form  the  body  protein.  And  so  it  appears  to  be  in  the 
case  of  fats.  The  process,  in  other  words,  permits  of  the  rearrangement 
of  fatty-acid  molecules,  as  a  result  of  which  the  newly  formed  fat  is  more 
adaptable  for  use  in  the  organism.  It  comes  to  be  more  like  the  char- 
acteristic fat  of  the  animal.  There  may  be  another  reason  for  the  proc- 


*Bloor  prepared  an  optically  active  mannitan  distearate,  but  found  it  to  have  a  very  high  melt- 
ing point  and  to  be  only  half  as  digestible  as  the  ordinary  fats.  Its  absorption  was  too  slow  and 
unsatisfactory  to  make  it  suitable  for  the  above  purposes.  He,  therefore,  proceeded  to  prepare  the 
di-ester  of  isomannitan  with  lauric  acid,  and  he  found  the  resulting  compounds  to  be  as  well-ab- 
sorbed as  ordinary  fat,  and  yet  to  possess  very  marked  dextrorotatory  power,  which,  of  course, 
they  lose  on  saponification.  This  fat  seemed  suitable,  therefore,  for  testing  the  above  question. 


FAT    METABOLISM  725 

ess.  It  will  be  remembered  that  lecithins,  which  constitute  the  most 
important  of  the  fatty  substances  of  the  cell  itself,  are  mixed  glycerides— 
that  is  to  say,  are  compounds  containing  a  variety  of  fatty  acids.  The 
rearrangement  of  the  molecules  of  neutral  fat  which  occurs  during  ab- 
sorption may  be  the  first  step  in  the  transformation  of  fat  into  lecithin. 

In  order  to  throw  further  light  on  the  question,  Bloor  has  performed  a  number  of 
interesting  experiments  in  which  the  chemical  properties  of  fats  before  and  after 
absorption  were  compared.  The  criteria  which  he  took  were  melting  point,  iodine 
value,  and  mean  molecular  weight;  the  melting  point  representing  the  solidity  of  the 
fat,  and  the  iodine  value,  its  degree  of  unsaturation — that  is,  the  number  of  double 
links  in  the  fatty-acid  chain.  It  was  found  that  during  absorption  very  considerable 
changes  occur  in  these  two  characteristics;  for  example,  when  fat  with  high  melting 
point  and  low  iodine  value  was  fed,  the  fat  in  the  thoracic  lymph  was  of  distinctly 
lower  melting  point  and  higher  iodine  value.  When  fat  with  a  low  melting  point  and 
a  high  iodine  value  was  fed,  the  reverse  change  occurred,  for  the  melting  point  of 
the  thoracic  lymph  fat  was  higher  and  the  iodine  value  lower.  These  results'  could  be 
explained  as  due  in  the  first  case  to  the  addition  of  oleic  acid  to  the  fat  during  its 
synthesis  in  the  intestinal  epithelium,  and  in  the  second  case  to  the  addition  of  some 
saturated  fatty  acid. 

When  a  fat  consisting  mainly  of  glyceride  and  saturated  fatty  acid,  but  with  a 
low  melting  point,  was  fed,  the  addition  of  oleic  acid  was  still  found  to  occair,  as 
judged  from  the  iodine  value.  This  indicates  that  the  change  is,  not  merely  in  order 
that  the  melting  point  of  the  absorbed  fat  may  be  lowered,  but  also  for  some  chemical 
reason.  In  a  fourth  series  of  experiments,  a  lowering  of  iodine  value  occurred  after 
feeding  with  cod-liver  oil,  which  contains  a  high  percentage  of  glycerides  of  highly 
unsaturated  fatty  acids. 

Evidently,  then,  the  intestine  possesses  the  power  of  modifying  the  com- 
position of  fat  during  its  absorption,  and  this  modification  is  apparently 
of  such  a  nature  that  it  causes  a  change  toward  the  production  of  a 
uniform  chyle  fat,  presumably  characteristic  of  the  animal  body.  The 
changes  are  probably  greater  than  could  be  produced  by  admixture  of 
the  absorbed  fat  present  in  the  normal  fasting  chyle,  but  the  source  of 
the  oleic  acid  or  of  the  saturated  acid  required  for  this  synthesis  is  at 
present  unknown. 

Regarding  the  transference  of  the  synthesized  fat  globules  from  the 
epithelial  cells  to  the  central  lacteal  it  is  believed,  with  Schafer,  that 
leucocytes  play  an  important  role.  They  engulf  the  fat  globules  and 
carry  them  to  the  lacteal  where  they  break  down  and  liberate  the  glob- 
ules. In  support  of  this  view  Clark  and  Clark  have  observed,  after  injec- 
tion of  fats  into  the  tails  of  tadpoles,  that  leucocytes  pass  out  from  the 
blood  vessels  and  accumulate  around  the  oil  globules,  ultimately  absorb- 
ing the  latter  and  then  wandering  to  near-by  lymph  vessels  into  which 
apparently  they  disgorge  their  loads  of  fat. 


CHAPTER  LXXX 

FAT  METABOLISM  (Cont'd) 

THE  FAT  OF  BLOOD 

Methods  of  Determination. — Normally  the  blood  contains  only  a  small  percentage 
of  fat,  but  after  a  fatty  meal  it  may  contain  so  large  an  amount  that  the  fat  actually 
rises  to  the  surface  of  the  blood  like  a  cream.  By  means  of  the  ultramicroscope,  ex- 
amination of  the  blood  in  the  dark  field  after  a  fat-rich  meal  reveals  the  presence  of 
glancing  particles,  the  so-called  "fat  dust."  These  particles  are  most  abundant  about 
six  hours  after  the  meal  has  been  taken,  and  they  gradually  disappear  by  the  twelfth 
hour.  They  do  not  appear  after  a  meal  when  the  thoracic  duct  is  ligated.  They  dis- 
appear when  oxygen  is  bubbled  through  the  blood. 

Fat  dust  has  also  been  found  abundantly  present  in  the  blood  of  embryo  guinea  pigs 
at  full  time,  but  not  in  the  mother 's  blood.  This  would  indicate  that  the  placenta  must 
have  the  power  of  taking  the  constituents  of  fat  from  the  mother's  blood  and  building 
them  into  fat,  which  then  passes  into  the  blood  of  the  fetus.  The  placenta  under  these 
conditions  acts  like  the  mammary  gland.  In  this  connection  it  is  of  interest  that  there  is 
also  much  fat  present  in  the  blood  of  pregnant  women.  The  fat  content  of  the  placenta 
is,  however,  greater  in  the  early  stages  of  pregnancy  than  later. 

Although  these  facts  have  been  known  for  some  time,  it  has  been  impossible,  either  on 
account  of  the  large  quantities  of  blood  required  for  a  chemical  examination  or  because 
of  the  difficulty  in  estimating  the  amount  of  fat  from  the  density  of  the  "fat  dust," 
to  follow  with  any  great  degree  of  accuracy  the  exact  chemical  changes  that  take  place 
in  the  fat  of  the  blood.  Recently,  however,  Bloor  has  succeeded  in  elaborating  methods 
by  which  the  fat  content  of  the  blood  can  be  determined  with  satisfactory  accuracy  in 
small  quantities  of  blood,  so  that  a  continuous  series  of  observations  can  be  made  over  a 
considerable  period. 

The  fat  is  extracted  from  the  blood  by  an  alcohol-ether  mixture  with  moderate  heat. 
An  aliquot  portion  of  the  filtrate  is  evaporated  in  the  presence  of  sodium  ethylate ,  which 
saponifies  the  fat.  The  residue,  consisting  of  soap,  is  well  washed  and  then  treated 
with  hydrochloric  acid  so  as  to  precipitate  the  fatty  acid.  The  density  of  the  precipitate 
thus  produced  is  compared  in  an  optical  apparatus,  called  a  nephelometer,  with  a 
standard  solution  of  two  milligrams  of  oleic  acid  treated  in  the  same  way.  The  fatty 
acids  in  human  blood  are  mainly  oleic  and  palmitic. 

The  lecithin  and  cholesterol  may  also  be  estimated  in  the  same  blood  extract.  For 
lecithin  the  above  extract  of  blood,  after  the  removal  of  the  alcohol  and  ether,  is  digested 
by  heating  with  concentrated  HNO3  and  H2SO4.  This  decomposes  the  lecithin,  liberating 
the  phosphorus,  a  solution  of  the  resulting  ash  being  rendered  faintly  alkaline  to  phenol- 
phthalein  and  then  slowly  added  to  a  silver  nitrate  solution.  The  density  of  the  pre- 
cipitate thus  produced  is  compared  in  the  nephelometer  with  that  of  a  precipitate  pro- 
duced in  the  same  amount  of  silver  nitrate  by  adding  to  it  a  standard  phosphoric  acid 
solution. 

For  cholesterol  an  aliquot  portion  of  the  above  extract  is  saponified  with  sodium 
ethylate  and  then  saturated  with  chloroform ;  the  chloroform  extract  is  mixed  with  acetic 

726 


FAT    METABOLISM  727 

anhydrid  and  H2SO4  (con.)  until  the  bluish  color  is  fully  developed  (Liebermann  reac- 
tion), the  intensity  of  which  is  then  compared  in  a  colorimeter  with  that  obtained  by 
similar  treatment  from  a  standard  cholesterol  solution. 

Variations  in  Blood  Fat. — In  the  dog  the  percentage  of  fat  in  the 
blood  is  remarkably  constant  under  normal  conditions.  After  a  fatty 
meal  the  increase  in  fat  begins  in  about  an  hour,  and  reaches  its  maxi- 
mum in  about  six.  The  increase  is  not  found  in  animals  in  which  the 
thoracic  duct  has  been  ligated.  Although  this  result  would  seem  to 
support  the  view  that  fat  absorption  occurs  exclusively  into  the  tho- 
racic duct  (page  723)  it  must  be  remembered  that  the  evidence  is  not 
convincing  since  the  shock  caused  by  so  severe  an  operation  may  account 
for  the  faulty  fat  absorption. 

Very  interesting  results  have  been  obtained  following  the  intravenous 
injection  of  emulsions  of  oil,  either  the  so-called  casein  emulsion  or  col- 
loidal suspensions.  Up  to  a  dose  of  0.4  gram  per  kilogram  of  body 
weight — which  by  calculation  would  suffice  to  raise  the  fat  content  of 
the  blood  by  100  per  cent — there  was  no  increase  in  fat  content.  In  or- 
der to  explain  this  disappearance  of  fat,  it  might  be  imagined  that  the 
injected  fat  particles  formed  emboli  in  the  smaller  capillaries.  Against 
such  a  view,  however,  is  the  fact  that  the  particles  of  fat  in  these  emul- 
sions are  one-half  to  one-seventh  the  size  of  a  red  corpuscle.  Although 
this  argument  is  no  doubt  of  some  weight,  it  should  be  remembered 
that  the  physical  condition  of  these  fine  fat  globules  is  not  the  same  as 
that  of  the  red  blood  corpuscle.  Their  surface  condition  may  be  such 
that  they  readily  agglutinate  so  as  to  form  small  masses,  which  may 
stick  at  the  branching  of  the  smaller  arterioles  and  capillaries.  Bloor 
himself  suggests  that  the  injected  fat  may  be  stored,  possibly  in  the  liver, 
since  the  fat  in  this  organ,  as  we  shall  see  later,  increases  under  similar 
conditions.  When  twice  the  above  quantity  was  fed  in  the  form  of  egg- 
yolk  fat,  some  of  it  persisted  in  the  blood  for  several  hours.  This  in- 
crease may  have  been  owing  to  the  flooding  of  the  temporary  storehouses 
with  fat,  or,  more  probably,  to  a  retarding  influence  that  lecithin  may 
have  on  fat  assimilation,  for  lecithin  itself  persists  in  the  blood  for  a 
long  time  after  intravenous  injection. 

During  fasting,  no  increase  in  blood  fat  was  found  unless  the  animal, 
by  special  feeding,  had  been  stuffed  with  excess  of  fat  prior  to  the  fast- 
ing period.  The  lipemia  in  this  case  indicates  that  fat  is  being  trans- 
ited from  one  place  to  another  to  serve  as  fuel  for  the  starving  tissues. 
Narcotics  were  found  to  produce  an  increase  in  blood  fat.  Ether  pro- 
duced this  increase  during  the  narcosis,  whereas  morphine  and  chloro- 
form did  not  do  so  until  after  recovery.  The  explanation  given  for  the 


728 


METABOLISM 


ether  effect  is  that  a  mixture  of  blood  and  ether  has  a  higher  solvent  power 
for  fat  than  blood  alone.  The  explanation  for  the  chloroform  and  mor- 
phine effects  is  that  a  certain  amount  of  breakdown  of  the  tissue  cells, 
in  which  lipins  are  set  free,  supervenes  upon  the  action  of  these  narcotics. 

The  blood  fat  also  becomes  enormously  increased  in  about  forty  hours 
after  the  administration  of  phlorhizin,  and  on  the  second  or  third  day 
after  the  administration  of  phosphorus.  The  special  significance  of 
these  facts  we  shall  consider  later  in  connection  with  the  relationship  of 
the  liver  to  fat  metabolism. 

By  comparison  of  the  fatty  acid,  lecithin,  and  cholesterol  contents  of 
blood  during  fat  absorption,  it  has  been  found  that  there  is  a  steady  but 
very  variable  increase  in  fatty  acid,  accompanied  by  an  increase  in 
lecithin,  which  varies  from  10  to  35  per  cent,  but  does  not  run  strictly 
parallel  with  the  fatty-acid  increase.  At  a  later  stage  there  may  also  be 
an  increase  in  cholesterol;  indeed  in  persistent  lipemia  cholesterol  may 
become  more  abundant  than  lecithin.  It  looks  as  if  fat  were  absorbed 
into  the  corpuscles  where  it  is  transformed  into  lecithin  which  is  then 
returned  to  the  plasma,  cholesterol  also  appearing  when  the  lecithin 
reaches  a  certain  concentration.  Separate  analyses  of  blood  plasma  and 
whole  blood  show  the  increase  of  lecithin  to  be  much  more  marked  in 
the  corpuscles  than  in  the  plasma,  whereas  the  fatty-acid  increase  is 
most  pronounced  in  the  plasma. 

To  illustrate  some  of  these  points  the  following  table  will  be  of  value. 
In  it  is  shown  the  average  distribution  of  fatty  acid,  lecithin  and  choles- 
terol in  normal  individuals  and  in  cases  of  diabetes,  in  which  disease, 

BLOOD  LIPOIDS  IN  NORMAL  AND  IN  DIABETIC  PERSONS 


NORMAL 
PER  CENT 

MILD 
DIABETES 
PER  CENT 

MODERATE 
DIABETES 
PER  CENT 

SEVERE 
DIABETES 
PER  CENT 

Fat  by  Bloor's        J 
Method                   1 

Whole  Blood 
Plasma 

0.59 
0.62 

0.83 

0.90 

0.91 
1.06 

1.41 
1.80 

Total  Fatty  AcidsJ 

Whole  Blood 
Plasma 
Corpuscles 

0.37 
0.39  . 
0.34 

0.59 
0.64 
0.45 

0.65 

0.75 
0.48 

1.01 
1.28 
0.62 

Lecithin 

Whole  Blood 
Plasma 
Corpuscles 

0.30 
0.21 
0.42 

0.32 
0.24 
0.42 

0.33 

0.28 
0.40 

0.40 

0.40 
0.40 

Cholesterol                J 

Whole  Blood 
Plasma 
Corpuscles 

0.22 
0.23 
0.20 

0.24 
0.26 
0.21 

0.26 
0.30 
0.20 

0.41 
0.51 
0.24 

Glycerides                  j 

Plasma 
Corpuscles 

0.10 
0 

0.38 
0.18 

0.46 
0.23 

0.84 
0.38 

Total  Lipoids 

Plasma 

0.68 

0.98 

1.16 

1.98 

FAT    METABOLISM  729 

as  has  been  known  for  long,  there  is  marked  disturbance  of  fat  metab- 
olism. The  table  shows  that  this  increase  affects  all  types  of  lipoids  in 
proportion  to  the  severity  of  the  disease. 

Bloor  considers  that  lecithin  which  is  soluble  in  water,  is  the  main 
form  in  which  fat  is  transported  in  the  blood.  The  lecithin  is  taken  up 
by  the  tissue  cells  in  which  there  are  enzymes  (esterases)  capable  of 
hydrolysing  it  so  as  to  produce  fat,  or  by  reversible  action,  of  converting 
the  fat  stored  in  the  cells  to  lecithin  which  is  then  sent  into  the  blood. 
The  fat  secreted  in  the  milk  can,  for  example,  all  be  accounted  for  by  the 
difference  between  the  lecithin  content  of  the  blood  plasma  passing 
through  the  gland  (Meigs).  Some  of  the  fat  is  also  transported  in  the 
blood  by  the  leucocytes  acting  as  phagocytes  towards  it. 

The  Destination  of  the  Fat  of  the  Blood. — In  general,  it  may  be  said 
that  the  blood  fat  is  transported  to  three  places:  (1)  the  depots  for  fat;  (2) 
the  liver;  and  (3)  the  tissues.  The  fat  present  in  each  of  these  places 
differs  from  that  in  the  others,  as  is  revealed  by  chemical  examination 
by  the  methods  described  on  page  719.  The  depot  fat  usually  yields  about 
95  per  cent  of  its  total  weight  as  fatty  acid.  The  tissue  fat,  on  the  other 
hand,  yields  only  about  60  per  cent  of  its  total  weight  as  fatty  acid. 
This  difference  indicates  that  the  fatty  acid  must  be  combined  in  the 
tissues  with  a  much  larger  molecule  than  is  the  case  in  the  fat  of  the 
depots.  This  large  molecule  is  probably  that  of  lecithin  or  other  phos- 
pholipin,  and  the  smaller  molecule  in  the  depots,  that  of  neutral  fat. 
The  liver  fat  takes  an  intermediate  position  between  depot  fat  and  tissue 
fat  in  its  yield  of  fatty  acid.  When  no  active  metabolism  of  fat  is  go- 
ing on,  the  liver  fat  is  like  that  of  the  tissues;  but  when  fat  metabolism 
is  active,  the  liver  fat  occupies  an  intermediate  position  between  tissue 
fat  and  depot  fat. 

Another  difference  among  the  fats  in  these  three  places  is  with  regard 
to  the  degree  of  saturation  of  the  fatty-acid  radicles.  This,  it  will  be 
remembered,  is  indicated  by  the  iodine  value;  the  higher  the  iodine 
value,  the  greater  the  desaturation  of  fatty  acid.  In  depot  fat  this  value 
is  relatively  low — for  example,  about  30  in  the  goat  and  about  65  in  man ; 
depending  somewhat  on  the  fat  taken  in  the  food,  compared  with  which 
it  is  usually  a  little  higher.  The  fat  in  the  tissues,  on  the  other  hand, 
has  a  high  iodine  value,  possibly  110  to  130.  The  iodine  value  of  the 
fat  of  the  liver  is  remarkably  inconstant,  being  about  the  same  as  that 
of  the  tissues  when  fatty-acid  metabolism  is  not  particularly  active,  but 
approximating  that  of  the  depots  when  fat  mobilization  is  proceeding. 
The  significance  of  this  fact  we  shall  consider  later. 


730 


METABOLISM 


The  Depot  Fat 

The  places  in  the  animal  body  where  depot  fat  is  deposited  in  great- 
est amount  are  the  subcutaneous  and  retroperitoneal  tissues.  These 
fat  depots  may  sometimes  become  of  enormous  size,  as  in  the  case  of 
the  famous  dog  of  Pfliiger,  of  whose  total  body  weight  40  per  cent  was 
due  to  fat.  Bloor  suggests  that  there  may  really  be  two  different  types 
of  fat  storage :  one  of  a  purely  temporary  character,  which  readily 
takes  up  and  liberates  the  fat,  but  which  is  of  limited  capacity  and 
possibly  under  the  control  of  some  quickly  acting  regulating  mech- 
anism, like  that  of  the  glycogenic  function  of  the  liver;  and  another 
of  a  more  permanent  nature,  into  which  the  fat  is  slowly  taken  up,  but 
the  capacity  of  which  is  very  much  greater. 

Two  questions  present  themselves  concerning  the  depot  fat:  (1)  where 
does  it  come  from,  and  (2)  what  becomes  of  it?  Regarding  the  source 
of  the  depot  fat,  there  is  no  doubt  that  it  comes  partly  from  the  fat  and 
partly  from  the  carbohydrate  of  the  food;  in  other  words,  it  is  either 
taken  ready-made  with  the  food  or  manufactured  in  the  organism.  That 
some  of  it  comes  from  the  fat  of  food  is  now  a  well-established  fact,  the 
evidence  for  which  need  not  detain  us  long.  The  best-known  experiment 
consists  in  first  of  all  starving  an  animal  until  its  stores  of  fat  are 
nearly  exhausted  and  then  feeding  it  with  some  "ear-marked"  fat- 
that  is,  with  some  fat  having  a  characteristic  property  which  it  will 
not  lose  during  absorption.  It  will  be  found  that  the  depot  fat  thereby 
deposited  presents  many  of  the  qualities  of  the  fed  fat.  The  "ear- 
marking" of  the  fat  may  be  secured  by  using  fats  of  different  melting 
points,  such  as  mutton  fat,  which  has  a  high  M.P.,  or  olive  oil,  which  has 
a  low  M.P.  On  feeding  a  previously  starved  dog  with  mutton  fat,  the 
M.P.  of  the  depot  fat  approaches  that  of  mutton  fat — he  becomes  a 
dog  in  sheep's  clothing;  whereas  when  olive  oil  is  fed,  the  subcutaneous 
fat  becomes  oily.  Or  again  we  may  "ear-mark"  the  fat  by  combining  it 
with  bromine,  when  the  deposited  fat  will  likewise  be  brominized  fat. 

It  must  not  be  imagined,  however,  that  no  change  takes  place  in  the 
fat  during  its  absorption  and  before  it  becomes  deposited  in  the  tissues. 
On  the  contrary,  the  stamp  of  individuality  is  put  upon  the  fat,  for,  as 
we  have  already  seen,  its  iodine  value  may  become  altered  and  its  melt- 
ing point  changed  during  the  process  of  absorption.  In  other  words, 
although  the  absorbed  fat  does  not  become  entirely  adapted  to  conform 
with  the  ordinary  qualities  of  the  depot  fat,  yet  it  tends  to  change  in 
this  direction. 

That  some  of  the  depot  fat  comes  from  carbohydrate  is  well  known  to 
stock  raisers.  When,  for  example,  an  animal  is  fed  on  large  quantities 
of  carbohydrate  and  kept  without  doing  muscular  exercise,  its  tissues 


FAT    METABOLISM  731 

become  loaded  with  fat.  Strict  scientific  proof  of  its  production  from  car- 
bohydrate is  given  in  the  old  experiments  of  Lawes  and  Gilbert,  who, 
it  will  be  remembered,  showed  that  the  fat  deposited  in  the  tissues 
of  a  growing  pig  is  greatly  in  excess  of  the  fat  that  could  have  been 
derived  from  the  fat  or  protein  which  was  meanwhile  metabolized. 
The  experiment  was  performed  on  two  young  pigs  from  the  same  litter 
and  of  approximately  equal  weight ;  one  was  killed  and  the  exact  amounts 
of  fat  and  nitrogen  in  the  body  determined;  the  other  was  fed  for  several 
months  on  a  diet  the  fat  and  protein  contents  of  which  were  accurately 
ascertained.  When  after  four  months  this  pig  was  killed  and  the  fat 
determined,  it  was  found  that  much  more  had  become  deposited  than 
could  be  accounted  for  by  the  fat  and  protein  of  the  food,  even  suppos- 
ing that  all  the  available  carbon  of  the  protein  had  become  converted 
into  fat.  The  only  conclusion  is  that  the  carbohydrate  must  have  been 
an  important  source  of  the  extra  fat. 

The  Destination  of  the  Depot  Fat. — The  depot  fat  becomes  mobilized 
and  transported  by  the  blood  to  the  active  tissues  whenever  the  energy 
requirements  of  the  body  demand  it.  During  starvation,  as  we  have 
seen,  the  depot  fat  is  used  to  supply  90  per  cent  of  the  energy  on  which 
the  animal  maintains  its  existence.  Before  the  fat  is  transported,  it  is 
possibly  reconverted  into  lecithin,  as  which  it  passes  through  the  cell 
walls.  Enzymes  capable  of  accelerating  the  hydrolysis  of  simple  esters 
and  of  lecithin  (esterases)  are  abundantly  present  in  practically  all  tis- 
sues while  there  are  only  traces  of  true  lipases  except  in  the  pancreas 

md  intestines.  These  esterases  would  seem  to  be  the  responsible  agents 
for  the  transfer  of  lipoids,  as  lecithin,  in  and  out  of  the  tissue  cells  al- 
though some  may  pass  in  particulate  form  as  neutral  fat.  It  is  probably 

mly  in  the  intestinal  epithelium  that  the  latter  is  synthetized  through 

:he  influence  of  lipase. 

The  Fat  in  the  Liver 

The  physiology  of  the  liver  fat  has  been  very  diligently  studied, 
particularly  by  Leathes  and  his  pupils.50  The  outcome  of  this  work 
has  been  to  show  that  the  liver  occupies  an  extremely  important  posi- 
tion in  the  metabolism  of  fat,  being,  as  it  were,  the  half  way  house 
in  the  preparation  of  the  fatty-acid  molecule  for  consumption  in  the 
tissues.  Fat  is  a  material  containing  large  quantities  of  potential  en- 
ergy. While  in  the  depots  this  potential  energy  is  so  locked  away  as 
to  be  unavailable  for  tissue  use.  To  make  it  available  the  depot  fat 
is  carried  to  the  liver,  where  the  energy  becomes  unlocked  but  not  actu- 
ally liberated.  The  fat  is  then  transported  to  the  tissues,  and  the  libera- 
tion of  the  energy  occurs.  Neutral  fat  is  like  wet  gunpowder:  it  con- 


732  METABOLISM 

tains  much  potential  energy,  but  not  in  a  suitable  condition  for  explo- 
sion. The  liver,  as  it  were,  dries  this  gunpowder,  whence  it  is  sent  to 
the  tissues  to  be  exploded. 

The  great  importance  of  the  liver  in  fat  metabolism  is  indicated  by 
comparison  of  the  percentages  of  fat — or  better  of  fatty  acid — contained 
in  it  under  different  conditions  of  nutrition.  In  the  ordinary  run  of 
slaughter-house  animals  the  liver  contains  from  2  to  4  per  cent  of  higher 
fatty  acid,  but  in  about  one  in  every  eight  animals  a  much  higher  per- 
centage will  be  found  to  occur.  The  same  is  true  in  laboratory  animals. 
In  the  case  of  the  human  liver  as  obtained  from  autopsies  in  certain 
classes  of  patients,  from  60  to  70  per  cent  of  the  dry  weight  of  the 
organ,  or  23  per  cent  of  the  moist  weight,  may  be  fatty  acid.  There  is 
no  other  organ  in  the  animal  body  that  is  ever  loaded  with  fat  to  this 
extent.  As  in  the  depots,  this  liver  fat  might  be  derived  either  from  fat 
carried  to  the  organ  from  elsewhere  in  the  body,  or  it  might  represent 
a  surplus  of  manufactured  fat. 

Transportation  of  Fat  to  the  Liver. — About  forty  hours  after  giving 
phlorhizin  to  a  dog,  it  has  been  found  that  enormous  quantities  of 
fat  appear  in  the  liver;  a  few  hours  later,  however,  this  excess  of  fat 
may  have  entirely  disappeared.  Fatty  infiltration  of  the  liver  is  also 
observed  in  phosphorus  poisoning,  although  in  this  case  the  fat  usu- 
ally persists  till  the  death  of  the  animal.  In  man,  in  delayed  chlo- 
roform poisoning  and  in  cyclical  vomiting,  considerable  quantities  of  fat 
may  be  present  in  the  liver  within  a  very  short  period  of  time  after  the 
onset  of  the  condition.  There  can  therefore  be  no  doubt  that  fat  is 
transported  to  the  liver  under  abnormal  conditions,  but  this  can  not 
be  taken  as  evidence  that  the  liver  has  anything  to  do  with  fat  metab- 
olism in  the  normal  animal.  Such  evidence  has,  however,  been  supplied 
by  Coope  and  Mottram,51  who  have  shown,  at  least  in  rabbits,  that  a  sim- 
ilar invasion  of  the  liver  with  fat  occurs  in  late  pregnancy  and  early 
lactation.  They  also  found  that  the  fatty  acid  deposited  in  the  liver 
in  late  pregnancy  gives  an  iodine  value  which  lies  nearer  to  that  of  the 
mesenteric  fatty  acid  than  is  the  case  in  normal  animals.  Mottram  con- 
cludes that  "wherever  .  .  .  there  is  abundant  fat  metabolism,  the 
liver  is  found  to  be  infiltrated  with  fats,  presumably  to  be  handed  on 
elsewhere  when  worked  up."  It  is  interesting  that  the  fetus  is  greedy 
of  unsaturated  fatty  acids. 

The  most  likely  source  of  the  fat  transported  to  the  liver  is  the  fat  pres- 
ent in  the  depots,  unless  when  digestion  is  in  progress,  when  it  may  be 
the  fat  from  the  intestine.  That  much  of  it  comes  from  the  depots  is 
easily  demonstrated.  Thus,  the  more  extensive  the  infiltration  of  the 
liver  with  fat,  the  more  closely  will  this  fat  be  found  to  agree  with  the 
depot  fat  in  its  chemical  characteristics.  This  has  been  very  clearly 


FAT    METABOLISM 


733 


shown  by,  first  of  all,  starving  an  animal  so  as  to  clear  the  depots  of  fat 
as  much  as  possible;  then  feeding  it  on  some  "ear-marked"  fat  (unusual 
melting-point  or  a  brominized  fat)  ;  and  after  another  day  or  so  of 
starvation,  so  as  to  clear  the  liver  itself  of  fat,  poisoning  the  animal 
with  phosphorus  or  phlorhizin.  The  liver  will  be  found  shortly  after- 
wards to  be  invaded  with  fat  which  has  all  the  ear-marks  of  that  on 
which  the  animal  had  been  fed. 

Evidence  of  the  same  character  has  been  furnished  in  a  series  of  clin- 
ical cases  by  observations  on  the  amount  of  fat  and  the  iodine  value  of 
the  fatty  acid  of  the  liver.  This  is  shown  in  the  accompanying  table. 

FATTY  ACIDS  OF  LIVER 


CAUSE  OF  DEATH 

HIGHER  FATTY 
ACIDS  PER  CENT 
OF  DRY  WEIGHT 

IODINE  VALUE 
OF  FATTY  ACIDS 

1. 

Pernicious  anemia 

12.1 

116.8 

XTrV"rTYlQl                          < 

2. 

Lobar  pneumonia 

13.7 

116.8 

JiN  \Jl  Jlldl 

figures 

3. 

4. 

Pernicious  anemia 
Diabetes 

14.25 
14.4 

116.0 
119.6 

5. 

Toxemic  jaundice 

15.6 

109.5 

Commencing 

6. 

Accident 

17.2 

103.5 

fatty 

7. 

Empyema 

21.5 

96.0 

change 

8. 

Phthisis 

25.4 

96.4 

:  9. 

Broncho-pneumonia 

38.4 

84.9 

10. 

Appendicitis 

44.0 

91.1 

Marked 

11. 

Carcinoma  of  bladder 

47.2 

77.8 

fatty 

12. 

Broncho-pneumonia 

54.6 

71.8 

change 

13. 

Ulcerative  colitis 

60.9 

80.3 

14. 

Accident 

66.3 

63.0 

15. 

Dysentery 

73.5 

69.1 

This  table  clearly  shows  that  the  more  fat  there  is  in  the  liver,  the 
nearer  this  fat  approaches  in  character  that  stored  in  the  depots  (viz.  65). 

That  some  of  the  fat  in  the  liver  may  come  directly  from  the  fat  re- 
cently absorbed  from  the  intestine  is  also  very  readily  demonstrable. 
Thus,  when  cocoanut  oil  was  placed  in  the  intestine  of  anesthetized  an- 
imals, along  with  bile  salts  and  glycerine,  it  was  found  by  Raper52  that 
per  cent  of  the  absorbed  oil  appeared  in  the  liver. 

The  characteristic  feature  of  cocoanut  oil  is  that  its  fatty  acids  are  also  volatile  in 
jam  and  are  saturated.     Some  of  the  fatty  acids  of  the  liver  are  volatile  in  steam, 
)ut  they  are  unsaturated.     By  distillation  in   steam  of  the   fatty  acids  obtained  by 
iponification  of  the  liver,  it  is  possible  to  determine  how  much  of  the  cocoanut  oil 
las  passed  to  the  liver. 

Similar  results  have  been  obtained  when  unsaturated  fatty  acids,  such 
those  contained  in  cod-liver  oil,  are  fed.  In  all  these  cases  the  rela- 
tionship of  the  fat  of  the  liver  to  that  of  the  food  is  even  more  evident  than 
that  between  food  fat  and  depot  fat,  because  in  the  liver  the  newly  absorbed 


734  METABOLISM 

fat  is  not  diluted  by  that  deposited,  it  may  be  months,  previously,  as  is 
the  case  in  the  connective  tissues. 

Changes  in  the  Fat  Deposited  in  the  Liver. — An  indication  of  the  nature 
of  the  change  is  furnished  by  observing  the  iodine  value  of  the  fat.  This,  it 
will  be  remembered,  indicates  the  degree  to  which  the  fatty  acid  is  unsatu- 
rated.  It  does  not  necessarily  indicate  the  number  of  unsaturated  bonds 
present  in  the  fatty-acid  molecule,  for  the  difference  in  iodine-absorbing 
power  may  depend  not  on  the  number  of  such  bonds  but  on  the  position  in 
the  chain  at  which  a  given  double  bond  is  inserted.  Even  with  this  reserva- 
tion, however,  it  is  evident  that  the  increase  observed  in  the  iodine  values 
shows  that  the  liver  has  the  power  of  desaturating  fat.  The  advantage  of 
this  change  depends  on  the  fact  that  the  desaturated  fatty  acid  will 
be  more  liable  to  break  up  than  the  saturated  fatty  acid.  In  other  words, 
the  double  linkage  will  weaken  the  chain  with  the  consequence  that  it  is 
liable  to  fall  apart  at  this  place;  such  at  least  is  the  natural  interpreta- 
tion which  the  chemist  would  put  on  the  result.  It  may  not,  however, 
be  the  correct  interpretation,  for  it  has  been  shown  that,  although  un- 
saturated fatty  acids  are  more  susceptible  to  chemical  change  than  sat- 
urated in  the  laboratory,  yet  when  fed  to  animals  they  appear  to  be 
more  stable  than  many  saturated  acids.  It  may  then  be  wrong  to  con- 
clude that  the  introduction  of  a  double  linkage  in  fat  necessarily  means 
the  liability  of  the  fatty-acid  chain  to  break  at  that  point.  However 
this  may  be,  it  seems  likely  that  one  function  of  the  liver  consists  in 
introducing  double  linkages  at  places  in  the  fatty-acid  chain,  as  a  result 
of  which  the  chain  breaks  at  these  places,  and  the  fragments  then  undergo 
further  oxidation. 

Double  linkages  may  be  introduced  not  only  in  one  place  in  a  fatty-acid  chain,,  but 
in  several.  For  example,  it  has  been  found  in  the  liver  of  the  pig,  after  oxidizing  the 
fatty  acids  with  permanganate,  that  oxidation  products  are  obtained  indicating  the  ex- 
istence of  unsaturated  acid  with  four  double  links.  Permanganate  (in  alkaline  solution) 
is  used  for  detecting  the  position  of  these  double  bonds,  because,  when  it  is  allowed 
to  act  on  unsaturated  fatty  acids  in  the  cold,  it  causes  hydroxyl  groups  to  be  introduced 
in  the  position  of  the  double  bonds.  When  the  oxidation  is  performed  at  a  moderate 
temperature,  the  fatty  acid  falls  apart  at  the  hydroxyl  groups.  A  fatty  acid  with  eight 
hydroxyl  groups  has  been  obtained  in  this  way  from  the  liver  of  the  pig.  The  presence 
of  the  hydroxyl  groups  has  been  confirmed  by  finding  that  an  octobromide  is  obtained 
by  treatment  with  bromine.  An  acid  of  the  same  formula  is  said  to  be  present  in  cod- 
liver  oil.  To  sum  up,  we  may  conclude  that  there  are  certain  positions,  in  the  chains  of 
carbon  atoms  which  constitute  the  fatty-acid  radicle,  where  the  liver  introduces  double 
bonds,  and  that  the  weakened  radicles  then  circulate  to  the  tissues,  where  they  break  up 
at  those  positions. 

Desaturation  is  probably  not  the  only  process  by  which  the  liver  assists  in 
the  metabolism  of  fat.  It  may  also  take  part  in  the  building  of  fatty- 
acid  radicles  into  the  complex  molecule  of  lecithin.  The  process  of  de- 


FAT    METABOLISM  735 

saturation  is  probably  a  preliminary  step  to  this  incorporation  of  the  fatty- 
acid  molecule  into  lecithin,  for  it  is  well  known  that  lecithin  contains  highly 
unsaturated  fatty-acid  radicles.  In  support  of  such  a  view  it  is  interesting 
to  note  that  in  alcohol-ether  extracts  from  normal  and  pathological  livers, 
the  lecithins,  which  are  precipitated  by  acetone,  have  higher  iodine  values 
(i.e.,  are  more  unsaturated)  than  the  neutral  fats  extracted  from  the  same 
liver,  which  also  have  higher  iodine  values  than  the  depot  fat  of  the  same 
animal.  Conversion  of  fat  into  lecithin  also  occurs  extensively  in  the 
blood  itself  (page  728). 

Desaturation  of  fatty  acids  occurs  in  other  places  besides  the  liver.  The 
relative  activity  of  the  different  tissues  in  this  regard  has  been  studied  by 
feeding  cats  with  fatty  fish  and  then  determining  the  iodine  value  of  fat 
from  various  places  in  the  body.  The  absorbed  fat  was  more  obvious  in  the 
liver  than  in  the  subcutaneous  tissues,  because  it  had  not  become  diluted 
with  fat  deposited,  it  may  have  been  months,  previously,  which  would  be  the 
case  in  the  fat  of  the  fat  depots;  and  it  was  found  that,  although  the 
iodine  value  of  the  subcutaneous  fat  was  slightly  raised,  that  of  the 
liver  was  much  more  so,  indicating  that  the  desaturation  process  had 
been  more  active  in  this  organ,  but  had  also  occurred  to  a  certain  extent 
in  the  depots. 

Before  leaving  this  subject  of  fat  in  the  liver,  it  is  important  to  re- 
call the  old  observation  of  Rosenthal,  that  a  more  or  less  reciprocal 
relationship  exists  between  glycogen  and  fat  in  the  liver.  When  much 
glycogen  is  present  there  is  little  or  no  fat,  and  vice  versa.  It  is  impor- 
tant to  note  that  the  exact  locations  of  fat  and  carbohydrate  in  the  he- 
patic lobule  are  somewhat  different. 

A  practical  clinical  application  of  the  above  work  is  found  in  the  fact 
that  fats  will  be  more  readily  utilized  by  the  body  when  they  contain  a 
high  percentage  of  unsaturated  fatty  acids.  It  is  possibly  for  this 
reason  that  Norwegian  cod-liver  oil  is  of  such  undoubted  nutritive  value. 
It  is  much  more  so  than  Newfoundland  cod-liver  oil,  because  in  the  prep- 
aration of  this  variety  oxidation  occurs,  which  makes  it  no  longer  unsat- 
urated. Fish  oils  in  general  are  more  unsaturated  than  other  animal 
oils,  and  are  for  this  reason  more  nutritious.  The  presence  of  vitamines 
rather  than  their  assimilative  properties  may,  however,  be  the  factor 
which  determines  the  nutritive  value  of  different  brands  of  cod-liver  oil. 

The  fat  in  the  tissues  differs  very  materially  from  that  of  the  liver  or 
the  depots.  Only  60  per  cent  of  this  fat  consists  of  fatty  acid,  which  is 
present  very  largely  as  part  of  the  lecithin  molecule,  thus  accounting  for 
the  high  iodine  value.  Some  is  probably  also  present  as  simple  glyceride, 
in  a  highly  unsaturated  and  therefore  very  fragile  condition. 


CHAPTER  LXXXI 

FAT  METABOLISM  (Cont'd) 

Two  very  important  questions  of  fatty-acid  metabolism  may  now  be 
considered:  namely,  (1)  how  is  fatty  acid  formed  from  carbohydrate? 
and  (2)  what  becomes  of  the  fragments  into  which  the  fatty-acid  molecule 
is  split  as  the  result  of  the  desaturation  process?  Although  these  prob- 
lems involve  chemical  details  of  a  somewhat  complex  nature,  we  must 
not  on  this  account  fail  to  consider  them;  for,  as  we  shall  see,  much  of 
what  is  known  has  an  important  practical  application  depending  on  the 
fact  that  certain  of  the  intermediary  substances  may  accumulate  in  the 
organism  and  develop  a  toxic  action. 

The  Production  of  Fatty  Acid  out  of  Carbohydrate. — If  we  place  the 
formulas  for  glucose  and  palmitic  acid  side  by  side,  thus: 

CH2OH-(CHOH)4-CHO  (glucose),  and 
CH3-(CH2)14-COOH  (palmitic  acid); 

we  shall  see  that  this  transformation  must  involve:  (1)  a  considerable 
alteration  in  the  structure  of  the  molecule,  (2)  the  removal  of  oxygen, 
and  (3)  the  fusion  of  several  glucose  molecules  into  one  molecule  of  fatty 
acid. 

The  conversion  of  carbohydrate  to  fat  therefore  involves  a  process  of 
reduction,  and  the  resulting  molecule  must  be  capable  of  yielding  more 
energy  when  it  is  oxidized  than  the  original  one  of  carbohydrate,  for 
obviously  the  system  02-CH2  (which  corresponds  to  fat)  will  develop 
more  energy  than  that  of  02  -  CHO  (which  corresponds  to  carbohydrate)  ; 
just  as  a  piece  of  wood  when  it  is  burned  will  develop  more  heat  than  a 
piece  of  charcoal.  This  explains  why  one  gram  of  fat  yields  9.3  calories 
of  heat,  and  one  gram  of  carbohydrate,  only  4.1  (page  571).  Fatty 
acid  therefore  contains  more  potential  energy  than  sugar,  and  in  explain- 
ing its  synthesis  from  sugar  in  the  animal  body  we  must  indicate  the 
source  of  the  extra  energy.  This  is  dependent  on  oxidation  of  some  sugar 
molecules — which  do  not  themselves  become  changed  to  fatty  acid — 
proceeding  side  by  side  with  the  reduction  which  affects  the  others  and 
is  represented  in  the  outcome  of  the  reaction  by  the  combustion  products 
C02  and  H20,  thus: 

6C6H1206  + 13  02  =  20  C02  +  C16H3202  +  20  H20. 
(glucose)  (fatty  acid) 

736 


FAT    METABOLISM  737 

What  evidence  have  we  that  such  a  process  actually  occurs  in  the  body? 
If  we  compare  the  intake  of  oxygen  with  the  output  of  carbon  dioxide 
in  the  respired  air,  we  shall  find  that  usually  there  is  less  of  the  latter; 
that  is  to  say,  the  respiratory  quotient,  as  this  ratio  is  called,  is  usually 
less  than  unity.  During  the  extensive  conversion  of  carbohydrate  into 
fat,  however,  which  occurs  during  the  fall  months  in  hibernating  animals, 
the  R.Q.  has  been  found  to  rise  as  high  as  1.4.  The  great  excess  of 
C02  -  output  over  02  -  intake  which  such  a  quotient  indicates  conforms 
with  the  above  equation. 

The  entire  dissimilarity  in  chemical  structure  between  the  molecules 
of  fat  and  carbohydrate  suggests  that  the  primary  step  in  the  conversion 
must  be  a  thorough  breakdown  of  the  carbohydrate  chain  into  compara- 
tively simple  molecules,  from  which  the  fat  molecules  are  then  recon- 
structed and  the  unnecessary  oxygen  set  free.  The  problem  is  to  ascer- 
tain the  chemical  structure  of  these  simpler  molecules  and  the  manner 
of  their  union  into  fatty  acid. 

The  Method  by  Which  the  Fatty  Acid  is  Broken  Down. — In  the  chemi- 
cal laboratory,  ordinary  oxidizing  agents  attack  the  fatty-acid  chain  at  the 
C-atom  next  the  carboxyl  (COOH)  group  (the  alpha  C-atom).  But 
this  can  not  occur  in  the  animal  body,  because  it  would  leave  behind  a 
smaller  chain  containing  an  uneven  number  of  C-atoms,  and  such  chains 
are  never  found  present  in  the  animal  fats.  On  the  contrary,  the  com- 
moner fats  all  contain  an  even  number  of  C-atoms,  thus :  Butyric,  C4H802 ; 
palmitic,  ClfiH3202;  stearic,  C18H3G02;  oleic,  C18H3402. 

The  intermediary  substances  which  are  produced  during  the  gradual 
breakdown  of  the  fatty-acid  molecule  in  the  normal  animal  are  of  a  very 
transitory  character  so  much  so  indeed  that  it  is  impossible  for  any  one 
of  them  to  accumulate  in  sufficient  amount  to  permit  of  isolation,  or  even 
detection,  by  chemical  means.  How  then  are  we  to  identify  the  inter- 
mediary products?  This  has  been  rendered  possible  by  the  discovery  that, 
when  anything  occurs  to  disturb  the  normal  course  of  fat  metabolism,  as, 
for  example,  when  the  tissues  are  deprived  of  carbohydrates  (as  in  star- 
vation or  in  severe  diabetes),  the  oxidation  of  the  fatty-acid  chain  stops 
short  when  a  chain  of  four  C-atoms  still  remains  unbroken.  These  last 
four  C-atoms  seem  to  form  a  residue  that  is  more  resistant  to  oxidation 
than  the  remainder  of  the  fatty-acid  molecule.  It  is  a  residue,  therefore, 
which  is  quite  readily  further  oxidized  to  C02  and  H20  under  normal  con- 
ditions, but  which,  undergoes  only  a  partial  oxidation  when  the  metab- 
bolism  is  upset,  resulting  in  the  production  of  various  intermediary  prod- 
ucts. These  accumulate  in  the  body  in  sufficient  amount  to  overflow  into 
the  urine,  from  which  they  can  be  isolated  and  identified. 

The  fatty  acid  with  4  C-atoms  is  "butyric,  CH3CH2CH2COOH,  and  the 


738  METABOLISM 

first  oxidation  product  formed  from  it  in  the  body  seems  to  be  (3-oxybuty- 
ric  acid,  CH3CHOHCH2COOH.  This  then  becomes  oxidized  to  form  a 
body  having  the  formula  CH3COCH2COOH,  acetoacetic  acid,  which,  on 
further  oxidation,  readily  yields  CH3COCH3,  or  acetone.  These  sub- 
stances (/?-oxybutyric  acid,  acetoacetic  acid  and  acetone)  appear  in  the 
urine  during  carbohydrate  starvation,  as  in  diabetes. 

It  might  be  objected,  however,  that  a  chemical  process  occurring  under 
abnormal  conditions  need  not  also  occur  in  the  normal  animal.  That  it 
probably  does,  however,  is  indicated  by  the  results  of  the  experiments 
of  Knoop  and  of  Embden  and  his  coworkers.  Knoop  conceived  the  idea 
of  introducing  into  the  fatty-acid  molecule  some  group  which  is  resistant 
to  oxidation  in  the  body.  The  phenyl  group  (C6H5)  was  found  to  have 
this  effect.  By  feeding  an  animal  with  the  phenyl  derivatives  of  acetic, 
propionic,  butyric,  and  valeric  acids,  it  was  found  that  the  urine  con- 
tained either  hippuric  (see  page  663)  or  phenaceturic  acid.  Both  of 
these  are  compounds  of  aromatic  acids  with  glycocoll  or  aminoacetic 
acid  (CH2NH2COOH),  one  of  the  protein  building-stones  and  always 
available  in  the  organism  to  form  such  compounds,  thus : 

( 1 )  CCH5COOH  +  CH2NH2COOH  =  C6H5CONHCH2  COOH. 

(benzole  (glycocoll)  (hippuric  acid) 

acid) 

( 2 )  C6H5CH2COOH  +  CH2NH2COOH  —  CCH5CH2CONHCH2COOH. 
(phenylacetic          (glycocoll)  (phenaceturic  acid) 

acid) 

When  either  benzoic  acid  (C6H5COOH)  or  phenylacetic  acid  (C6H5CH2- 
COOH)  is  formed  in  the  body  as  a  result  of  the  oxidation  of  phenyl 
derivatives  of  the  higher  fatty  acids,  the  acid  combines  with  glycocoll 
according  to  the  above  equations.  From  this  it  follows  that  if  oxidation 
occurs  so  that  two  C-atoms  are  thrown  off  at  a  time  (/3-oxidation),  fatty 
acids  with  an  even  C-atom  chain  should  yield  hippuric  acid,  and  those 
with  an  uneven  chain,  phenaceturic.  This  was  found  to  be  the  case,  as 
the  accompanying  table  shows. 


ACID   FED 

OXIDATION 
PRODUCT 

EXCRETED  AS 

Benzoic  acid,  C6H6.COOH 
Phenylacetic   acid,    C6H6  .  CH2  .  COOH 

Not  oxidized 
Not  oxidized 

Hippuric  acid 
Phenaceturic 

acid 

Phenylpropionic  acid,  C6H5 . CH2 . CH2 . COOH  C6H5.COOH  Hippuric  acid 

Phenylbuty ric  acid,  C6HB .  CH2 .  CH2 .  CH2 .  COOH  C0H5 .  CH2 .  COOH  Phenaceturic 

acid 
Phenylvaleric  acid,  C6H5 .  CH2 .  CH2 .  CH .  CH2 .  COOH       C0H5 .  COOH  Hippuric  acid 

(From  Dakin.) 


FAT    METABOLISM  739 

Embden's  experiments  are  equally  convincing.  He  studied  the  forma- 
tion of  acetone  in  defibrinated  blood  perfused  through  the  freshly  excised 
liver.  Normally  only  a  trace  of  this  substance  is  formed,  but  when  fatty 
acids  with  an  even  number  of  carbon  atoms  were  added  to  the  blood, 
they  gave  rise  to  a  marked  increase  in  acetone,  whereas  those  with  an 
uneven  chain  failed  to  cause  any  change.  The  acetone  was  found  to  be 
derived  immediately  from  acetoacetic  acid.  The  following  table  shows 
the  results. 


NORMAL  FATTY  ACID  FORMATION  OF 

ACETOACETIC  ACID 

Acetic  acid  CH3.COOH 

Propionic  acid  CH3.CH2.COOH 

Butyric  acid  CH3 .  CH2 .  CH2 .  COOH  + 

Valeric  acid  CH3.CH2.CH2.CH2.COOH 

Caproic  acid  CH3 .  CH2 .  CH2 .  CH2 .  CH, .  COOH  + 

Heptylic  acid  CH3 .  CH, .  CH2 .  CH2 .  CH~2 .  CH., .  COOH 

Octoic  acid  CH3.CH2.CH2.CH2.CH2.CH2.CH2.COOH  + 

Nonoic  acid  CH3 .  CH2 .  CH2 .  CH2 .  CH2 .  CH2 .  CH2 .  CH2 .  COOH 

Decoie  acid  CH3 .  CH2 .  CH2 .  CH2 .  CH2 .  CH2 .  CH2 .  CH2 .  CH2 .  CH2 .  COOH  + 

(From  Dakin.) 

For  a  long  time  it  was  difficult  for  chemists  to  understand  how  such 
a  process  of  oxidation  at  the  /?-C-atom  could  occur,  since  they  were 
unable  to  bring  it  about  in  the  laboratory  by  the  use  of  the  ordinary 
oxidizing  agents,  but  recently  Dakin  has  removed  the  difficulty  by  show- 
ing that  hydrogen  peroxide  (H202)  oxidizes  fatty  acids  just  exactly  in 
this  way. 

We  may  sum  up  the  results  of  these  experiments  and  observations  by 
stating  that  normal  saturated  fatty  acids  and  their  phenyl  derivatives  can 
undergo  oxidation,  not  only  in  the  animal  body,  but  also  in  vitro,  in  such 
a  manner  that  the  two  (or  some  multiple  thereof)  terminal  C -atoms  are 
removed  at  each  successive  step  in  their  decomposition. 

But  we  must  not  be  too  hasty  in  concluding  from  these  experiments  that  the  steps 
in  the  process  are  necessarily  in  the  order  of  first,  the  production  of  a  /3-hydroxy  acid, 
and  second  the  oxidation  of  this  to  a  Ketone  group.  The  mere  presence,  side  by  side, 
of  /3-hydroxybutyric  acid  and  of  acetone  in  the  above  experiments  does  not  indicate 
which  is  the  antecedent  of  the  other,  and  indeed  there  are  several  experimental  facts 
that  seem  to  show  that  the  hydroxy  acid  may  be  derived  from  the  ketone.  For  example 
when  acetoacetie  acid  is  added  to  minced  liver  and  the  mixture  incubated,  ^3-hydroxy- 
butyric acid  is  formed  (a  reduction  process),  although  less  usually  the  reverse  action 
(oxidation)  may  occur  when  /3-hydroxy  acid  is  added.  A  reversible  reaction  must  there- 
fore be  capable  of  occurring  between  these  two  substances,  thus : 

reduction 
CH3.CHOH.CH2.COOH  < CH3 . CO . CH2 . COOH. 

oxidation 
(^-oxy butyric  acid)       >       (acetoacetie  acid) 


740  METABOLISM 

We  know  practically  nothing  as  to  the  conditions  determining  whether  oxidation  or 
reduction  shall  predominate,  but  there  are  two  significant  facts  that  one  should  bear  in 
mind:  (1)  that  a  plentiful  supply  of  oxygen  is  necessary  for  the  oxidative  process,  and 
(2)  that  the  presence  of  readily  oxidizable  material  in  the  liver  (e.g.,  carbohydrates) 
may  determine  the  direction  which  the  reaction  shall  take.  It  is  commonly  said  that 
fats  burn  in  the  fire  of  carbohydrates,  and  it  may  be  that  the  undoubted  diminution  in 
acidosis  which  occurs  in  diabetes  when  carbohydrate  food  is  given  is  dependent  upon  the 
directive  influence  which  its  combustion  in  the  liver  has  on  the  above  processes.  But 
we  must  be  cautious  not  to  transfer  results  obtained  by  experiments  with  minced  liver 
in  judging  of  the  reactions  which  occur  during  life.  Provisionally,  then,  we  must  assume 
either  that  /3-hydroxybutyric  acid  is  a  necessary  stage  in  the  oxidation  of  butyric  acid 
or  that  it  is  formed  by  reduction  of  acetoacetic  acid,  which  is  really  the  first  step  in 
that  process. 

Of  course  there  is  no  evidence  in  the  above  experiments  that  the  higher  fatty  acids 
are  also  broken  down  by  the  removal  of  two  C-atoms  at  a  time,  nor  has  it  been  possible 
to  detect  any  ketonic  or  /3-hydroxy  derivatives  of  them  in  the  animal  body.  We  can  only 
reason  from  analogy  that  a  similar  process  may  occur,  although  some  support  is  fur- 
nished for  such  a  view  by  the  fact  that  ketonic  fatty  acids  have  been  found  in  vegetable 
organisms. 

What,  then,  it  may  be  asked,  is  the  relation  of  the  desaturation  of  fatty  acids  which 
we  have  seen  occurs  in  the  liver  (and  probably  elsewhere)  to  the  /3  oxidation?  There 
can  be  no  doubt  that  both  processes  can  occur  in  the  animal  body,  indeed  in  the  same 
organ,  e.g.,  the  liver;  and  it  is  important  to  ascertain  their  relationship  to  each  other. 
The  conclusion  which  would  seem  to  conform  best  with  the  known  facts  is  that  the  de- 
saturation  process  occurs  (in  the  liver)  so  as  to  break  up  the  long  fatty-acid  chain  into 
smaller  chains,  which  are  then  capable  of  /3  oxidation  (in  the  tissues) ;  desaturation  may 
be  the  process  by  which  the  molecule  is  rough  hewn,  and  /3  oxidation  that  by  which  the 
resulting  pieces  are  finally  split  to  their  smallest  pieces — that  is,  to  molecules  of  the  size 
of  acetic  acid,  which  are  finally  completely  burnt  to  carbonic  acid  and  water. 

The  increase  of  iodine  value  observed  by  Leathes  and  his  coworkers  need  not,  as  has 
already  been  pointed  out,  necessarily  indicate  that  new  double  linkages  have  been  intro- 
duced in  the  fatty-acid  chain;  it  may  merely  indicate  that  structurally  isomeric  deriva- 
tives which  absorb  iodine  more  readily  have  been  formed.  Direct  evidence  of  desatura- 
tion has,  however,  been  offered  by  Hartley,  who  isolated  the  unsaturated  fatty  acids  (by 
dissolving  the  lead  soaps  in  ether)  from  pig's  liver  and  then  proceeded  to  oxidize  them 
with  alkaline  permanganate.  When  the  olein  of  the  depot  fat  is  thus  treated  at  a  low 
temperature,  two  hydroxyl  groups  become  attached  where  the  double  linkage  existed 
(forming  dioxystearic  acid),  and  when  the  mixture  is  now  warmed,  the  molecule  splits 
into  two  at  this  place,  forming  two  lower  acids  (pelargonic  and  azelaic)  : 

(1)   CH3-(CH2)7CH:CH(CH2)7COOH; 
(oleic  acid) 

OH  OH 

/  / 

(2)  CH3-  (CH2)7-CH-  -CH (CH2)7COOH; 

(dioxystearic  acid) 

(3)  CH3     (CH2)7COOH  +  COOH-(CH2)7COOH. 

(pelargonic  acid)          (azelaic  acid) 

We  may  conclude  from  this  that  the  double  linkage  in  the  oleic  acid  of  the  depot  fat 
exists  between  the  ninth  and  tenth  C-atoms.  But  it  is  otherwise  in  the  case  of  the  un- 
saturated acid  from  the  liver  (pig's),  for  under  the  above  process  of  oxidation  this 
yielded  caproic  acid,  which,  since  this  acid  has  six  C-atoms,  would  indicate  that  the 


FAT    METABOLISM  741 

double  linkage  existed  between  the  sixth  and  seventh  C-atoms.  Another  interesting  fact 
brought  to  light  by  the  experiments  was  that  a  tetraoxystearic  acid  was  formed,  which 
fell  apart  in  such  a  way  as  to  indicate  that  the  hydroxyl  groups  occurred  between  the  sixth 
and  seventh  and  between  the  ninth  and  tenth  C-atoms.  The  occurrence  of  this  substance 
would  be  satisfactorily  explained  by  the  introduction  into  the  molecule  of  oleic  acid  of  a 
second  double  bond — i.  e.,  between  the  sixth  and  seventh  C-atoms.  ' '  The  acids  found  in 
the  pig's  liver  may  be  accounted  for,  in  other  words,  by  supposing  that  desaturation 
of  stearic  acid  and  of  the  ordinary  (depot)  oleic  acid  'Occurs  by  the  introduction  of  a 
double  link  between  the  sixth  and  seventh  carbon  atoms  in  each  case" — (Leathes).  Still 
other  double  links  may,  however,  be  introduced  into  the  fatty-acid  chain,  for  acids  of  the 
linolic  acid  series  are  present  in  cod-liver  oil.  Finally,  it  is  of  interest  to  note  that  caproic 
acid  is  a  product  of  the  above  oxidation  process,  for  it  has  an  even  number  of  C-atoms 
and  therefore  will  form  /3-oxybutyric  acid. 

To  go  into  these  chemical  problems  any  further  here  would  be  out  of 
place.  One  other  fact,  should,  however,  be  borne  in  mind — namely,  that 
the  unsaturated  acids  may  be  formed  from  saturated  acids  through  the 
intermediate  formation  of  /?-hydroxy  and  /?-ketonic  acids.  Their  mere 
presence,  in  other  words,  should  not  be  taken  as  evidence  that  the  oxida- 
tion of  fatty  acids  is  initiated  by  the  introduction  of  an  hydroxyl  group 
at  the  ft  position  in  the  chain. 


CHAPTER  LXXXII 

CONTEOL  OF  BODY  TEMPERATURE  AND  FEVER 

The  classification  of  animals  into  two  groups — warm-blooded  and  cold- 
blooded— according  to  their  ability  to  maintain  the  body  temperature  at 
a  constant  level,  is  more  or  less  arbitrary.  Between  the  two  groups  an- 
other exists,  represented  mainly  by  hibernating  animals,  in  which  at 
certain  times  of  the  year  the  animal  is  warm-blooded  and  at  other  times 
cold-blooded.  The  ability  of  the  higher  mammals  to  maintain  a  constant 
body  temperature  may  or  may  not  be  present  at  the  time  of  birth.  The 
heat-regulating  mechanism  of  the  human  infant  for  example  remains  ill 
developed  for  some  time,  so  that  exposure  to  cold  is  liable  to  lower  the 
body  temperature  to  a  dangerous  degree. 

VARIATIONS  IN  BODY  TEMPERATURE 

In  animals  in  which  the  heat-regulating  mechanism  is  fully  developed, 
there  is  not,  even  during  perfect  health,  entire  constancy  in  temperature 
in  the  different  parts  of  the  body  or  in  the  same  part  at  different  periods 
of  the  day.  The  average  rectal  temperature  of  man  is  usually  stated  as 
being  37°  C.  (98.6°  F.),  but  the  diurnal  variation  may  amount  to  1°  C., 
being  highest  in  the  late  afternoon  and  lowest  during  the  night.  There 
are  probably  several  causes  for  this  variation,  and  they  are  in  part  at 
least  dependent  upon  the  greater  metabolic  activities  of  the  waking 
hours  and  upon  the  taking  of  food.  Apart  from  these  influences,  how- 
ever, others  which  are  less  evident  appear  to  operate;  for  it  has  been 
found  that,  when  the  daily  program  is  reversed  by  night  work,  the  usual 
diurnal  variation,  although  much  less  pronounced,  still  remains  evident 
even  after  this  reversal  in  habit  may  have  been  kept  up  for  years. 
It  is  of  interest  to  note  in  this  connection  that  nocturnal  birds  have  their 
maximum  temperature  at  night  and  their  minimum  during  the  day. 

Regarding  the  temperature  in  different  parts  of  the  body,  that  of  the 
rectum  is  usually  about  1°  C.  higher  than  that  of  the  mouth,  and  this 
again  higher  than  that  of  the  axilla.  Of  these  three  the  mouth  tempera- 
ture is  the  most  variable,  for  many  conditions,  such  as  mouth  breathing, 
talking,  drinking  cool  liquids  and  even  exposure  to  cold  air,  are  sufficient 
to  lower  markedly  the  temperature  of  this  region.  When  the  mouth 
temperature  is  carefully  taken  by  leaving  the  bulb  of  the  thermometer 

742 


CONTROL    OF   BODY    TEMPERATURE    AND    FEVER  743 

under  the  tongue  for  a  minute  or  more,  it  is  practically  the  same  as  the 
temperature  of  the  arterial  blood  of  the  hand  when  this  is  exposed  to  the 
ordinary  conditions  of  .outside  temperature.  Greater  differences  than 
1°  C.  in  the  temperature  of  different  regions  of  the  body  are  often  ob- 
served in  feeble  individuals  and  in  those  with  some  circulatory  disturb- 
ance. 

FACTORS  IN  MAINTAINING  THE  BODY  TEMPERATURE 

The  body  temperature  represents  the  balance  between  heat  production 
and  heat  loss.  The  production  is  effected  mainly  in  the  muscles  by  the 
oxidative  processes  which  are  constantly  ensuing  there.  When  the 
activity  of  the  muscles  is  abolished  by  paralyzing  the  terminations  of 
the  motor  nerves  with  curare,  the  temperature  of  warm-blooded  animals 
immediately  falls  or  rises  according  to  the  temperature  of  the  environ- 
ment. A  curarized  warm-blooded  animal  is  thus  made  to  behave  like  a 
cold-blooded  one.  Increased  muscular  activity,  on  the  other  hand, 
promptly  raises  the  body  temperature  by  1°  or  2°  C.,  above  which,  how- 
ever, a  further  rise  does  not  occur,  provided  nothing  has  been  done  to 
interfere  with  the  mechanism  by  which  the  excess  of  heat  is  got  rid  of 
from  the  body.  The  temperature  in  such  cases  adjusts  itself  at  a  higher 
level,  at  which  it  remains  fairly  constant  however  strenuous  the  exer- 
cise. It  is  possible  that  a  certain  amount  of  heat  may  also  be  generated 
by  the  chemical  processes  occurring  in  the  liver  and  other  viscera,  but 
when  compared  with  the  muscles  this  source  of  heat  is  undoubtedly  in- 
significant. Many  of  these  chemical  processes,  as  in  the  liver,  instead 
of  producing,  actually  absorb  heat,  so  that  the  balance  between  heat- 
producing  and  heat-evolving  mechanisms  may  or  may  not  come  out  in 
favor  of  the  liberation  of  heat. 

The  production  of  heat  goes  on  all  the  time  in  muscles  on  account  of 
the  condition  of  tonic  contraction  in  which  they  are  held  (see  page  905), 
and  which  is  also  necessary  for  keeping  the  joints  in  the  proper  degree 
of  flexion  or  extension.  When  more  heat  is  required  by  the  animal  body, 
the  tone  of  the  muscles  increases  independently  of  the  function  which 
they  may  be  performing  in  controlling  the  position  of  the  joints.  This 
increased  tone  may  become  so  pronounced  that  it  causes  visible  contrac- 
tions, which  we  recognize  as  shivering.  Whenever  the  insensible  hyper- 
tonicity  and  the  shivering  are  inadequate  to  produce  a  sufficient  amount 
of  heat,  the  animal  instinctively  moves  about  in  order  that  the  greater 
contractions  may  liberate  more  heat. 

The  heat  is  produced  in  the  muscles  by  oxidation  of  the  foodstuffs  that 
have  been  assimilated  from  the  blood.  Even  during  the  process  of  as- 
similation itself  a  certain  amount  of  heat  is  generated;  this  is  known 


744  METABOLISM 

as  the  specific  dynamic  action  of  the  foodstuff,  and  is  most  pronounced 
with  protein  and  least  so  with  carbohydrate  (page  574).  Advantage 
may  be  taken  of  this  heating  power  of  protein  to  produce  more  heat 
when  the  cooling  conditions  are  excessive ;  in  winter,  for  example,  there 
is  an  inclination  to  take  more  protein  food  than  during  summer,  and  the 
per  capita  consumption  of  such  food  is  much  greater  in  peoples  living  in 
temperate  zones  than  in  those  living  in  the  tropics.  The  ultimate  amount 
of  heat  produced  by  oxidation  is  greatest  with  fat  and  least  with  carbo- 
hydrate. 

Heat  loss  in  man  is  effected  partly  through  the  lungs,  but  mainly 
through  the  skin.  Through  the  latter  pathway  heat  is  lost  by  the  physical 
processes  of  heat  conduction  and  radiation  and  by  the  evaporation  of  the 
sweat.  Through  the  lungs  it  is  lost  mainly  in  the  vaporization  of  the 
water  contained  in  the  expired  air  (latent  heat  of  vapor).  The  amount 
of  heat  lost  from  the  skin  by  conduction  and  radiation  depends  on  the 
temperature  of  the  skin,  which  again  depends  on  the  rate  at  which  the 
blood  is  circulating  through  the  cutaneous  vessels.  Under  ordinary  con- 
ditions of  external  temperature  two  or  three  times  as  much  heat  is  lost 
by  these  methods  as  by  evaporation.  The  losses  by  evaporation,  under 
conditions  of  rest  and  average  external  temperature,  are  about  equally 
divided  between  the  lungs  and  the  skin. 

Under  average  conditions  in  man  the  main  regulation  of  heat  loss  is  ef- 
fected ~by  variations  in  the  skin  temperature  brought  about  by  peripheral 
vaso-constriction  and  dilatation.  The  marked  sensitivity  of  the  cutaneous 
blood  supply  to  changes  in  the  temperature  of  the  environment  has  been 
very  clearly  shown  by  observations  made  with  the  hand  calorimeter  of 
Stewart  described  elsewhere  (page  296).  When  the  bloodflow  through 
the  hand  is  examined  in  a  person  who  has  been  exposed  to  the  outside 
air,  it  may  be  little  more  than  half  that  which  it  attains  after  he  has 
been  in  a  warm  room  for  some  time.  In  the  outside  air  the  vessels  con- 
strict to  prevent  heat  loss  by  conduction  and  radiation;  in  the  warm  room 
they  dilate  to  facilitate  this  loss.  The  afferent  impulses  which  reflexly 
control  the  change  in  the  cutaneous  blood  circulation  may  be  set  up  by 
local  applications  of  heat  or  cold,  as  can  be  shown  in  the  hand-calorim- 
eter experiments  by  applying  a  cold  pad  to  the  skin  of  the  correspond- 
ing forearm,  or  allowing  an  electric  fan  to  blow  on  the  arm  when 
an  immediate  curtailment  of  bloodflow  takes  place.  Or  the  reflex  may  be 
excited  from  distant  skin  areas,  as  illustrated  in  the  curtailment  in  blood- 
flow  observed  when  the  opposite  hand  to  that  on  which  the  observation 
is  being  made  is  placed  in  cold  water.  The  magnitude  of  the  change 
in  cutaneous  circulation  is  more  or  less  dependent  upon  the  extent 
of  the  area  of  the  body  that  is  exposed  to  the  change  in  temperature. 


CONTROL    OF    BODY    TEMPERATURE   AND    FEVER  745 

it  has  recently  been  shown  that  the  blood  becomes  diluted  with  tissue 
fluid  when  more  surface  cooling  has  to  occur. 

Although  afferent  impulses  from  the  skin  are  therefore  of  great  im- 
portance in  adjusting  the  cutaneous  blood  supply  according  to  the 
amount  of  surface  cooling  that  has  to  occur,  a  further  effect  is  also  pro- 
duced on  them  by  the  action  on  the  nerve  centers  of  temperature  dif- 
ferences in  the  blood  itself.  Thus,  when  the  temperature  of  blood  going 
to  the  brain  is  raised  by  placing  the  carotid  arteries  on  some  heating  de- 
vice or  when  the  region  of  the  corpora  striata  is  directly  warmed,  the 
skin  vessels  become  dilated  as  if  the  animal  had  been  exposed  to  general 
warmth,  and  the  rectal  temperature  tends  to  fall  (Barbour56). 

When  the  loss  of  heat  by  radiation  and  conduction  is  no  longer  ade- 
quate to  prevent  a  rise  in  body  temperature,  or  when  the  processes  can 
not  operate  on  account  of  a  high  temperature  in  the  environment,  the 
loss  of  heat  from  the  skin  is  mainly  dependent  upon  the  evaporation  of 
sweat.  Under  ordinary  conditions  this  evaporation  takes  place  at  such 
a  rate  that  there  is  no  visible  perspiration  on  the  surface  of  the  body — 
the  so-called  insensible  perspiration.  When  the  heat  loss  by  this  channel 
must  become  greater,  the  perspiration  is  produced  in  larger  amount,  so 
that  it  collects  on  the  surface  of  the  body ;  and,  provided  the  conditions  of 
the  environment  are  such  that  evaporation  can  readily  take  place  (low 
relative  humidity),  the  amount  of  cooling  of  the  body  that  can  be  effected 
becomes  very  great.  A  man  may  exist  without  any  marked  rise  in  body 
temperature  in  a  very  hot  environment  even  when  he  is  exposed  to  an  out- 
side temperature  that  is  the  same  as  that  of  his  body,  or  even  greater.  To 
encourage  evaporation,  however,  he  should  be  naked  or  very  lightly  clad, 
and  the  air  should  be  kept  in  constant  motion  so  that  the  layers  of  air 
next  to  the  skin,  which  ordinarily  very  quickly  become  saturated  with 
vapor,  are  transferred  and  replaced  by  dryer  air.  Movement  of  the  air 
also  increases  the  heat  loss  by  convection,  provided  the  temperature  of 
the  air  is  not  too  near  that  of  the  body. 

The  importance  of  the  movement  of  air  in  the  regulation  of  heat  loss 
has  been  clearly  demonstrated  by  Leonard  Hill,54  F.  S.  Lee,  and  others, 
and  will  be  fully  discussed  in  the  chapter  on  ventilation  (page  754). 

The  stimulus  to  increased  sweating  has  been  thought  to  be  dependent 
mainly  on  changes  in  the  temperature  of  the  blood  since  sweating  does 
not  immediately  set  in  when  the  body  is  subjected  to  heat,  as  by  a  warm 
bath  or  a  hot  pack.  It  usually  takes  from  ten  to  twenty  minutes  after 
the  person  has  been  placed  in  the  bath  or  surrounded  by  the  warm  blan- 
kets of  the  pack  before  sweating  becomes  pronounced.  It  has  been 
shown,  however,  that  the  body  temperature  does  not  require  to  be  raised 
before  sweating  sets  in.  In  a  hot  bath  sweating  starts  on  the  forehead 


746  METABOLISM 

before  there  is  any  change  in  rectal  temperature  and  if  the  hand  be 
plunged  in  cold  water  the  sweating  stops  at  once  (cf.  Barbour). 

Loss  of  heat  by  evaporation  of  sweat  occurs  only  in  certain  animals. 
It  is  practically  absent,  for  example,  in  the  dog.  The  degree  to  which 
it  may  occur  also  varies  in  different  individuals  of  the  same  species. 
Dilution  of  the  blood  accompanies  it.  The  power  of  withstanding  high 
temperatures  is  proportional  in  man  to  the  facility  with  which  he  per- 
spires. Where  sweating  is  interfered  with  by  skin  diseases, — by  ichthy- 
osis,  for  example, — exposure  to  heat  or  increased  heat  production,  as  by 
muscular  activity,  may  raise  the  body  temperature  to  a  dangerous  degree. 

Another  factor  upon  which  the  efficiency  of  evaporation  of  sweat  in 
cooling  the  body  depends  is  the  relative  humidity  of  the  air.  When  this 
is  high,  evaporation  of  water  into  it  can  not  occur,  and  it  is  on  this 
account  that  an  increase  in  body  temperature  is  much  more  likely  to 
occur  in  warm,  humid  atmospheres  than  in  those  that  are  dry.  At  the 
same  temperature  people  can  live  in  perfect  comfort  in  the  dry  air  of  the 
open  plains,  but  suffer  immediately  from  rise  of  temperature  when  they 
go  into  the  humid  air  of  the  river  valleys.  Similarly,  work  in  hot  fac- 
tories or  in  mines  is  quite  possible  at  very  high  temperatures  if  the  air 
is  kept  dry  and  in  motion,  but  becomes  impossible  when  the  air  is  moist. 
In  judging  of  the  adequacy  of  air  from  this  point  of  view,  it  is  there- 
fore important  to  take  not  the  ordinary  dry-bulb  thermometer  reading 
but  that  of  the  wet-bulb.* 

In  animals,  like  the  dog,  that  do  not  perspire  over  the  surface  of  the 
body,  vaporization  of  the  water  in  the  expired  air  is  the  most  important 
method  of  regulation  of  heat  loss.  When  such  an  animal  is  exposed  to 
warmth  or  when  the  region  of  the  corpora  striata  is  artificially  warmed, 
the  breathing  immediately  becomes  much  quicker  and  deeper,  so  that 
pulmonic  ventilation  is  greatly  increased  and  much  more  water  is  carried 
out  as  vapor  with  the  expired  air.  To  vaporize  the  water  large  quanti- 
ties of  heat  are  required  (seen  in  the  latent  heat  of  steam).  In  man  this 
method  is,  ordinarily,  not  of  great  importance,  but  it  may  become  so 
when  sweating  is  interfered  with,  as  in  ichthyosis.  The  more  rapid 
breathing  also  facilitates  cooling  by  increasing  the  conduction  of  heat 
from  the  mucous  membranes  of  the  tongue,  mouth,  throat,  etc.  The  im- 
portance of  this  method  of  cooling  has  been  shown  by  finding  that  after 
the  introduction  of  a  tracheal  cannula  a  dog  can  not  withstand  an  in- 
crease of  external  temperature  nearly  so  well  as  a  normal  animal. 


*The  wet-bulb  thermometer  registers  a  temperature  that  is  lower  than  that  of  the  dry-bulb  in 
inverse  proportion  to  the  relative  humidity  of  the  air.  When  the  air  is  completely  saturated  with 
moisture,  the  temperature  recorded  by  the  two  instruments  will  be  the  same;  when  it  is  perfectly 
dry,  the  difference  will  be  maximal. 


CONTROL    OF   BODY    TEMPERATURE   AND   FEVER  747 

THE  CONTROL  OF  TEMPERATURE 

In  the  case  of  man  the  body  temperature  is  very  largely  under  volun- 
tary control,  as  by  the  choice  of  clothing  and  the  artificial  heating  of  the 
room.  Desirable  as  this  voluntary  control  of  heat  loss  may  be,  there  can 
be  little  doubt  that  it  is  often  managed  to  the  detriment  of  good  health. 
Living  in  overheated  rooms  during  the  cooler  months  of  the  year  so 
diminishes  the  loss  of  heat  from  the  body  that  the  tone  and  heat-produc- 
ing powers  of  the  muscular  system  are  lowered.  Not  only  does  this 
diminish  the  resistance  to  cold,  but  it  causes  the  food'  to  be  incompletely 
metabolized  so  that  it  is  stored  away  as  fat.  The  superficial  capillaries 
also  become  constricted  and  the  skin  bloodless  and  " pasty."  It  is  not 
looks  alone  that  suffer,  however,  but  health  as  well,  for  by  having  so 
little  to  do  the  heat-regulating  mechanism  gets,  as  it  were,  out  of  gear, 
so  that  when  it  is  required  to  act,  as  when  the  person  goes  outside  to 
the  cold  air,  it  may  not  do  so  as  promptly  as  it  should,  with  the  result 
that  the  body  temperature  falls  somewhat  and  catarrh,  etc.,  are  the 
result.  There  can  be  little  doubt  that  much  of  the  benefit  of  open-air 
sleeping  is  owing  to  the  constant  stimulation  of  the  metabolic  processes 
which  it  causes. 

As  will  be  inferred  from  what  has  been  said  above,  the  control  between 
heat  production  and  heat  loss  is  effected  through  a  nerve  center  located 
in  or  near  the  corpora  striata.  In  most  animals,  when  the  spinal  cord 
is  cut  in  the  cervical  region,  the  body  temperature  quickly  falls  unless 
artificially  maintained.  In  the  case  of  man,  on  the  other  hand,  it  has 
usually  been  observed,  after  accidental  section  of  the  spinal  cord  in  the 
cervical  region,  that  a  rise  in  temperature  occurs.  In  twenty-four  un- 
complicated cases  of  spinal-cord  injury  in  man,  collected  from  the  rec- 
ords of  Guy's  Hospital  by  Gardiner  and  Pembrey,  it  was  found  that 
nineteen  showed  hyperthermia  (sometimes  amounting  to  43.9°  C.),  and 
only  five,  hypothermia  (sometimes  27.6°  C.).  If  the  patient  lived,  the 
ultimate  effect  of  the  section,  as  in  the  lower  animals,  would  no  doubt 
be  the  loss  of  the  power  of  maintaining  a  constant  temperature. 

The  extent  to  which  the  animal  comes  to  behave  as  if  cold-blooded,  after 
section  of  the  spinal  cord,  varies  considerably  according  to  the  level  of 
the  lesion;  if  the  cord  is  cut  in  the  upper  thoracic  region,  for  example, 
the  regulation  against  cold,  although  distinctly  less  efficient  than  normal, 
is  far  better  than  when  the  section  is  made  through  the  cervical  cord. 
This  difference  is  dependent  on  the  fact  that  after  the  lower  lesion  much 
larger  muscular  groups  and  skin  areas  are  left  intact,  so  as  to  make 
regulation  possible.  Section  of  the  dorsal  cord  in  mice  has  been  found 
by  Pembrey  to  abolish  entirely  the  increased  metabolism  which  occurs 
in  normal  mice  when  they  are  exposed  to  cold. 


748  METABOLISM 

In  the  light  of  these  experiments  it  is  probable  that  the  difference  in 
the  effects  produced  on  body  temperature  by  section  of  the  cervical 
spinal  cord  in  man  and  the  lower  animals  depends  on  the  relative  im- 
portance of  the  heat-producing  and  heat-dissipating  mechanisms.  When 
the  control  of  heat  loss  is  paralyzed  in  the  smaller  animals,  the  cooling 
of  the  body  becomes  excessive  in  relation  to  the  amount  of  heat  produced 
in  the  paralyzed  muscles,  because  the  body  surface  is  extensive  in  com- 
parison with  the  body  weight  (see  page  586).  In  the  larger  animals  such 
as  man,  on  the  other  hand,  the  cooling  effect  is  much  less  marked,  espe- 
cially when,  as  is  common  after  spinal  cord  injuries,  the  patient  is  kept 
unusually  warm. 

FEVER 

The  clinical  application  of  a  knowledge  of  the  mechanism  of  heat  regu- 
lation in  the  animal  body  concerns  the  causes  of  fever.  In  the  most 
familiar  form  fever  is  produced  by  infectious  processes,  but  it  may  also 
be  owing  to  various  other  causes,  among  which  may  be  mentioned  the 
parenteral  injection  of  foreign  protein,  excessive  destruction  of  protein 
substances  in  the  body  itself,  the  action  of  certain  drugs,  and  lastly, 
injury  to  the  base  of  the  brain  or  lesions  of  the  upper  levels  of  the  spinal 
cord.  Various  types  of  fever  are  recognized:  when  the  temperature  re- 
mains constantly  above  the  normal,  it  is  known  as  continuous  fever; 
when  oscillations  occur  but  the  temperature  never  falls  to  the  normal 
level,  it  is  known  as  remittent;  when  it  attains  the  normal  level  at  cer- 
tain periods  during  the  day,  it  is  known  as  intermittent. 

The  Mechanism  of  Fever 

During  a  sudden  rise  in  body  temperature  there  is,  on  the  one  hand,  in- 
creased heat  production  in  the  muscles,  and  on  the  other,  dimin- 
ished heat  loss  from  the  surface  of  the  body.  The  fever  is  therefore 
due  to  an  exaggeration  of  the  processes  ~by  which  the  body  normally  re- 
acts to  conditions  which  tend  to  lower  the  body  temperature.  The  increased 
muscular  tone  thus  induced  often  causes  visible  contractions,  familiar 
as  shivering;  and  the  constriction  of  the  cutaneous  blood  vessels  pro- 
duces the  subjective  sensation  of  chills,  and  causes  the  skin  to  become 
pale  and  cold  to  the  touch.  The  skin  muscles  also  contract,  producing 
" goose  skin."  During  this  stage,  objective  demonstration  of  the  cur- 
tailment of  the  skin  circulation  can  be  secured  by  observation  of  the 
bloodflow  through  the  hands  and  feet  (page  296).  When  the  temperature 
suddenly  falls  again,  (the  crisis,  as  it  is  called)  the  muscles  become  flaccid 
and  produce  less  heat,  and  the  cutaneous  blood  vessels  dilate,  as  has 
been  shown  by  measurements  of  the  bloodflow  of  the  hands  and  feet. 


CONTROL   OF   BODY   TEMPERATURE   AND   FEVER  749 

At  the  same  time  also,  the  sweat  glands  are  stimulated  and  marked  per- 
spiration occurs.  It  is  significant  that  fever  can  be  caused  by  injection 
of  very  strong  sugar  solutions  intravenously.  These  attract  water  from 
the  tissues  and  so  interfere  with  the  giving  off  of  heat. 

Concerning  the  cause  of  continuous  fever,  it  must  be  assumed  that  the 
balance  between  heat  production  and  heat  loss  has  been  adjusted  at  a 
higher  plane  than  normal.  We  cannot  explain  the  fever  on  the  basis 
either  that  heat  production  alone  is  increased  or  that  heat  loss  alone  is 
diminished,  for  in  neither  of  these  cases  would  the  temperature  stand 
at  a  permanent  level  but  would  steadily  rise  or  fall  according  to  which 
mechanism  was  disturbed.  The  thermogenic  nerve  centers,  while  set 
at  the  higher  plane  of  fever,  are  still  capable  of  responding  in  the  usual 
way  to  the  influences  which  cause  the  body  temperature  to  change  in  a 
normal  person.  For  example,  when  a  fever  patient  is  subjected  to 
a  hot  bath  so  that  his  body  temperature  rises  about  0.2  to  0.5  degrees  C., 
sweating  occurs  just  as  in  a  normal  individual;  or  if  exercise  is  taken 
the  increased  amount  of  heat  thereby  produced  in  the  muscles  is  dissi- 
pated in  the  usual  way.  When,  on  the  other  hand,  the  patient  is  exposed 
to  cold,  the  vessels  of  the  skin  contract  and  he  shivers. 

Although  fever  is  not  caused  by  an  actual  disturbance  of  balance  be- 
tween heat  production  and  heat  loss,  neither  of  these  processes  is  pro- 
ceeding at  its  normal  rate.  That  there  is  a  distinct  increase  in  the  total 
heat  production  of  the  body  in  acute  fevers  in  well-developed  persons 
has  been  shown  by  means  of  the  respiration  calorimeter.  This  increased 
heat  production  is  not  observed  in  patients  who  have  been  brought  into 
a  weakened  condition  and  in  whom  the  muscular  tissues  have  become 
atrophied  by  long-continued  fever.  The  increased  heat  production  in 
continuous  fever  is  mainly  dependent  upon  the  increase  in  body  tem- 
perature and  is  not  one  of  its  causes,  as  is  evident  from  the  fact  that  far 
larger  quantities  of  heat  are  frequently  produced  in  normal  individuals 
as  a  result  of  muscular  exercise  or  the  taking  of  large  quantities  of 
protein-rich  food.  The  heat  thus  produced  is,  however,  very  quickly 
dissipated,  so  that  only  a  temporary  rise  in  temperature  occurs,  (cf. 
Hewlett.57)  A  large  heat  production  also  occurs  in  hyperthyroidism 
without  a  corresponding  rise  in  body  temperature  (page  578). 

Similarly,  it  can  be  shown  that  in  continuous  fever  there  is  a  relative 
inefficiency  in  the  mechanism  of  heat  dissipation.  When  the  temperature 
of  a  normal  person  is  artificially  raised  through  about  1°  C.,  a  marked 
increase  in  cutaneous  bloodflow  and  profuse  perspiration  are  invariably 
noted.  In  a  patient  with  fever  of  the  same  degree,  on  the  other  hand, 
there  is  practically  no  change  in  the  skin  circulation;  indeed,  it  is  usually 
diminished,  and  there  is  no  unusual  perspiration.  The  heat-regulating 


750  METABOLISM 

mechanism  is  now  fixed  on  a  plane  that  is  higher  than  the  normal,  so 
that  although  further  increase  in  body  temperature,  as  we  have  seen, 
calls  forth  responses  like  those  in  a  normal  individual,  yet  at  the  fever 
temperature  itself  there  are  none  of  the  reactions  which  a  normal  individ- 
ual would  exhibit  if  his  temperature  were  artificially  raised  to  that  level.57 
The  adjustment  of  the  temperature  at  the  higher  level  is  by  no  means 
so  perfect  as  it  is  at  the  normal  level  of  health,  so  that  a  normal  subject 
is  more  resistant  to  the  effects  of  cold  than  is  a  patient  with  fever.  The 
degree  of  response  of  the  fever  patient,  however,  varies  considerably 
from  time  to  time ;  a  cold  bath  in  typhoid  fever,  for  example,  lowers  the 
body  temperature  much  less  effectively  at  an  early  stage  in  the  disease, 
when  the  fever  is  more  or  less  continuous,  than  later  when  it  is  becoming 
of  the  intermittent  type.  In  the  third  week  of  the  disease  the  cold  bath 
more  readily  brings  down  the  temperature  and  keeps  it  down  for  a  longer 
time  than  during  the  first  or  second  week.  The  mechanism  for  heat  loss 
is  also  deranged  in  fever,  which  explains  the  rise  in  temperature  that  is 
likely  to  follow  the  performance  of  even  moderate  muscular  exercise  or 
the  taking  of  too  hearty  a  meal  in  tuberculous  and  convalescent  typhoid 
patients. 

Changes  in  the  Body  During  Fever 

In  seeking  for  the  cause  of  fever  which  is  evidently  of  an  obscure 
nature,  it  is  necessary  to  collect  all  the  information  we  can  regarding 
the  metabolic  changes  that  are  then  occurring  in  the  animal  body.  A 
few  of  the  most  significant  facts  that  have  so  far  been  collected  may 
be  mentioned  here.  Some  of  the  most  important  concern  the  dis- 
turbance in  nitrogenous  equilibrium  caused  by  the  considerable  loss  of 
nitrogen  which  takes  place  in  fever  patients  when  they  are  fed  on 
the  usual  hospital  diet  prescribed  for  such  cases.  This  loss  of  nitro- 
gen is  no  doubt  the  result  of  the  partial  starvation  in  which  the  pa- 
tient is  kept;  for  it  has  been  shown  by  Shaffer  and  Coleman55  that 
patients  with  typhoid  fever  may  be  maintained  in  nitrogenous  equi- 
librium by  feeding  them  with  relatively  large  amounts  of  carbohy- 
drate, which  acts  by  protecting  the  protein  of  the  body  from  disintegra- 
tion (see  page  605).  The  protein  minimum  to  which  fever  patients  can 
be  reduced  is  nevertheless  considerably  higher  than  the  minimum  in 
normal  individuals. 

From  the  above  results  as  a  whole,  it  is  probably  safe  to  conclude  that 
there  is  a  specific  destruction  of  protein  going  on  in  the  body  during  fever. 
Further  evidence  of  such  a  destruction  is  furnished  by  the  presence  in 
the  urine  of  excessive  amounts  of  creatinin,  of  purine  bases,  and,  it  is 
said,  of  incompletely  hydrolyzed  proteins,  such  as  the  albumoses  (pro- 


• 


CONTROL    OF    BODY    TEMPERATURE    AND    FEVER  751 

teoses.)  Moreover,  when  the  fever  suddenly  terminates  in  crisis,  there 
is  a  marked  increase  in  the  excretion  of  urea  (the  epicritical  urea  in- 
crease), which  indicates  that  an  extensive  deamination  of  protein  build- 
ing stones  (amino  acids)  is  occurring.  The  so-called  "diazo  reaction" 
obtained  in  the  urine  during  the  fever  is  also  believed  to  depend  on  the 
presence  of  abnormal  protein-disintegration  products. 

As  to  the  specific  cause  of  the  increased  protein  disintegration,  little 
is  known.  Several  factors  may  operate:  (1)  the  partial  starvation  of  the 
patient,  entailing  an  increased  breakdown  of  protein  to  meet  the  calorie 
requirements;  (2)  the  high  temperature,  which  in  itself  may  stimulate 
increased  protein  metabolism,  for  it  has  been  shown  that,  when  normal 
animals  are  artificially  warmed,  protein  metabolism  becomes  increased; 
and  (3)  toxic  protein-decomposition  products  specifically  causing  an  ex- 
cessive breakdown  of  protein. 

Although  there  is  increased  protein  breakdown  during  fever,  it  must 
not.be  forgotten  that  when  food  is  refused  only  about  20  per  cent  of  the 
total  expenditure  of  the  body  is  derived  from  this  foodstuff,  80  per  cent 
coming  from  non-nitrogenous  material,  which  must  be  fat,  because  the 
available  carbohydrates  are  used  up  at  an  early  stage. 

Since  the  general  metabolism  is  increased,  the  excessive  breakdown  of 
the  fatty  substances,  occurring  as  it  does  in  the  presence  of  a  diminished 
combustion  of  carbohydrates,  interferes  with  the  proper  oxidation  of  the 
fatty-acid  molecules  and  leads  to  the  appearance  of  so-called  acidosis 
products  in  the  urine,  and  consequently  to  a  relative  increase  in  the 
urinary  ammonia  (page  650).  A  tendency  to  acidosis  therefore  exists. 
The  acidosis  may  reach  a  considerable  degree  of  severity  and  cause  the 
tension  of  carbon  dioxide  in  the  alveolar  air  to  become  diminished.  Since 
a  similar  degree  of  acidosis  may  be  produced  in  partially  starved  ani- 
mals by  overheating  them  with  moist  air,  but  not  so  if  the  animals  are 
liberally  fed  with  carbohydrates,  it  is  probably  safe  to  conclude  that 
abundance  of  carbohydrate  is  advisable  in  the  food  that  is  furnished  to 
fever  patients. 

Another  interesting  metabolic  change  in  fever  concerns  the  salt  bal- 
ance. This  is  studied  by  observing  the  amount  of  sodium  chloride  excreted 
by  the  urine.  As  is  well  known,  this  becomes  markedly  diminished  until 
the  crisis  of  the  fever,  when  it  suddenly  increases.  The  salt  retention  is 
related  to  the  concentration  of  the  blood,  a  marked  rise  in  which  is  usually 
accompanied  by  a  rise  in  temperature  and  is  an  unfavorable  prognostic  sign. 
Salt  retention  is  more  marked  in  certain  types  of  fever  than  in  others,  and 
it  is  essentially  different  in  nature  from  the  salt  retention  that  has  been  ob- 
served to  occur  in  nephritis.  This  difference  has  been  brought  to  light  by 
examination  of  the  chloride  content  of  the  blood.  In  nephritis,  the  concen- 


752  METABOLISM 

tration  of  chlorides  in  the  blood  is  considerably  increased,  whereas  in  fever 
it  is  markedly  diminished.  The  deficiency  in  salt  elimination  cannot  be  at- 
tributed to  a  deficiency  of  salt  in  the  food,  for  it  sets  in  before  the  diet 
has  been  curtailed  and,  when  salt  is  given  to  a  febrile  patient,  it  is  re- 
tained in  the  body  to  a  greater  degree  than  is  the  case  in  the  normal 
individual. 

Belonging  to  this  group  of  fevers  must  also  be  considered  the  im- 
portant ones  produced  by  the  intravenous  injection  of  certain  forms  of 
protein,  as  those  of  egg  white  or  those  derived  from  the  bodies  of  bac- 
teria or  from  the  laked  corpuscles  of  a  foreign  blood.  The  fever  in 
these  cases  is  no  doubt  caused  by  a  mechanism  closely  related  to  that 
responsible  for  anaphylaxis  (see  page  90).  It  is  believed  that  many  cases 
of  so-called  aseptic  fever,  occurring  after  severe  contusions  or  other 
wounds,  may  be  the  result  of  destruction  of  proteins  within  the  body. 
Similarly  the  rise  in  temperature  during  infections  may  be  owing  to 
the  breakdown  of  protein  by  microorganisms  within  the  cells. 

The  Essential  Cause  of  Fever 

It  is  possible  that  the  essential  cause  for  fever  is  that  poisonous  sub- 
stances (such  as  toxins)  cause  the  tissues  to  break  down  and  so  increase 
the  osmotic  pressure  of  their  protoplasm.  Water  is  therefore  attracted 
into  them  from  the  blood,  the  volume  of  which  in  circulation  is  thereby 
reduced.  This  reduction  affects  the  superficial  capillaries  relatively  more 
than  the  deeper  ones  and  so  tends  to  cool  down  the  skin,  as  a  result 
of  which  the  nervous  reflexes  against  cold  are  aroused  and  the  superficial 
capillaries  constricted.  The  view  that  removal  of  water  from  the  blood 
is  a  most  important  element  in  fever  is  supported  not  only  by  the  fact, 
already  stated,  that  the  blood  has  been  found  to  be  more  concentrated 
in  fever  but  also  by  numerous  observations  on  the  influence  of  drugs. 
Those  which  cause  concentration  of  blood  are  likely  also  to  cause  rise 
in  body  temperature,  such,  for  example,  as  certain  diuretics  (purines, 
sugars,  etc.),  intravenous  injection  of  hypertonic  salt  solutions  (3  per 
cent  Nad)  and  certain  cathartics,  such  as  aloin.  Cocaine  causes  fever 
partly  by  blood  concentration.  Antipyretics,  on  the  other  hand,  (such  as 
acetyl  salicylic  acid)  act  mainly  by  increasing  heat  elimination,  although 
under  certain  conditions  (as  in  coli  fever)  they  may  also  cause  dilution  of 
the  blood  (Barbour). 

While  increased  concentration  of  the  blood  is  undoubtedly  an  impor- 
tant factor  in  fever  it  must  also  be  remembered  that  upset  of  the  control 
of  heat  production  and  loss  through  action  on  the  heat  regulating  or 
thermogenic  centers  may  also  be  involved. 


CONTROL    OF    BODY    TEMPERATURE    AND    FEVER  753 

The  Heat-regulating  Center 

In  all  discussions  on  the  regulation  of  body  temperature  and  the 
causes  of  fever,  it  is  assumed  that  a  heat-regulating  or  thermogenic 
center  exists  somewhere  in  the  brain.  It  is  believed  to  be  located 
about  the  optic  thalami  or  corpora  striata,  for  it  has  been  found  in 
rabbits  that  destruction  of  the  brain  anterior  to  this  region  does  not 
cause  any  change  in  body  temperature,  whereas  destruction  behind  it 
is  followed  by  an  entire  upset  in  the  heat-regulating  mechanism.  Fur- 
thermore, artificial  puncture  of  this  part  of  the  brain  causes  marked 
elevation  in  body  temperature  in  rabbits  (heat  puncture).  Most  in- 
teresting experiments  have  been  recorded  by  Barbour,56  who  succeeded 
in  applying  heat  or  cold  locally  in  the  region  of  the  centers.  By  the 
application  of  cold,  increased  muscular  metabolism,  on  the  one  hand, 
and  diminished  heat  loss,  on  the  other,  were  excited;  and  conversely, 
when  warmth  was  applied,  an  increased  heat  loss  and  a  diminished  heat 
production  were  observed.  Irritation  of  this  region  of  the  brain  in  man, 
as  after  cerebral  hemorrhage,  is  also  accompanied  by  remarkable  dis- 
turbances in  heat  regulation.  It  is  believed  by  many  that  the  essential 
cause  of  fever  in  infective  conditions,  is  an  action  on  these  centers  by  toxic 
substances  which  develop  in  the  blood. 

Significance  of  Fever  to  the  Organism 

It  is  impossible  at  present  to  state  definitely  whether  fever  is  a  re- 
action of  the  organism  against  some  infection  and  therefore  of  benefit 
in  assisting  the  organism  to  combat  it,  or  whether  it  is  in  itself  an  un- 
favorable condition.  The  question  can  certainly  not  be  answered  by 
observing  the  behavior  of  bacteria  growing  at  different  temperatures 
in  various  media  outside  the  body.  That  certain  bacteria  should  be 
found  not  to  thrive  at  incubator  temperatures  equal  to  those  found  in 
the  body  during  fever,  does  not  at  all  prove  that  this  fever  is  of  sig- 
nificance as  a  means  of  combating  the  growth  of  the  bacteria  in  the 
body.  It  is  undoubted  that,  where  the  body  temperature  becomes  ex- 
cessively high,  the  correct  treatment  is  to  keep  it  down  as  much  as 
possible.  On  the  other  hand,  the  reduced  mortality  that  has  followed 
the  introduction  of  the  cold-bath  treatment  in  typhoid  fever  may  not 
be  due  so  much  to  the  reduction  in  body  temperature  itself  as  to 
the  favorable  effect  produced  on  the  nervous  system  and  circulation. 
We  certainly  know  that  in  normal  animals  moderate  degrees  of  hyper- 
pyrexia  brought  about  by  exposure  to  moist  heat  are  well  borne  for  consider- 
able periods  of  time,  thus  indicating  that  it  is  the  infection  and  not  the 
hyperthermia  that  causes  the  serious  damage  to  the  body  in  infectious 
fevers. 


CHAPTER  LXXXIII 

THE  PHYSIOLOGICAL  PRINCIPLES  OF  VENTILATION 

The  well-being  of  a  conscious  animal  in  relationship  to  its  environment 
constitutes  the  main  problem  of  the  study  of  ventilation.  In  the  case  of 
animals  leading  an  outdoor  life,  it  is  a  problem  of  relatively  little  im- 
portance, but  for  those  like  man  which  spend  much  of  their  time  in 
confined  spaces,  it  is  a  problem  of  great  importance,  because  it  becomes 
necessary  to  determine  the  limits  within  which  the  outside  influences  may 
be  altered  without  detriment  to  health  or  comfort.  This  problem  is  con- 
sidered here  because  it  is  closely  related  to  that  of  the  body  temperature. 

The  Relationship  Between  the  Chemical  Composition  of  the  Air  and 
the  Well  Being  of  the  Body. — When  our  knowledge  of  the  function  of 
breathing  became  developed  to  the  extent  of  showing  that  an  animal 
requires  the  oxygen  of  the  air  for  the  living  processes  of  its  body,  and 
as  a  result  of  these  processes  that  it  produces  carbonic  acid,  which  is 
then  added  to  the  air,  it  was  natural  to  suppose  that  the  unfavorable  ef- 
fect of  overcrowded  confined  spaces  was  due  either  to  the  using  up  of 
the  available  oxygen  or  to  a  poisonous  action  of  the  carbonic  acid. 

It  needs  only  a  few  words  to  point  out  how  utterly  erroneous  were 
these  earlier  explanations.  That  deficiency  of  oxygen  is  no  factor  is  in- 
dicated by  the  facts,  first,  that  this  gas  is  seldom  reduced  by  more  than 
one  per  cent,  even  in  the  most  crowded  places;  and  secondly,  that  people 
live  a  normal  existence  at  altitudes  at  which  the  oxygen  percentage,  meas- 
ured at  sea  level,  is  reduced  to  less  than  two-thirds  the  normal. 

It  is  not  altogether  easy  to  understand  why  excess  of  C02  was  thought 
to  be  responsible  for  the  evil  effects  of  vitiated  atmospheres.  No  doubt 
the  chief  reason  was  that  the  percentage  of  this  gas  is  often  raised  in 
such  atmospheres,  but  this  is  nothing  more  than  coincidence,  for  on  the 
one  hand  most  unsuitable  conditions  may  exist  when  the  percentage  of 
C02  is  normal,  and  on  the  other,  air  loaded  with  almost  a  hundred  times 
the  percentage  found  even  in  the  most  polluted  atmosphere  can  be  breathed 
for  indefinite  periods  of  time  without  any  unfavorable  symptoms. 

As  a  matter  of  fact,  even  in  the  open,  we  are  constantly  taking  into  the  pulmonary 
alveoli  large  percentages  of  CO2,  for  obviously  with  each  inspiration  the  first  air  to  be 
drawn  in  is  that  which  remains  over  in  the  air  passage  from  the  preceding  expiration. 
This  air  contains  somewhere  about  5  per  cent  of  CO,,  and  in  quiet  breathing  it  amounts 
in  volume  to  about  one-third  of  all  the  air  that  is  drawn  in  from  the  outside.  This  in 
itself  indicates  that  CO,  per  se  can  not  be  poisonous,  and  when  we  consider  further  the 

754 


THE    PHYSIOLOGICAL    PRINCIPLES    OF    VENTILATION  755 

now  well-known  fact  that  a  certain  amount  of  this  gas  in  the  alveoli  is  absolutely  es- 
sential to  the  well-being  of  the  animal,  the  whole  hypothesis  of  its  toxic  action  becomes, 
to  say  the  least  of  it,  absurd.  Indeed  so  important  is  the  presence  of  this  constant 
amount  of  CO2  in  the  alveolar  air  that  whenever  there  comes  to  be  a  marked  increase  in 
the  amount  of  CO2  in  the  atmosphere,  the  breathing  becomes  greater,  so  as  to  ventilate 
the  air  sacs  more  thoroughly,  and  thus  keep  the  relative  amount  of  CO2  in  them  at  the 
normal  level.  The  extent  of  this  increase  in  respiration  is  usually  so  small  as  to  be 
unnoticed  by  the  individual,  and  certainly  increased  breathing  is  not  one  of  the  symp- 
toms of  which  persons  complain  who  are  living  in  polluted  atmospheres. 


In  the  face  of  such  evidence,  even  the  most  ardent  supporters  of  the 
theory  that  the  vitiated  air  owes  its  evil  influence  to  C02,  were  compelled 
to  abandon  their  position,  but  they  did  not  do  so  without  a  final  attempt  to 
retain  for  determinations  of  C02  a  certain  significance  in  the  appraisement 
of  the  healthfulness  of  air.  Their  new  interpretation  was  to  the  effect  that 
the  C02  percentage  is  proportional  to  the  amount  of  deleterious  organic 
matter,  and  for  many  years  this  view  prevailed.  It  is  still  believed  by  some 
that  an  increase  from  the  normal  of  3  to  10  parts  of  C02  per  10,000  parts 
of  air  indicates  a  degree  of  organic  pollution  which  is  dangerous  to  health. 
More  recent  work  definitely  shows,  however,  that  this  view  also  must  be 
abandoned,  and  there  remains  for  C02-analysis  only  the  secondary  value 
that  it  indicates,  in  a  readily  measurable  way,  to  what  extent  the  inside  air 
is  being  mixed  by  ventilation  with  pure  air  from  the  outside.  However 
free  this  dilution  may  be,  the  atmosphere  may  still  be  deleterious  to  health 
and  comfort  unless  certain  other  properties  of  it  are  incidentally  altered. 

This  interpretation  of  the  value  of  C02  analysis  naturally  leads  to  a  con- 
sideration of  the  next  possibility,  namely,  that  the  air  in  confined  spaces 
is  contaminated  by  the  accumulation  of  organic  poisons  derived  from  the 
exhaled  air  of  the  persons  living  in  it. 

It  is  many  years  ago  now  since  experiments  apparently  proving  this  hypothesis  were 
published.  These  have  been  shown  to  be  entirely  fallacious,  and  we  need  refer  to  only 
one  group  of  them  here,  namely,  those  that  were  devised  to  show  that  inhalation  by  one 
animal  of  volatile  proteins  contained  in  the  exhaled  air  of  others  caused  anaphylactic 
reactions  (page  90).  As  proof  for  this  hypothesis,  experiments  were  performed  in 
which  a  man  breathed  through  a  filter  of  glass  wool  (to  catch  any  saliva)  into  a  cooled 
vessel,  and  the  condensed  vapor  was' then  inoculated  in  appropriate  dosage  into  guinea 
pigs,  so  as  to  sensitize  them,  and  a  month  or  so  later  the  animals  were  inoculated  with  a 
minute  trace  of  human  blood  serum.  The  injected  animal  showed  decided  symptoms  of 
anaphylactic  shock,  whereas  other  animals  not  previously  sensitized  were  unaffected  by 
the  injection  of  the  same  amount  of  serum.  Such  results  taken  by  themselves  did  seem 
to  afford  substantial  support  for  the  new  hypothesis,  but  it  is  almost  certain  that  they 
depended  on  contamination  of  the  condensed  vapor  by  traces  of  saliva  which  it  is  im- 
possible to  keep  out  by  any  kind  of  filter.  This  saliva  contains  traces  of  soluble  protein 
(mucin)  which  had  been  responsible  for  the  anaphylactic  reaction.  The  symptoms  are, 
however,  entirely  dissimilar  from  those  of  a  vitiated  atmosphere.  Hay  fever,  some  forms 


756  METABOLISM 

of  asthma,  and  the  reaction  which  some  persons  show  when  near  to  horses  may  be  due 
to  anaphylaxis,  but  the  symptoms  are  not  at  all  like  those  of  persons  breathing  polluted 
air. 

Once  and  for  all,  the  toxic  theory,  as  we  may  call  it,  both  in  its  new 
and  its  old  form,  is  disproved  by  a  very  simple  series  of  experiments  per- 
formed a  few  years  ago  by  Leonard  Hill,  Flack  and  others.72  These  ob- 
servers kept  rats  and  guinea  pigs  in  deep  boxes  so  that  they  were  huddled 
together  in  a  very  poorly  ventilated  place,  the  atmosphere  of  which  indeed 
often  contained  1  per  cent  of  C02 — ten  times  more  than  the  legal  limit. 
The  animals  lived  and  thrived  for  months,  although  they  must  have  been 
breathing  air  which  was  highly  contaminated  by  the  supposed  volatile 
proteins.  Not  only  did  the  animals  show  no  symptoms  while  in  the  box, 
but  they  failed  to  exhibit  any  anaphylactic  reaction  when,  after  some 
time,  they  were  inoculated  subcutaneously  with  the  serum  of  animals  of 
the  other  species  living  with  them  in  the  box.  This  was  really  a  most 
excellent  test  of  the  anaphylactic  theory  because  there  are  probably  no 
two  animals  in  which  anaphylaxis  is  more  pronounced  than  in  the  rat 
and  guinea  pig.  The  only  things  that  were  found  to  be  of  importance 
in  maintaining  the  animals  in  a  thriving  condition  were  cleanliness  and 
plenty  of  food. 

By  an  eliminative  process  we  are  gradually  approaching  the  correct 
solution  of  our  problem,  but  before  we  proceed  to  consider  this,  it  may 
be  well  to  remark  that  the  odor  of  polluted  air  has  nothing  whatever  to  do 
with  its  unhealthy  influence,  except  in  so  far  as  it  excites  disgust  and  puts 
one  off  his  appetite.  Indeed  one  very  soon  becomes  so  accustomed  to  these 
odors  that  they  fail  entirely  to  be  sensed  after  a  short  period  in  contact 
with  them.  Their  influence  is  entirely  psychological.  In  many  trades 
and  occupations  people  are  constantly  exposed  to  odors  that  are  almost  un- 
bearable to  one  who  is  unused  to  them,  and  these  people  are  perfectly  heal- 
thy, and  indeed  do  not  complain  at  all  of  the  smells. 

We  have  so  far  considered  in  what  is  approximately  their  chronological 
order  the  various  hypotheses  that  have  been  brought  forward  to  account 
for  the  harmful  influence  of  vitiated  atmospheres.  We  have  done  this 
mainly  in  order  to  correct  any  false  conclusions  that  may  still  exist  in 
connection  with  the  subject. 

And  if  further  evidence  be  demanded  to  justify  this  position,  there  is 
one  crucial  experiment  which  once  and  for  all  shows  that  changes  in  the 
chemical  composition  of  the  atmosphere  has  no  relationship  whatsoever  to 
the  unhealthful  influence  of  vitiated  air.  This  experiment  is  all  the  more 
convincing  because  it  was  performed  on  healthy  young  men.  In  its  simplest 
form  it  consists  in  crowding  as  many  persons  as  possible  into  an  airtight 
cabinet,  provided  with  an  electric  fan,  and  with  the  necessary  apparatus 
for  measurements  of  the  physical  and  chemical  conditions  of  the  air. 

The  following  is  a  description  of  the  results  of  such  an  experiment: 


THE   PHYSIOLOGICAL    PRINCIPLES    OF    VENTILATION  757 

"After  44  minutes  the  dry-bulb  thermometer  stood  at  87°  F.,  the  wet  bulb  at  83°  F. 
The  carbon  dioxide  had  risen  to  5.26  per  cent.  The  oxygen  had  fallen  to  15.1  per  cent. 
The  discomfort  felt  was  great;  all  were  wet  with  sweat  and  the  skin  of  all  was  flushed. 
The  talking  and  laughing  of  the  occupants  had  gradually  become  less  and  then  ceased. 
On  putting  on  the  electric  fans  and  whirling  the  air  in  the  chamber  the  relief  was  im- 
mediate and  very  great,  and  this  in  spite  of  the  temperature  of  the  chamber  continuing 
to  rise.  On  putting  off  the  fans  the  discomfort  returned.  The  occupants  cried  out  for 
the  fans.  No  headache  or  after  effects  have  followed  this  type  of  experiment  which 
has  been  repeated  five  times. "  (Leonard  Hill)  Long  before  the  discomfort  had  become 
extreme  the  oxygen  percentage  became  so  low  that  matches  would  not  light.  The  disin- 
clination to  smoke  cigarettes  was  not  noticed  until  some  time  after  it  was  impossible 
to  light  them. 

In  other  experiments  of  similar  type  the  person  in  the  cabinet  was  allowed 
to  breathe  outside  air  through  a  tube,  but  with  no  amelioration  of  the  un- 
comfortable feeling,  or  a  person  outside  the  chamber  breathed  for  hours 
the  air  inside  it  through  a  tube  without  suffering  any  discomfort.  Clearly 
therefore  neither  the  chemical  nature  of  the  air,  nor  the  presence  of  toxic 
substances  in  it,  has  any  relationship  to  its  evil  influence.  But  the  experi- 
ment is  not  merely  destructive  of  previously  held  hypotheses ;  it  also  points 
the  way  to  the  true  solution  of  the  problem,  for  it  indicates  that  stagna- 
tion of  air  loaded  with  moisture  has  some  very  close  relationship  to  the 
discomfort.  It  shows  that  a  change  in  the  physical  rather  than  the  chemical 
properties  of  the  air  is  the  real  cause  of  its  deleterious  action. 

THE  RELATIONSHIP  BETWEEN  THE  PHYSICAL  CONDITION  OF  THE  AIR  AND 
THE  WELL-BEING  OF  THE  BODY 

The  changes  observed  in  the  preceding  experiment  can  affect  but  one 
function  of  the  body,  namely,  that  of  heat  dissipation,  and  by  so  doing 
cause  disturbances  in  the  mechanism  of  heat  control.  This  does  not  nec- 
essarily imply  that  this  disturbance  is  so  great  as  actually  to  cause  an  in- 
crease in  the  body  temperature,  although  this  is  very  commonly  observed 
in  persons  who  have  been  for  some  time  in  crowded  places,  but  it  interferes 
with  a  mechanism  which  is  responsible  not  alone  for  proper  heat  regulation 
but  also  for  the  maintenance  of  a  correct  relationship  of  blood  supply 
to  different  parts  of  the  body,  and  for  tonic  stimulation  of  the  nervous 
system. 

It  is  in  connection  with  this  phase  of  the  subject,  more  than  any  other, 
that  many  people  find  it  difficult  to  understand  the  true  significance  of 
relative  humidity  to  the  well-being  of,  the  body.  The  difficulty  depends 
on  the  fact  that  the  relative  humidity  has  an  opposite  influence  at  low 
and  high  temperatures.  In  the  former  case  it  increases  the  conductivity 
of  the  atmosphere  for  heat  and  has  a  cooling  influence,  and  in  the  latter 
it  interferes  with  the  evaporation  of  sweat,  and  has  a  heating  influence. 
Below  about  65°  F.  the  cooling  effect  of  moist  air  is  prominent  because 
there  is  little  sweating,  therefore  a  cold  wet  atmosphere  is  chilling — it 


758  METABOLISM 

conducts  heat  away.  At  about  70°  F.  the  cooling  effect  of  air  disappears 
and  sweating  occurs.  The  evaporation  of  the  sweat  now  causes  cooling, 
the  degree  of  which  varies  inversely  with  the  relative  humidity.  Be- 
tween these  two  temperatures,  i.e.,  65°  and  70°  there  is  a  range  in  which 
humidity  has  little  influence — a  neutral  region.  The  influence  of  high 
relative  humidity  on  bodily  comfort  at  temperatures  above  the  neutral 
temperature  becomes  very  marked  indeed  at  85°  F.  and  at  a  relative  hu- 
midity of  90  per  cent,  for  example,  unfavorable  symptoms  appear  in  a 
few  minutes,  when  there  is  no  movement  of  the  air. 

Relative  humidity  and  temperature  alone  are  not,  however,  the  only 
physical  conditions  to  be  considered.  Another  is  the  movement  of  the 
air,  for  even  under  the  unfavorable  conditions  just  cited,  immediate 
relief  is  afforded  if  an  electric  fan  be  started,  as  it  will  be  recalled  was 
the  result  in  Hill's  experiment.  The  movement  of  the  air  enables  it, 
though  nearly  loaded  to  its  full  capacity  with  moisture,  to  carry  away 
considerable  quantities  of  heat  in  small  loads. 

The  wearing  of  clothes  greatly  affects  the  rate  with  which  these  changes  occur.  The 
clothes  act  as  barriers,  preventing  the  movement  and  exchange  of  air  around  the  body. 
The  garment  next  the  skin  entraps  a  layer  of  air  which  is  more  or  less  at  the  same 
temperature  as  the  skin,  and  which  soon  becomes  saturated  with  moisture  at  that  tem- 
perature. Between  the  inner  garments  and  those  over  them  other  layers  of  air  are  en- 
trapped, each  one  being  at  a  somewhat  lower  temperature  and  containing  less  moisture 
than  the  one  inside.  These  layers  of  air,  therefore,  form  stepping  stones,  as  it  were,  be- 
tween the  extreme  conditions  next  the  surface  of  the  skin,  and  the  environment  of  the 
clothed  body.  Obviously  if  the  layers  of  air  next  the  skin  are  to  be  renewed  at  such 
a  rate  that  they  remain  cooler  than  the  skin  and  unsaturated  with  moisture  the  clothing 
must  be  adjusted  to  suit  the  outside  conditions. 

There  is  every  reason  for  believing  that  it  is  because  of  interference 
with  the  processes  of  heat  loss  that  improperly  ventilated  and  over- 
crowded places  are  uncomfortable.  The  moisture  exhaled  and  evapo- 
rated from  the  bodies  soon  raises  the  relative  humidity  so  that  heat  loss 
is  retarded  from  the  skin,  and  the  heat  that  is  actually  given  off  raises 
the  temperature  so  that  loss  from  the  body  by  radiation  and  convection 
becomes  suppressed.  As  the  temperature  steadily  rises,  the  air  takes  up 
more  and  more  moisture,  with  the  result  that  less  and  less  heat  comes  to 
be  lost  from  the  lungs  in  saturating  the  expired  air  with  vapor.  The 
physical  conditions  of  the  environment  become  unsuitable  for  the  physi- 
ological mechanism  of  heat  loss,  although  meanwhile  heat  production 
goes  steadily  on.  The  body  furnaces  are  not  damped  down  in  propor- 
tion as  the  loss  of  heat  diminishes,  and  the  consequence  is  a  rise  in  the 
temperature  of  the  blood — a  mild  fever.  Now  it  is  well-known  that  the 
cellular  activities,  which,  taken  together,  make  up  the  life  process  of 
the  body  are  extraordinarily  sensitive  to  change  of  temperature;  their 
chemical  activities  become  interfered  with,  they  demand  more  oxygen. 


THE   PHYSIOLOGICAL   PRINCIPLES    OF   VENTILATION  759 

they  fail  to  get  rid  of  effete  products  properly,  substances  which  have 
no  action  on  them  under  the  ordinary  conditions  of  temperature  become 
toxic  and  so  forth.  A  highly  abnormal  internal  environment  therefore 
becomes  created  around  the  living  tissues  of  the  body. 

The  Relationship  between  the  Conditions  of  Ventilation  and  Suscepti- 
bility to  Infections. — But  short  of  a  measurable  rise  in  the  temperature, 
improperly  ventilated  places  cause  reactions  in  the  human  body  that  are 
responsible  not  only  for  the  discomfort  which  is  experienced,  but  also  for 
a  lowering  of  resistance  to  infections.  These  reactions  are  due  in  the 
first  instance  to  alteration  in  the  temperature  differences  between  the 
skin  and  the  underlying  tissues.  Normally,  as  has  been  remarked  before, 
this  difference  maintains  at  the  skin  a  constant  stimulation  of  the  ther- 
mic nerves,  and  this  stimulation  is  important  in  maintaining  the  tone  of 
the  nerve  centers.  The  nerve  cells  that  control  the  functions  of  the 
body  do  not  originate  impulses;  they  only  act  when  other  afferent  im- 
pulses arrive  at  them.  There  are  many  varieties  of  stimuli  which  may 
excite  these  afferent  impulses,  but  none  more  important  than  those  which 
excite  the  heat  nerves  of  the  skin.  This  stimulation  depends  on  the  rate 
at  which  heat  is  passing  through  the  sense  organs  (or  receptors),  in 
which  these  nerves  terminate.  It  is  necessary  to  emphasize  that  it  is 
the  rate  of  change  that  acts  as  the  stimulus,  and  this  depends  on  the  dif- 
ference between  the  deep  and  superficial  temperatures.  When  the  skin 
vessels  become  dilated,  so  large  a  volume  of  blood  reaches  the  surface 
that  this  difference  becomes  slight,  and  the  thermic  receptors  are  not 
stimulated.  There  are  many  practical  applications  of  these  principles; 
thus  it  is  because  of  stimulation  of  the  thermic  skin  nerves  that  cold 
baths  have  a  bracing  effect,  that  the  open-air  treatment,  as  in  tuberculo- 
sis, tones  up  the  body  and  enables  it  the  better  to  hold  its  own  against 
the  tubercle  bacillus,  and  that  sleeping  out  of  doors  is  the  best  tonic  for 
maintaining  good  health.  In  the  open-air  treatment  it  is  true  that  the 
body  is  closely  wrapped  up — that  is  essential — but  this  does  not  elim- 
inate the  cooling  influence,  for  not  only  does  the  cool  air  play  on  the 
exposed  face  and  hands,  in  the  skin  of  both  of  which  the  thermic  nerves 
are  very  sensitive,  but  it  acts  also  on  these  nerves  in  the  skin,  under  the 
clothes,  for  the  clothing  merely  serves  to  regulate  the  rate  of  cooling. 
This  still  goes  on  very  much  more  than  it  would  with  much  less  clothing 
in  an  atmosphere  that  is  stagnant,  hot,  and  humid.  Open  windows  in 
bedrooms  are  never  so  healthy  as  open-air  porches,  because  there  is  no 
draft.  It  is  the  draft  that  is  important.  Naturally  it  must  be  regulated 
so  that  it  is  not  restricted  to  one  part  of  the  body  only — that  obviously 
would  introduce  conditions  to  which  the  body  is  unaccustomed — it 
must  blow  equally  all  over.  There  is  probably  no  greater  fallacy  in  pop- 
ular hygiene  than  that  drafts  are  dangerous.  Like  all  good  and  desirable 


760  METABOLISM 

things  they  become  so  only  when  they  are  improperly  used — when  a  per- 
son, overheated  by  being  in  a  hot  atmosphere,  is  suddenly  subjected  to  a 
restricted  draft,  of  course  there  is  danger  that  the  sudden  change  of 
conditions,  affecting  one  part  of  the  body  only,  will  cause  vascular  dis- 
turbances that  may  be  undesirable,  but  if  the  conditions  be  properly  con- 
trolled, drafts  are  the  healthiest  things  and  the  best  tonics. 

It  is  a  common  experience  not  only  that  ordinary  colds,  but  more 
serious  infections  as  well,  can  be  directly  traced  to  some  unsuitable 
condition  of  ventilation;  such  as  sudden  exposure  to  a  draft  while  over- 
heated, or  going  out  into  a  cold,  damp  atmosphere  from  an  overheated 
room.  What  is  the  reason  for  the  infection  under  these  conditions?  At 
the  outset  we  must  recognize  that  all  these  conditions,  colds,  catarrhs, 
bronchitis,  just  like  the  more  acute  infectious  diseases,  as  diphtheria, 
pneumonia,  cerebrospinal  fever,  etc.,  are  due  to  microorganisms,  and  the 
question  therefore  is  why  should  unfavorable  ventilating  conditions  so 
frequently  be  the  immediate  cause  of  the  attack. 

There  are  two  methods  by  which  the  infection  might  occur.  First,  by 
a  great  increase  in  the  number  of  organisms  in  the  air,  and  secondly  by 
a  lowering  of  the  resistance  of  the  body  towards  the  organisms,  which 
would  not  then  require  to  become  increased  in  numbers.  The  former 
method  is  usually  known  as  mass  infection,  and  there  can  be  no  doubt 
that  it  is  very  common,  perhaps,  indeed,  is  the  commonest  cause  for 
infection.  The  organisms,  of  course,  come  from  infected  individuals, 
who  add  them  to  the  atmosphere  in  the  exhaled  air,  particularly  when 
this  is  forcibly  discharged  as  in  coughing  or  sneezing,  or  even  in  speaking. 

Evidence  of  the  importance  of  this  factor  is  as  follows.  If  the  mouth  be  rinsed  with 
a  culture  of  some  readily  recognizable  organism  not  commonly  present  in  detectable 
amounts  in  the  atmosphere,  and  the  person,  standing  in  front  of  a  row  of  P'etri  dishes 
each  containing  some  culture  medium  upon  which  the  organism  will  grow,  then  speaks  at 
ordinary  pitch,  the  plates  after  proper  incubation  develop  colonies  of  the  organism,  those 
nearest  the  speaker  having  most,  but  even  those  at  a  distance  of  several  feet  also  show- 
n.g  them. 

A  serious  problem  in  zoological  gardens  has  been  to  keep  animals  that  are  highly 
susceptible  to  tuberculosis  free  from  this  disease.  The  higher  apes,  for  example,  inevi- 
tably succumb  to  this  disease,  being  infected  by  the  bacilli  exhaled  by  persons  standing 
in  front  of  their  cages.  Many  of  the  latter  harbor  these  bacilli,  though  they  may  not 
show  any  of  the  symptoms  of  tuberculosis.  Now  it  has  been  found  that  if  glass  screens 
are  erected  in  front  of  the  cages,  the  animals  remain  almost  free  from  the  disease. 

But  mass  infection  does  not  suffice  to  explain  the  cause  for  the  onset 
of  attacks  of  many  conditions  that  are,  nevertheless,  fundamentally  due 
to  bacteria,  such  as  ordinary  colds.  These  can  frequently  be  traced  to 
some  chill,  or  wet  feet,  or  exposure  to  sudden  change  in  temperature.  In 
such  cases  it  is  believed  that  the  bacteria  are  present  on  the  mucous  mem- 
branes of  the  upper  respiratory  passages,  but  that  they  remain  inactive 


THE   PHYSIOLOGICAL   PRINCIPLES    OF   VENTILATION  761 

because  of  the  normal  protective  influences  which  exist  on  these  surfaces. 
So  long  as  the  blood  supply  is  normal,  these  protective  influences  are 
adequate  to  protect  the  body  from  invasion,  but  if  this  should  become  cur- 
tailed, then  the  bacteria  become  active  and  set  up  pathological  processes. 
Evidence  favoring  this  view  has  been  obtained  by  several  recent  investi- 
gators by  finding  that  the  blood  supply  of  the  upper  respiratory  passages 
becomes  decidedly  curtailed  when  the  surface  of  the  body  is  cooled.  For 
example  Leonard  Hill  and  Muecke  some  years  ago  examined  with  a  spec- 
ulum the  mucous  membranes  of  the  nose  under  various  conditions,  par- 
ticularly out  of  doors,  and  in  rooms  which  were  ventilated  and  heated  to 
an  average  degree.  Out  of  doors  the  mucosa  was  pale  and  taut,  and  when 
touched  by  a  probe  did  not  show  any  pitting.  This  is  the  normal  con- 
dition. Indoors  it  was  common  to  find  the  membrane  decidedly  swollen, 
flushed  with  blood  and  covered  with  thick  secretion,  and  when  a  probe 
was  pressed  on  it  a  depression  resulted  lasting  for  some  time.  In  one 
case  that  was  frequently  examined  during  these  observations  there  was 
a  deflected  septum  which  only  partly  blocked  the  nasal  passage  on  one 
side  when  the  person  was  outside,  but  which  did  so  completely  under  un- 
favorable conditions  of  ventilation.  It  is  this  swelling  of  the  nasal 
mucosa  and  probably  of  that  of  the  cavities  which  extend  upward  from  it 
on  to  the  forehead  that  causes  the  sense  of  stuffiness  and  probably  also 
the  headaches  which  are  common  in  crowded,  overheated  places. 

The  conditions  found  to  bring  about  these  changes  with  greatest  cer- 
tainty were  when  the  feet  were  cold  and  the  air  round  the  head  was 
warm,  conditions  which  are  just  exactly  the  opposite  of  those  obtaining 
out  of  doors.  Here  the  head  is  usually  more  quickly  cooled  than  the  feet 

scause  convection  currents  of  cool  air  play  around  it  freely,  whereas 
lext  the  ground  the  air  is  more  stagnant.    Besides,  if  the  sun  is  shining. 

ie  earth  becomes  heated  by  absorbing  the  heat.     The  temperature  as 

igistered  by  a  thermometer,  either  wet  or  dry  bulb,  may  be  the  same 
at  the  feet  as  at  the  head.  It  is  not  this  that  counts,  however,  it  is  the 
rate  of  cooling  which  is  dependent,  mainly,  on  the  movement  of  the  air. 
Now  in  a  poorly  ventilated  room,  such  for  example  as  one  heated  by  a 
stove,  or  even  by  radiators,  and  in  which  there  is  no  movement  of  air, 
the  feet  become  colder  than  the  head,  and  it  is  under  these  conditions 
that  the  nasal  membranes  become  swollen.  It  ought  to  be  emphasized 
that  the  cause  for  these  changes  is  not  cold  feet  alone.  It  is  the  com- 
bination of  cold  feet  and  hot  head.  Out  of  doors,  it  is  well  known,  that 
any  one  may  stand  with  cold  feet  for  hours  without  any  risk  of  catching 
cold,  but  then  the  head  is  really  cooling  as  fast  as  the  feet,  because  of 
.convection  currents. 

The  ideal  system  of  warming  a  room  is  to  supply  radiant  heat  near 


762  METABOLISM 

the  floor  level;  open  fires,  properly  flued  modern  gas  fires,  and  electric 
heaters  at  floor  level  are  the  best  methods  to  attain  this. 

Suppose  the  person  subjected  to  conditions  which  cause  the  mucous 
membrane  to  become  swollen  and  congested  should  go  outside,  then  the 
membrane  at  once  becomes  pale  because  the  blood  vessels  constrict,  but 
for  some  time  it  remains  swollen  and  boggy  and  continues  to  show  pitting 
with  a  probe.  It  is  while  in  this  state  that  it  offers  favorable  conditions 
for  the  growth  of  bacteria.  The  membrane  is  swollen  and  covered  with 
secretion,  and  the  blood  flow  is  cut  down.  The  natural  defensive  agen- 
cies that  are  normally  carried  by  the  blood  do  not  succeed  in  combating 
the  multiplication  of  the  bacteria  in  the  swollen  membrane.  After  some 
time  out  of  doors  the  blood  supply  returns  because  it  is  required  to  warm 
up  the  cool  air,  but  this  reaction  does  not  occur  before  the  mucosa  has 
regained  its  normal  condition.* 

The  protective  influence  of  a  rapid  blood  flow  through  the  nasal  mem- 
brane is  possibly  the  explanation  of  the  relative  immunity  from  infec- 
tious colds  of  those  who  work  in  air  containing  irritating  gases,  such  as 
workers  in  various  kinds  of  chemical  factories.  Even  the  irritation  set  up 
by  coal  dust  may,  by  similar  methods,  afford  some  protection  against  in- 
fection by  the  tubercle  bacillus — for  phthisis  is  relatively  infrequent 
among  coal  miners.  The  supposedly  antiseptic  action  of  ozone  is  prob- 
ably due  to  a  similar  irritating  effect.  Any  benefit  that  may  be  derived 
from  its  presence  in  the  atmosphere  can  not  otherwise  be  explained.  It 
is  possible  that  a  useful  prophylactic  practice  to  avoid  infection,  such  as 
that  of  influenza,  would  be  to  stimulate  the  nasal  mucosa  at  intervals  by 
snuff,  but  this  may  be  an  unwise  suggestion. 

After  becoming  acclimatized  to  outdoor  conditions,  the  nasal  mucous 
membrane  is  in  a  much  more  favorable  condition  to  withstand  infection 
than  indoors  because  of  the  very  rapid  blood  flow  that  is  necessary  in  or- 
der to  supply  heat  with  which  to  warm  up  the  inspired  air.  This  more 
rapid  blood  flow,  and  the  freer  flow  of  lymph  which  accompanies  it,  is 
reinforced  by  increased  secretion,  which  assists  to  wash  away  invading 
bacteria.  Mass  infection  being  equal  inside  and  outside,  the  animal  body 
can  withstand  it  much  less  satisfactorily  in  the  former  case. 

Many  other  observations  bearing  on  the  relationship  between  chilling 
and  immunity  to  infection  have  been  recorded,  but  it  would  take  us  be- 
yond our  subject  to  discuss  them  here.  Because  of  their  accuracy  and  the 
excellent  control  of  possible  fallacies,  it  is  important,  however,  to  say 
something  about  the  recent  investigations  of  Mudd  and  Grant.73  These 
observers  measured  the  temperature  of  the  mucous  membranes  of  the 
palate,  tonsils  and  pharynx  by  means  of  thermo-couples  before  and  dur- 


*The  congestion  of  the  mucous  membrane  brought  about  by  warm  moist  air  does  not  probably 
depend  on  dilatation  of  the  small  arteries — entailing-  increased  flow  of  blood,  but  rather  on  dila- 
tation of  the  capillaries  and  therefore  a  stagnation  of  blood. 


1 


THE    PHYSIOLOGICAL    PRINCIPLES    OF    VENTILATION  763 

ing  application  to  the  skin  of  cold  towels,  or  while  cold  air  from  a  fan 
was  allowed  to  play  on  it.  A  rise  in  temperature  would  indicate  that  the 
part  had  become  more  vascular,  and  a  fall,  the  contrary.  That  this  in- 
terpretation was  the  correct  one  was  confirmed  by  direct  inspection  of 
the  degree  of  flushing  (redness).  It  was  found  that  chilling  the  body 
surface  immediately  caused  a  fall  in  the  temperature  of  the  mucous  mem- 
branes which  could  not  be  accounted  for  by  any  accompanying  change 
in  blood  pressure,  or,  entirely  at  least,  by  changes  in  respiration  or  by 
lowering  of  the  temperature  of  the  blood.  The  conclusions  are  "that  chill- 
ing of  the  body  surface  causes  reflex  vasoconstriction  and  ischemia  in 
the  mucous  membranes  of  the  palate,  f  aucial  tonsils,  oropharynx  and  naso- 
pharynx. ' ' 

The  Methods  for  Determining  the  Healthfulness  of  Air. — Although  the 
present  review  does  not  venture  to  discuss  the  methods  that  are  employed 
for  the  measurement  of  the  various  physical  properties  which  have  to 
be  considered  in  gauging  its  influence  on  health,  or  the  engineering 
problem  of  how  ideal  conditions  may  be  maintained,  it  may  not  be  out 
of  place  to  mention,  in  connection  with  the  former  of  these,  that  the 
physical  property  to  which  most  attention  should  be  devoted  is  the  cool- 
ing power.  This  can  not  be  done  by  reading  an  ordinary  thermometer, 
for  this  instrument  only  registers  the  temperature  of  the  piece  of  wood 
and  of  the  wall  against  which  it  is  hung.  It  registers  the  same  whether 
the  air  is  dry  or  moist,  or  whether  it  is  stagnant  or  moving.  Somewhat 
more  information  regarding  cooling  power  is  afforded  by  readings  of  a 
wet-bulb  thermometer,  an  instrument  in  which  the  bulb  is  kept  constantly 
moist,  so  that  evaporation  occurs  from  it.  This  evaporation  tends  to  cool 
the  thermometer,  in  proportion  to  its  rate,  and  since  this  is  dependent 
mainly  on  the  degree  to  which  the  air  can  take  up  more  moisture,  we  can 
tell  by  the  use  of  a  formula  or  tables  the  relative  degree  of  humidity  of 
the  air.  Still  this  does  not  tell  us  the  real  degree  of  cooling  which  the 
atmosphere  can  bring  about.  It  does  not  adequately  register  the  cooling 
which  is  dependent  upon  the  movement  in  the  air,  the  so-called  convec- 
tion currents.  To  afford  this  information  Leonard  Hill  has  invented  what 
he  calls  the  Kata  thermometer,  by  which  the  rate  of  cooling  is  directly 
measured.  The  instrument  consists  of  an  alcohol  thermometer  with  a  rel- 
atively large  bulb,  and  with  the  scale  registering  between  105°  F  and  90° 
F.  It  is  placed  in  warm  water  at  about  the  former  temperature,  and  is 
then  removed,  and  the  time  required  for  the  temperature  to  fall  from 
100°  F.  to  95°  F.  is  measured  by  means  of  a  stop  watch.  This  time  di- 
vided by  a  factor  determined  for  each  instrument,  and  written  on  the 
stem,  gives  the  actual  amount  of  heat  in  millicalories  per  square  centi- 
meter per  second  which  would  be  given  off  from,  say  the  surface  of  the 
human  body,  under  similar  environmental  conditions.  Hill  and  his  as- 


764  METABOLISM 

sociates3  have  shown  that  much  important  information  concerning  the 
cooling  power  of  the  atmosphere  can  be  gained  in  this  way,  which  can 
not  be  gained  by  any  other. 

METABOLISM  REFEKENCES 

(Monographs  and  Original  Papers) 

iLusk,  Graham:     The  Elements  of  the  Science  of  Nutrition,  W.  B.  Saunders  Co..  ed. 

3,  1917. 

^Cathcart,  E.  P.:  The  Physiology  of  Protein  Metabolism,  Monographs  on  Bio- 
chemistry, Longmans,  Green  &  Co.,  1912. 

sTaylor,  A.  E.:     Digestion  and  Metabolism,  Lea  &  Febiger,  New  York,  1912. 
^Underbill,  F.  P. :     The  Physiology  of  the  Amino  Acids,  Yale  Press,  New  Haven,  1915. 
sMacleod,  J.  J.  E.:     Diabetes,  Its  Pathological  Physiology,  E.  Arnold,  1913. 
saFiirth,  von:     The  Problems  of  Physiological  and  Pathological  Chemistry,  etc.,  J.  B. 

Lippincott  Co.,  1916. 
sbJones,  W.:     Nucleic  Acids,  Monographs  in  Biochemistry,  Longmans,  Green  &  Co., 

1914. 

ecMendel,  Lafayette  B.:     Ergebnisse  der  Physiologic,  1911. 

s^Leathes,  J.  B.:     The  Fats,  Monographs  in  Biochemistry,  Longmans,  Green  &  Co. 
seMathews,  A.  P.:     Physiological  Chemistry,  Wm.  Wood  &  Co.,  1917. 
sfDakin,  H.  K. :     Oxidations  and  Eeductions  in  the  Animal  Body,  Monographs  in  Bio- 
chemistry, Longmans,  Green  &  Co.,  1912. 
sgLeathes,  J.  B.:    Problems  in  Animal  Metabolism,  1906. 
6Du  Bois,  E.  F.,  and  collaborators :     Clinical  Chemistry,  Papers  1  to  25,  Arch.  Int.  Med., 

1915-17,  xvi-xix. 

7Benedict,  F.  G.:     Am.  Jour.  Physiol.,  1916,  xli,  275  and  292. 

sMendel,  Lafayette  B.:     Harvey  Lecture,  J.  B.  Lippincott  Co.,  1914-1915,  p.  101. 
sMcCollum,  E.  V.,  and  collaborators:     Numerous  papers  in  Jour.  Biol.   Chem.,  be- 
ginning 1913. 

"Hopkins,  F.  Gowland,  and  Willcock,  E.  G.:     Jour.  Physiol.,  1906,  xxxv,  88. 
nBayliss,  W.  M.:     The  Physiology  of  Food  and  Economy  in  Diet,  Longmans,  Green 

&  Co.,  1917. 
i2McCollum,  E.  V.:     Harvey  Lecture,  Jour.  Am.  Med.  Assn.,  1917. 

,  J.  E.,  Carson- White,  E.  P.,  and  Saxon,  G.  J.:     Jour.  Biol.  Chem.,  1913,  xv, 
181;  ibid.,  1915,  xxi,  309. 
,  W.:     Biochem.  Ztschr.,  1909,  xxii,  452. 
isFunk,  Casimir:     Ergebnisse  der  Physiologic,  1915. 
isMcKillop,    M.:       Food    Values:      What    They    Are    and    How    to    Calculate    Them, 

Eutledge. 

isaMcCay,  D.  Major:     The  Protein  Element  in  Nutrition,  E.  Arnold,  London,  1912. 
irPembrey,  M.  S.:     Chemistry  of  Eespiration,  in  Schafer's  Text  Book  of  Physiology, 

1898,  i. 

isAllen,  F.  P.:     Glycosuria  and  Diabetes,  Boston,  1913. 
isJoslin:     Diabetes. 

zoWoodyatt,  E.  T.,  Sansum,  W.  D.,  and  Wilder,  E.  M.:  Jour.  Am.  Med.  Assn.,  1915, 
Ixv,  2067.  Also  Taylor,  A.  E.,  and  Hulton,  F.:  Jour.  Biol.  Chem.,  1916,  xxv, 
173. 

2iMacleod,  J.  J.  E.,  and  Fulk,  M.  E.:     Am.  Jour.  Physiol.,  1917,  xlii,  193. 
22Hamman,  L.,  and  Hirschmann:     Arch.  Int.  Med.,  1917,  xx,  761-788. 
23Cannon,  W.  B.:     Bodily  Changes  in  Pain,  Hunger,  Fear  and  Eage,  D.  Appleton  & 

Co.,  1915. 

24Knowlton,  F.  P.,  and  Starling,  E.  H.:     Jour.  Physiol.,  1912,  xlv,  146. 
25patterson,  S.  W.,  and  Starling,  E.  H.:     Jour.  Physiol.,  1913,  xlvii,  135;  also  Cruick- 

shank  and  Patterson:     Ibid.,  p.  113. 
26Macleod,  J.  J.  E.:      (a)  Jour.  Biol.  Chem.,  1913,  xv,  497;    (b)  Physiol.  Rev.,  1921,  i, 

208. 

27Murlin,  J.  E.:     Jour.  Biol.  Chem.,  1913,  xvi,  79. 
28Cruickshank:     Jour.  Physiol.,  1913,  xlvii,  1. 

29Macleod,  J.  J.  E.,  and  Pearce,  E.  G.:     Zentralbl.  f.  Physiol.,  1913,  xxvi,  1311. 
sowoodyatt,  E.  T.:     Jour.  Am.  Med.  Assn.,  1916,  Ixvi,  1910. 


THE   PHYSIOLOGICAL   PRINCIPLES   OF   VENTILATION  765 

Slyke,  D.  D.:  The  Present  Significance  of  the  Amino  Acids  in  Physiology  and 
Pathology,  Harvey  Lectures,  J.  B.  Lippincott  &  Co.,  1915-1916,  p.  146.  Also 
papers  in  Jour.  Biol.  Chem.,  1911,  ix,  185;  xii,  275;  ibid.,  1912,  xii,  301  and  399; 
ibid.,  1913,  xiii,  121,  125  and  187. 

in,  O.,  and  Denis,  W.:     Jour.  Biol.  Chem.,  xi,  87  and  493;  ibid.,  1912,  xii,  14  and 
253. 

33 Abel,  J.  J.:    The  Mellon  Lecture,  Science,  1915,  xlii,  135. 

3*Hewlett,  A.  W.,  Gilbert,  L.  O.,  Wickett,  A.  D.:     Arch.  Int.  Med.r  1916,  xviii,  636. 

ssLosee,  J.  E.,  and  Van  Slyke,  D.  D.:     Jour.  Am.  Med.  Assn.,  1917,  cliii,  94. 

36Shaffer,  P.  A.:     Am.  Jour.  Physiol.,  1908,  xxviii,  1. 

37Cathcart,  E.  P.:    Jour.  Physiol.,  1907,  xxxv,  500. 

ssMyers  and  Fine:    Jour.  Biol.  Chem.,  1913,  xiv,  9. 

ssLevene,  P.  A.:     Cf.  W.  Jones.*° 

4oJones,  W.:  Nucleic  Acids,  Monographs  on  Biochemistry,  Longmans,  Green  &  Co., 
1914. 

^Benedict,  S.  E.:     Harvey  Lecture,  1915-16. 

*2Hunter,  A.,  and  Givens,  M.  H.:     Jour.  Biol.  Chem.,  1914,  xviii,  403. 

43Burian,  E.,  and  Schur,  H.:  Cf.  Macleod  in  Eecent  Advances  in  Physiology  and  Bio- 
chemistry, ed.  by  Leonard  Hill,  E.  Arnold,  London,  1905. 

44Mendel,  Lafayette  B.,  and  Lyman,  J.  F.:     Jour.  Biol.  Chem.,  1910,  viii,  115. 

45Taylor,  A.  E.,  and  Eose,  W.  C. :     Jour.  Biol.  Chem.,  1913,  xiv,  419. 

46Hopkins,  F.  G.,  and  Hope,  W.  B.:     Jour.  Physiol.,  1899,  xxiii,  277. 

47Ascoli,  M.,  and  Izar,  G. :  Ztschr.  f .  Physiol.  Chem.,  1909,  Iviii,  529 ;  ibid.,  1911,  Ixiii, 
319. 

*8McClure,  C.  W.,  Vincent,  B.,  and  Pratt,  J.  H.:     Am.  Jour.  Physiol.,  1916,  xlii,  596. 

*9Bloor,  W.  E.:  Jour.  Biol.  Chem.,  1912,  xi,  429;  ibid.,  1913,  xv,  105;  ibid.,  1914,  xvi, 
517;  ibid.,  1912,  xi,  141;  ibid.,  1915,  xxi,  421;  ibid.,  1914,  xix,  1;  ibid.,  1915, 
xxiii,  317;  ibid.,  1914,  xvii,  317;  ibid,  1915,  xxii,  133.  Also  Bloor  and  Knudson: 
Jour.  Biol.  Chem.,  1916,  xxvii,  107;  ibid.,  1916,  xxiv,  447;  Bloor,  Joslin  and 
Homer:  Ibid.,  1916,  xxvi,  417;  ibid.j,  1916,  xxv,  577.  (49b)  Physiol.  Eev., 
1922,  ii,  92. 

soLeathes,  J.  B.:     The  Fats,  Monographs  on  Biochemistry,  Longmans,  Green  &  Co. 

siCoope,  E.,  and  Mottram,  V.  H.:     Jour.  Physiol.,  1914,  xlix,  23;  ibid.,  1915,  xlix,  157. 

52Eaper,  H.  S.:     Jour.  Biol.  Chem.,  1913,  xiv,  117. 

ssSmedley,  I.  D.:     Proc.  Phys.  Soc.,  Jour.  Physiol.,  1912,  xiv,  25. 

s*Hill,  Leonard:  Address  to  the  Phys.  Sec.  Brit.  Assn.  for  the  Adv.  of  Sci.,  Section, 
J,  1912. 

ssShaffer,  P.  A.,  and  Coleman,  W.:     Arch.  Int.  Med.,  1909,  iv,  538. 

seBarbour,  H.  G. :  Arch.  f.  Exper.  Path.  u.  Pharmac.,  1912,  Ixx,  1;  Jour.  Pharmac. 
and  Exper.  Therap.,  1913,  v,  105 ;  Physiol.  Eev.,  1921,  i,  295. 

^Hewlett,  A.  W.:     Monographic  Medicine,  D.  Appleton  £  Co.,  1917,  i. 

ssHunter,  A.,  and  Campbell,  W.  E.:     Jour.  Biol.  Chem.,  1918,  xxxiii,  169. 

59Thompson,  Sir  W.  H. :     Biochem.  Jour.,  1917,  xi,  307. 

eoRingsbury,  F.  B.,  and  Bell,  E.   T.:     Jour.  Biol.  Chem.,   1915,  xxi,   297. 

siLynch,  V.:     Am.  Jour.  Physiol.,  1919,  xlviii,  258. 

62Leathes,  J.  B. :     Problems  of  Animal  Metabolism,    (London,  1906). 

63Maeleod,  J.  J.  E. :     Jour.  Biol.  Chem.,  1906,  ii,  231. 

e^Cruikshank  and  Patterson:     Jour.  Physiol.,  1913,  xlvii,  381;  ibid.,  1914,  xlix,  67. 

<55Clark,  A.  H.:     Johns  Hopkins  Hos.  Eeports,  1919,  xviii. 

eeHarris,  J.  A.,  and  Benedict,  T.  G. :     Eeport  Carnegie  Institution  of  Washington,  1919. 

G7Means,  J.  H.,  and  Aub,  J.  C. :     Arch.  Int.  Med.,  1919,  xxiv,  645. 

esDavis,  N.  C.,  and  Hall,  C.  C.,  and  Whipple,  G.  H. :     Arch.  Int.  Med.,  1919,  xxiii,  689. 

69Banting,  C.  F.,  Best,  C.  E.,  Collip,  J.  B.,  Campbell,  W.  E.,  and  Fletcher,  A.  A.: 
Canadian  Med.  Jour.,  1922  (March). 

7oHopkins,  F.  Gowland,  and  Chick,  Hariette:  Medical  Eesearch  Committee  National 
Health  Insurance,  Special  Eeport  No.  38,  1920,  H.  M.  Stationary  Office,  Imperial 
House,  Kingsway,  London,  W.C.  2. 

7iOsborne,  T.  B.,  and  Mendel,  J. :     Jour.  Biol.  Chem.,  1917,  xxxi,  144. 

72Hill,  L.:  Special  Eeport  No.  32.  The  Science  of  Ventilation  and  Open  Air  Treat- 
ment, Medical  Eesearch  Committee,  H.  M.  Stationary  Office,  London,  1919. 

73Mudd,  S.,  and  Grant,  L.  B.:     Jour.  Med.  Eeseareh,  1919,  xl,  53. 

74Allen,  F.  M.,  Wishart,  M.  B.,  and  Smith,  L.  M. :  Arch.  Int.  Med.,  1919,  xxiv,  523. 
Also  Murlin,  J.  E.,  and  Nites,  W.  I. :  Am.  Jour.  Med.  Se.,  1917,  cliii,  79. 

75McCarrison,  E. :     Food  and  Deficiency  Disease,  1921. 


PART  VIII 
THE  ENDOCRINE  ORGANS,  OR  DUCTLESS  GLANDS 

(Revised  by  N.  B.  Taylor) 


CHAPTER  LXXXIV 

GENERAL  CONSIDERATIONS,  THE  ADRENAL  GLANDS 

In  order  that  the  various  activities  of  the  animal  organism  may  act 
efficiently  as  a  whole,  it  is  necessary  that  those  of  one  part  be  correlated 
with  those  of  another.  This  correlation  of  function  is  mediated  either 
through  the  nervous  system  or  through  the  action  on  one  part  of  the 
body  of  substances  produced  in  another  part  and  carried  between  them  by 
the  blood.  Control  through  the  nervous  system  is  especially  developed  for 
those  functions  which  have  to  be  brought  promptly  into  play,  such  as 
muscular  movement  and  the  other  physiological  processes  concerned  in  the 
adjustment  of  the  organism  to  quickly  changing  conditions  of  its  environ- 
ment. Control  through  the  blood  is  the  mechanism  by  which  the  metabolic 
activities  of  different  organs  are  mainly  correlated.  The  chemical  sub- 
stances involved  are  often  called  internal  secretions. 

Some  of  these  internal  secretions  are  merely  by-products  of  metabolism, 
and  are  only  incidentally  used  for  the  purpose  of  bringing  about  control 
between  different  parts  of  the  body.  To  this  group  belong  carbon  dioxide, 
which  may  act  on  the  respiratory  and  other  nerve  centers,  and  urea,  which 
may  stimulate  increased  activity  of  the  kidneys.  Indeed,  the  list  of  sub- 
stances included  under  such  a  definition  of  internal  secretions  is  almost 
illimitable,  and  to  designate  by  the  special  name  of  hormone  every  con- 
stituent that  can  affect  physiological  functions,  as  some  have  done,  can  lead 
only  to  confusion.  The  internal  secretions  with  which  we  are  more 
directly  concerned  are  those  that  are  specially  produced  for  the  purpose 
of  controlling  the  metabolic  functions.  They  are  given  the  general  name 
of  autacoids  (E.  A.  Schafer).3  Autacoids  may  be  either  the  sole  product 
of  some  special  gland  or  a  secondary  product  of  glands  which  have  other 
functions.  To  the  former  class  belong  the  autacoids  produced  by  the  para- 
thyroid, thyroid,  pituitary  and  adrenal  glands,  and  to  the  latter,  those 
produced  by  the  pancreas  and  generative  glands. 

766 


THE   ENDOCRINE   ORGANS,    OR   DUCTLESS   GLANDS  767 

Autacoids  have  further  been  subdivided  by  Schafer  into  two  classes 
according  to  whether  they  excite  metabolic  processes  or  depress  them. 
Examples  of  excitatory  autacoids,  also  designated  as  hormones,  are  the 
epinephrine  produced  by  the  adrenal  glands,  which  excites  the  termina- 
tions of  the  sympathetic  nervous  system,  and  pituitrin  produced  by  the 
posterior  lobe  of  the  pituitary  gland,  which  excites  plain  muscular  fiber. 
Inhibiting  autacoids,  also  called  chalones,  are  not  so  commonly  known,  but 
are  illustrated  by  the  substance  contained  in  extract  of  the  placenta, 
which  tends  to  prevent  the  secretion  of  milk. 

Autacoids  may  have  either  an  immediate  or  a  delayed  action ;  the  effect 
which  they  produce  may  be  like  that  with  which  we  are  familiar  as  the 
result  of  stimulation  of  the  nerve  supply  of  a  gland,  being  illustrated 
again  by  the  effect  of  epinephrine,  or  they  may  act  so  slowly  that  it  is 
only  after  a  considerable  period  of  time  during  which  they  have  been 
in  the  organism  in  excess,  that  any  apparent  effect  is  produced.  The 
slowly  acting  autacoids  have  been  called  morpho genetic,  and  they  are 
well  illustrated  in  the  internal  secretions  of  the  anterior  lobe  of  the 
pituitary  and  of  the  generative  glands — secretions  which  affect  growth. 

Regarding  the  chemical  nature  of  autacoids,  certain  facts  stand  out  prominently. 
Being  very  largely  the  products  of  glands,  it  might  be  imagined  that  they  would  be 
enzymic  in  nature,  for  enzymes  are  now  known  to  be  the  most  important  active  agents  in 
bioplasm  as  well  as  the  active  agents  in  many  of  the  external  secretions,  like  those  of 
the  salivary,  gastric  and  intestinal  glands.  Autaeoids,  however,  are  not  enzymes.  They 
are  far  simpler  in  chemical  structure,  and  are  not  destroyed  by  heat  in  the  presence  of 
water.  They  are  represented  by  a  comparatively  small  molecule,  and  are  therefore 
dialyzable.  This  latter  fact  justifies  the  hope  that  it  may  be  possible  to  prepare  them 
or  their  simpler  salts  in  crystalline  form — a  hope  which  has  already  been  realized  in 
the  case  of  thyroxin  and  epinephrine.  Progress  has  likewise  been  made  in  isolating 
the  active  principles  of  the  anterior  and  posterior  lobes  of  the  pituitary  gland.  To 
sum  up,  then,  we  may  say  that  an  autacoid  is  a  specific  organic  substance,  formed 
by  the  cells  of  one  organ  and  secreted  into  the  circulating  fluid,  which  carries  it  to  other 
organs,  upon  which  it  produces  effects  similar  to  those  of  drugs. 

Methods  of  Investigation 

To  investigate  the  function  of  an  autacoid,  careful  studies  are  made  of 
the  effects  produced  (1)  by  excision  of  the  gland  which  furnishes  the 
autacoid  and  (2)  by  administering  intravenously  or  subcutaneously  or 
>rally  extracts  prepared  from  the  gland.  Frequently,  also  light  is  thrown 
on  the  function  of  the  autacoid  by  observing  the  effect  which  fol- 
lows prolonged  feeding  with  the  endocrine  organ  that  manufactures  it 
and  by  observing  the  pathological  changes  in  the  various  endocrine  organs 
in  diseased  conditions.  Embryological  and  histological  studies  are  also  of 
the  greatest  importance.  A  difficulty  in  investigating  the  function  of 
an  endocrine  organ  lies  in  the  fact  that  the  secretion  of  no  one  gland 


768  THE   ADRENAL    GLANDS 

acts  independently  of  those  from  other  glands.  On  the  contrary,  there  is 
undoubtedly  a  close  association  of  function,  so  that  we  can  not  tell 
whether  a  change  of  function  observed  after  removal  of  some  gland  or 
administration  of  some  extract  is  a  direct  consequence  of  the  experi- 
mental procedure,  or  is  induced  by  some  secondary  effect  developed  on 
another  endocrine  organ.  It  will  no  doubt  take  many  years  before  suf- 
ficient data  have  been  collected  to  enable  us  definitely  to  state  what  the 
particular  function  of  each  endocrine  organ  may  be.  Since  most  progress 
has  been  made  in  connection  with  the  adrenal  gland,  it  will  be  advan- 
tageous to  consider  the  functions  of  this  gland  first. 

ADRENAL  GLAND 

In  mammals  the  adrenal  gland  is  composed  of  two  parts,  the  cortex 
and  the  medulla.  The  origins  of  these  two  are  quite  different,  and  though 
in  mammals  they  are  intimately  associated  in  anatomical  position,  in  other 
groups  of  animals  they  are  more  or  less  separate,  being  completely  so 
in  fishes.  This  not  infrequent  separation  of  cortex  and  medulla,  together 
with  their  distinctive  origins,  suggests  different  functions  for  the  two. 
Experimental  investigation  supports  this  view. 

The  Cortex 

The  cortex  on  microscopic  examination  is  seen  to  be  composed  of  rows  of  epithelial 
cells  arranged  more  or  less  in  columns  except  at  the  periphery,  where  they  form  glomeru- 
lar  masses,  and  next  the  medulla,  where  they  assume  a  reticular  formation.  The  cells 
of  the  greater  part  of  the  cortex,  unlike  those  of  the  medulla,  contain  no  granules  with 
special  staining  qualities,  but  they  do  contain  particles  which  are  believed  to  be  com- 
posed of  cholesterol  esters  and  lecithin.  In  the  cells  of  the  reticular  portion  of  the 
cortex,  however,  pigment  particles  are  not  infrequently  observed.  The  blood  supply  of 
the  cortex  is  not  nearly  so  rich  as  that  of  the  medulla,  being  represented  by  fine  arterioles 
which  run  inwards  from  the  capsule  towards  the  medulla  in  the  connective  tissue  that 
Des  between  the  columns  of  cortical  cells.  Nerves  similarly  penetrate  into  the  cortex, 
some  supplying  its  blood  vessels  and  cell  columns,  but  most  of  them  proceeding  to  the 
medulla.  They  are  derived  from  a  network  of  nerve  fibers  in  the  capsule  of  the  organ, 
and  the  nerve  supply  of  this  network  comes  partly  from  the  suprarenal  plexus,  and  partly 
from  the  splanchnic  nerve.  Embryologically  the  cortex  is  developed  from  the  cells  of 
the  genital  ridge,  that  is,  from  mesodermic  cells. 

Very  little  is  known  concerning  the  function  of  the  adrenal  cortex  al- 
though there  is  little  doubt  that  it  is  closely  related  to  the  development 
of  the  sexual  organs.  The  evidence  for  this  is  as  follows:  (1)  It  arises 
from  the  mesoderm  in  common  with  the  sexual  organs.  There  is  also 
a  remarkable  similarity  between  the  cortical  cells  and  those  of  the  corpus 
luteum.  (2)  In  cases  of  sexual  precocity  it  is  found  that  the  adrenal 
cortex  is  much  hypertrophied.  Also,  certain  tumors  of  the  cortex  occur- 
ring in  young  children  are  associated  with  premature  development  of  the 


THE   ENDOCRINE   ORGANS,    OR   DUCTLESS   GLANDS  769 

secondary  sexual  characters.  The  subjects  of  these  growths  (Pig.  191), 
which  are  termed  hypernephromata,  present,  in  many  cases,  a  most  re- 
markable appearance.  A  boy,  for  instance,  of  four  or  five  years  may 
possess  the  sexual  development  of  a  mature  male,  the  testicles  are  en- 
larged, hair  grows  upon  the  chest  and  pubis,  and  a  moustache  or  a  beard 
may  develop.  There  may  be  also  undue  muscular  development  or  ex- 
treme obesity  of  an  adult  type,  so  that  these  prodigies  have  been  likened 
in  appearance  to  "an  infant  Hercules"  (Weber)  or  "a  burly  brewer's 


Fig.   191. — Child  aged  4J4   years  suffering  from  hypernephroma.     (Guthrie.) 

drayman"  (Guthrie).4  In  female  children  the  breasts  hypertrophy,  hair 
appears  upon  the  mons  veneris  and  labia  majora,  the  uterus  tends  toward 
the  mature  type,  and  menstruation  may  occur.  In  appearance  these 
patients  resemble  stout  little  women.  (3)  The  cortex  becomes  hypertro- 
phied  during  pregnancy.  (4)  It  is  ill-developed  in  sexual  deficiency.  (5) 
Changes  occur  in  it  during  the  estrual  cycle  of  many  animals.  In  the 
frog  during  the  mating  season  it  becomes  greatly  enlarged  at  the  ex- 
pense of  the  medullary  tissue  and  develops^  peculiar  pear-shaped  ele- 
ments, the  "summer  cells"  of  Stilling.  (6)  After  castration  the  cortex  is 
said  to  be  hypertrophied.  (7)  The  innermost  portion  of  the  cortex,  some- 


770  THE   ADRENAL   GLANDS 

times  called  the  boundary  zone,  is  much  hypertrophied  in  the  human  fetus, 
but  this  hypertrophy  entirely  disappears  after  the  first  year  of  extrauterine 
life. 

The  other  functions  of  the  cortex  are  not  as  yet  known,  but  there  is  very 
strong  evidence  that  they  are  of  great  importance  to  the  welfare  of  the 
animal.  It  has  been  suggested  that  the  passage  of  blood  through  the 
cortex  before  reaching  the  medulla  indicates  that  some  change,  which 
is  preparatory  to  the  main  change  occurring  in  the  medulla,  takes  place 
in  the  blood  while  it  is  in  the  cortex.  This  view  is  partly  substantiated 
by  the  observation  that  when  an  excised  jportion  of  cortex  is  incubated 
at  body  temperature,  a  substance  develops  in  it  which  has  an  action 
like  that  of  the  hormone  of  the  medulla — epinephrine.  It  is  possible, 
however,  that  this  action  is  due  to  the  fact  that  certain  of  the  decomposition 
products  of  protein  develop  an  epinephrine-like  action  (see  page  536). 

A  detoxicating  function  has  been  ascribed  to  the  cortex.  This  possi- 
bility has  been  suggested  by  the  fact  that  cobra  venom,  to  which  had 
been  added  an  emulsion  of  this  portion  of  the  gland,  was  rendered  innoc- 
uous. (Meyers).5  The  addition  of  other  tissue  extracts  to  the  poison 
was  without  effect. 

The  weight  of  evidence  favors  the  view  that  it  is  the  cortex  and  not 
the  medulla  which  is  essential  to  life.  Biedl2  claims  to  have  removed  the 
cortex  leaving  the  medulla  intact ;  the  operation  resulted  invariably  in 
the  death  of  the  animals.  Conversely  he  found  that,  in  cats  and  dogs, 
the  adrenals  could  be  removed  with  impunity  to  the  extent  of  seven 
eighths  of  their  bulk,  provided  that  the  portion  remaining  consisted  of 
cortex.  Wheeler6  endeavored  to  remove  the  medulla,  leaving  the  cortex 
intact ;  though  this  was  not  wholly  successful,  it  is  a  noteworthy  fact  that 
it  was  those  animals  only,  in  which  the  cortex  was  inadvertently  injured, 
that  succumbed  to  the  operation.  Evidence  for  the  indispensability  of  the 
cortex  is  also  offered  from  the  clinical  side.  Cases  of  acute  adrenal  de- 
ficiency, followed  by  rapid  death,  occur,  in  which  the  medulla,  postmor- 
tem, shows  few  or  no  lesions  or  disease  of  a  longstanding  nature,  whereas 
acute  lesions  are  observable  in  the  cortex. 

The  Medulla 

Histologically  the  medulla  is  composed  of  masses  of  polygonal  cells 
with  blood  sinuses  between  them.  The  blood  supply  is  derived  from  ves- 
sels that  have  proceeded  to  the  medulla  through  the  capsule,  and  it  is 
extremely  rich,  being  indeed  the  richest  blood  supply  to  any  organ  in  the 
body,  greater  even  than  that  to  the  thyroid  gland.  The  nerves  form  a 
dense  plexus,  extending  into  and  between  the  secretory  cells.  The  most 
characteristic  feature  of  the  cells  composing  the  medulla  is  the  presence 
in  them  of  granules  which  stain  readily  with  chromic  acid,  and  are  hence 


THE   ENDOCRINE   ORGANS,    OR   DUCTLESS   GLANDS  771 

often  called  chromaffin  cells.    There  are  also  some  cells  containing  coarser 
granules  that  are  soluble  in  water  and  do  not  stain  with  chrome  salts. 

Embryologically,  the  medulla  is  developed  from  tissue  common  to  it  and  the  sym- 
pathetic nervous  system.  From  that  part  of  the  neuroblast  in  which  are  laid  down  the 
primitive  ganglia  of  the  posterior  roots,  masses  of  cells  are  split  off  which  become  the 
common  ancestors  of  the  sympathetic  ganglia  and  the  chromaffine  system.  These  cell 
groups  wander  from  their  sites  of  origin  and  come  to  lie  along  the  vertebral  bodies, 
ranging  themselves,  in  the  case  of  the  abdomen,  on  either  side  of  the  aorta.  One  mass 
seeks  the  adrenal  cortex,  which  has  been  formed  at  a  prior  stage  of  development,  and 
passes  into  its  interior.  Differentiation  of  these  cells  then  proceeds  in  two  directions, 
those  lying  along  the  aorta  form,  for  the  most  part,  sympathetic  ganglia;  those  within 
the  adrenal  cortex  develop  into  chromaffin  cells  to  constitute  the  medulla  of  the  gland. 
These  embryological  considerations  will  enable  us  to  understand  the  close  functional  re- 
lationship which,  as  we  shall  see,  exists  between  the  sympathetic  nervous  system  and  the 
adrenal  medulla. 

The  intimate  anatomical  association  of  the  cortex  and  medulla  renders 
the  removal  of  one  part  alone,  if  not  an  actual  impossibility,  a  procedure 
at  least,  of  extreme  difficulty.  On  this  account,  with  the  exception  of  the 
investigations  cited  above,  attention  has  been  paid  only  to  the  effects  pro- 
duced by  removal,  or  by  the  injection  of  extracts  of  the  whole  gland. 

Adrenalectomy 

Excision  of  the  adrenal  gland  in  most  animals  is  very  quickly  fatal, 
the  only  well-known  exception  being  in  the  case  of  the  white  rat,  in  which 
excision  of  both  adrenals  may  not  be  incompatible  with  life.  For  some 
time  after  recovery  from  the  anesthetic  the  animal  upon  which  double 
adrenalectomy  has  been  performed  usually  behaves  in  a  perfectly  normal 
fashion,  although  it  may  be  less  lively  and  less  inclined  to  feed  than 
usual.  Very  soon,  however,  generally  within  twenty-four  or  forty- 
eight  hours,  definite  symptoms  of  muscular  weakness  are  apparent.  This 
weakness  soon  becomes  extreme,  and  is  accompanied  by  a  feeble  pulse, 
a  depression  of  body  temperature,  and,  later,  by  dyspnea.  After  an 
interval  which  is  never  longer  than  a  few  days,  death  supervenes,  being 
sometimes  preceded  by  convulsions. 

When  only  one  adrenal  is  removed,  very  few  animals  succumb;  and 
if  some  time  is  allowed  to  elapse  so  that  the  immediate  shock  of  the 
operation  has  disappeared,  it  will  usually  be  found  that  removal  of  the 
remaining  adrenal,  although  ultimately  fatal,  is  not  so  quickly  so  as 
when  both  glands  are  removed  at  one  operation.  The  reason  for  this 
result  is  that  opportunity  is  given  for  a  compensatory  hypertrophy  of 
accessory  adrenal  bodies  to  occur.  Such  accessory  adrenal  bodies  may 
be  composed  of  cortical  or  medullary  tissue,  and  there  is  a  growing  belief 
that  the  cortical  tissue  is  the  more  important.  Chromaffin  tissue  is  found 
in  most  animals  along  the  front  of  the  aorta,  between  the  renal  arteries, 


772  THE  ADRENAL   GLANDS 

where  it  can  usually  be  recognized  by  staining  the  tissue  with  chromic  acid. 
Sometimes  accessory  chromaffin  tissue  is  located  in  distant  parts, 
as  in  the  epididymis  of  the  rat,  for  example.  It  is  said  that  life  can 
be  maintained  if  one-eighth  of  the  total  amount  of  the  adrenal  substance 
be  present  in  the  body.  Attempts  to  prolong  life  after  adrenalectomy 
by  adrenal  transplantation  have  almost  invariably  met  with  negative 
results,  because  the  graft  undergoes  a  rapid  process  of  necrosis  and  dis- 
appears; although  it  is  said  that  transplantation  may  sometimes  be  suc- 
cessfully accomplished  if  the  grafting  is  done  into  the  kidney.  Adminis- 
tration of  suprarenal  extract  is  also  without  definite  benefit  after 
adrenalectomy. 

Adrenal  Disease  in  Man. — Besides  the  hypertrophy  of  the  cortex,  which 
has  already  been  alluded  to,  destructive  disease  (usually  tuberculous) 
of  the  adrenal  gland  occurs,  which  has  been  recognized  to  be  the  cause 
•of  a  characteristic  clinical  condition  known  as  Addison's  disease.  This 
condition,  which  runs  a  more  or  less  protracted  course  and  is  almost  in- 
variably fatal,  is  characterized  by  muscular  weakness,  low  blood  pres- 
sure, pigmentation  of  the  skin  and  gastrointestinal  disturbances.  Injec- 
tions of  epinephrine  have  little  or  no  influence  over  the  symptoms  or  over 
the  course  of  the  disease ;  administration  of  extracts  of  the  whole  gland 
are,  perhaps,  of  more  benefit.  Though  it  is  almost  universally  accepted 
that  inadequacy  of  the  adrenals  is  responsible  for  the  disease,  the  imme- 
diate cause  of  the  symptoms  is  obscure,  nor  is  it  known  whether  cortex  or 
medulla  is  at  fault.  It  might  appear  that  the  muscular  weakness  and  ar- 
terial hypotonus  were  due  to  incompetency  of  the  medulla;  yet  the  results 
of  epinephrine  administration  do  not  support  such  a  conclusion.  Further- 
more, as  we  shall  see,  it  has  been  demonstrated  conclusively  that  epine- 
phrine is  not  a  factor  in  the  maintenance  of  normal  arterial  tone  (page 
785). 

The  bronzing  of  the  skin,  a  prominent  symptom  of  Addison's  disease,  is 
due  to  an  increase  of  the  normal  pigment — melanin — in  the  Malpighian 
layer.  To  account  for  the  excessive  deposition  of  pigment  (chromatosis) 
Halle7  has  suggested  that  there  is  an  increase  of  tyrosine,  the  precursor 
of  melanin,  in  the  tissues.  Part  of  the  tyrosine  of  the  body  is  believed 
to  be  converted,  under  normal  conditions,  into  epinephrine.  This  belief 
is  supported  by  a  comparison  of  the  formulae  of  the  two  substances 
(epinephrine  C9H13N03,  tyrosine  CaH^NOg)  and  by  the  following  experi- 
ment: An  emulsion  of  the  gland  was  divided  into  two  halves,  to  one  of 
which  tyrosine  was  added;  the  two  portions  were  incubated  for  six  days, 
after  which  period  analysis  showed  that  the  portion  to  which  the  amino 
acid  had  been  added  contained  from  15  to  33  per  cent  more  epinephrine 
than  the  control.  That  melanin  may  be  produced  by  the  action  of  the 
enzymes  upon  tyrosine  is  well  known,  for  example,  an  extract  of  the 


THE   ENDOCRINE   ORGANS,    OR   DUCTLESS   GLANDS  773 

tissue  forming  the  wall  of  the  inksac  in  the  cuttle  fish  will,  upon  the  ad- 
dition of  tyrosine,  produce  a  sepia  pigment.  Halle's  hypothesis,  then, 
implies  that  the  tyrosine  which  under  normal  circumstances  would  be 
employed  for  the  manufacture  of  epinephrine,  is,  in  the  case  of  adrenal 
deficiency  converted  into  pigment.  Attractive  though  this  hypothesis  may 
be,  it  should  be  pointed  out  that  Ewins  and  Laidlaw8  have  failed  to  con- 
firm it. 

In  addition  to  this  chronic  form  of  adrenal  disease  cases  of  acute 
adrenal  insufficiency  occur.  Death,  which  very  rapidly  ensues,  may  be 
preceded  by  symptoms  of  cerebral  hemorrhage,  or  acute  abdominal  dis- 
ease or  may  follow  a  short  period  of  extreme  myasthenia.  In  other  in- 
stances death  is  sudden  and  unheralded,  and  that  the  adrenals  are  re- 
sponsible is  revealed  by  finding  that  they  are  the  seat  of  extensive  disease. 
This  may  be  manifested  by  areas  of  necrosis,  by  hemorrhage  or  by  ve- 
nous thrombosis.  In  a  case  reported  recently  by  Boyd,9  the  subject, 
prior  to  the  rapidly  fatal  attack,  was  in  apparently  good  health.  An 
autopsy  showed  the  medullary  tissue  to  be  entirely  consumed  by  a  process 
of  long  standing,  whereas  the  cortex  was  the  seat  of  an  acute  lesion  which 
apparently  was  the  cause  of  the  fulminating  symptoms. 

Suprarenal  Extracts — Preparation 

Injection,  particularly  intravenous,  of  extract  of  the  adrenal  gland 
has  furnished  us  with  most  of  the  evidence  upon  which  our  knowledge 
regarding  the  function  of  this  organ  depends.  Such  an  extract  is  best 
made  by  grinding  the  entire  gland  with  fine  sand  in  a  mortar  and  then 
extracting  with  a  weak  (decinormal)  solution  of  hydrochloric  acid.  The 
extract  may  then  be  boiled,  filtered  through  muslin  and  nearly  neutral- 
ized, preferably  by  means  of  sodium  acetate.  If  kept  in  this  acid  reac- 
tion, the  active  principle  of  the  extract  does  not  materially  deteriorate 
with  time,  but  if  it  be  neutralized  or  considerably  diluted,  destruction 
due  to  oxidation  occurs,  as  evidenced  by  a  distinct  browning  of  the 
solution.  The  active  principle  of  such  extracts  has  been  isolated  in  a 
crystalline  form  (Takamine  and  Abel).  It  has  been  given  various  names 
(adrenalin,  suprarenin,  adrenin,  etc.),  but  the  tendency  is  definitely 
towards  the  use  of  epinephrine.  Chemically,  epinephrine  has  been  found 
to  be  orthodioxyphenylethylolmethylamine. 

HO 

^>  -*CH(OH)  -  CH2NHCH3. 

It  will  be  noted  that  it  is  closely  related  to  tyrosine  (see  page  639).  It 
is  also  closely  related  to  a  group  of  substances  (amines)  occurring  in 
^utrid  meat  and  to  which  the  active  principles  of  ergot  belong.  It 


774  THE   ADRENAL   GLANDS 

contains  an  asymmetric  carbon  atom  (asterisked  in  formula),  which 
indicates  that  there  must  be  three  varieties  of  epinephrine,  differing 
from  one  another  in  the  effect  which  they  produce  on  the  plane  of 
polarized  light  (i.e.,  a  dextro-  and  a  levo-rotatory  and  a  racemic  form). 
Epinephrine  can  be  prepared  by  synthetic  means,  the  first  product  of 
this  synthesis  being  the  racemic  salt,  which  can  then  be  split  by  appro- 
priate methods  into  dextro-  and  levo-  varieties.  The  levo-  variety  ap- 
pears to  be  identical  in  its  pharmacological  action  with  the  natural  product. 
The  dextro-  variety  on  the  other  hand  has  only  poorly  developed  physio- 
logical activities  (about  seven  per  cent  that  of  the  levo-  variety),  while 
the  racemic  variety  comes  in  between  the  two  in  its  action.  A  valuable 
assay  of  the  amount  of  epinephrine  in  tissue  extracts  can  be  made  by 
the  method  of  Cannon,  Folin  and  Denis,10  in  which  an  acid  extract  of 
the  gland  is  treated  with  phosphotungstic  acid,  and  the  blue  color  thereby 
developed  compared  colorimetrically  with  a  standard  blue. 

Physiological  Action 

The  physiological  effects  of  the  intravenous  injection  of  epinephrine  are 
markedly  excitatory  and  slightly  inhibitory  in  nature.  We  will  consider 
the  excitatory  action  first.  Immediately  after  the  intravenous  injection 
of  as  small  an  amount  as  0 '00008  milligrams  per  kilogram  of  body  weight, 
a  distinct  rise  in  arterial  blood  pressure  may  be  observed.  When  the 
rise  is  distinct,  it  is  accompanied  by  a  slowing  of  the  pulse.  This  slow- 
ing is  caused  by  stimulation  of  the  vagus  center,  as  is  evidenced  by  the 
fact  that  if  the.  vagus  nerves  are  cut,  or  sufficient  atropine  administered 
to  paralyze  them,  the  same  dose  of  epinephrine  produces  not  a  slowing 
but  a  quickening  of  the  pulse,  and  consequently  a  much  greater  rise  in 
blood  pressure.  The  vagus  action  is  developed  not  because  of  an  effect 
of  epinephrine  on  the  vagus  center,  but  secondarily  because  of  the  rise 
in  blood  pressure. 

These  preliminary  experiments  indicate  that  the  locus  of  action  of 
epinephrine,  so  far  as  the  circulatory  system  is  concerned,  is  mainly  on 
the  small  blood  vessels,  constricting  them  and  thus  raising  the  peripheral 
resistance.  This  conclusion  can  readily  be  confirmed  by  applying  the 
epinephrine  directly  to  the  blood  vessels  of  the  exposed  mesentery,  or 
by  enclosing  a  vascular  organ  such  as  the  kidney  in  a  plethysmo graph 
during  the  injection  of  epinephrine,  when  a  great  diminution  in  volume, 
accompanying  the  rise  of  arterial  blood  pressure,  will  be  observed.  The 
vasoconstricting  effect  of  epinephrine  does  not  become  developed  on  the 
large  blood  vessels  near  the  heart  on  account  of  the  deficiency  in  muscu- 
lar tissue  in  their  walls.  Indeed,  these  vessels  may  become  passively 
dilated  because  of  the  increased  blood  pressure.  The  arterioles  of  dif- 


THE   ENDOCRINE   ORGANS,    OR   DUCTLESS   GLANDS  775 

ferent  parts  of  the  circulation  are  not  equally  sensitive  to  epinephrine ; 
those  of  the  splanchnic  area  are  most  sensitive,  whereas  those  of  the 
heart — the  coronary  vessels — do  not  respond  at  all  in  most  animals  (see 
page  268).  The  pulmonary  and  cerebral  vessels  have  a  variable  reactivity 
to  epinephrine. 

The  effect  on  the  vessels  persists  after  complete  destruction,  not  only 
of  the  central  nervous  system,  but  also  of  the  vasomotor  nerves;  epi- 
nephrine still  acts,  for  example,  on  vessels  the  nerve  fibers  of  which 
have  been  allowed  to  degenerate  by  cutting  them  several  days  before  the 
epinephrine  is  applied.  This  would  seem  to  indicate  that  the  epinephrine 
acts  directly  on  the  muscular  tissue  in  the  walls  of  the  blood  vessels, 
but  this  does  not  appear  to  be  the  case,  for  it  has  been  found  that  epi- 
nephrine is  incapable  of  acting  on  tissues  which  are  devoid  of  sympathetic 
nerve  fibers,  and  is  also  inactive  on  those  tissues  in  the  embryo  which  have 
not  yet  received  any  nerve  supply.  In  brief,  then,  although  epinephrine 
acts  only  on  blood  vessels  that  are  supplied  by  the  sympathetic  nervous 
system,  it  is  not  on  the  nerve  fibers  that  the  epinephrine  unfolds  its 
action.  We  shall  see  immediately  that  this  conclusion  is  in  conformity 
with  the  results  of  observations  made  on  structures  other  than  the  blood 
vessels. 

Other  muscular  structures  excited  by  epinephrine  are  as  follows: 
(1)  the  dilator  muscle  of  the  pupils,  especially  after  the  nerve  supply  has 
been  destroyed  by  extirpation  of  the  superior  cervical  ganglion;  (2)  the 
sphincters  of  the  pylorus  and  of  the  ileocecal  valve;  (3)  the  muscle  fibers 
of  the  spleen,  the  vagina,  the  uterus,  the  vas  deferens,  and  the  retractor 
penis.  Regarding  the  action  on  the  uterus,  however,  it  should  be  noted 
that  a  different  response  may  be  obtained  according  to  whether  the 
uterus  is  pregnant  or  not.  The  plain  muscles  of  the  orbit  and  globe  of 
the  eye  are  sometimes  excited  by  suprarenal  extract,  causing  the  eyes  to 
protrude,  the  palpebral  fissure  to  become  large  and  the  third  eyelid  to 
be  retracted,  changes  which  are  very  like  those  which  develop  as  a 
result  of  fright. 

Inhibitory  effects  of  epinephrine  on  muscle  are  exhibited  by  the  follow- 
ing: (1)  the  muscle  of  the  intestine;  (2)  the  stomach;  (3)  the  esophagus; 
(4)  the  gall  and  urinary  bladders. 

The  effect  of  epinephrine  in  inhibiting  the  rhythmic  contractions  of 
isolated  portion  of  the  intestine  in  oxygenated  Ringer's  solution  is  a 
rery  striking  phenomenon,  and  one  which,  as  we  shall  see,  may  be  very 
successfully  employed  for  detecting  small  quantities  of  epinephrine. 

The  effects  of  epinephrine  on  glandular  structures  are  the  same  as  those 
rhich  would  be  produced  by  stimulation  of  the  sympathetic  nerve  supply 
of  the  gland.  Thus,  the  secretions  of  the  lachrymal  gland,  the  salivary 


776  THE   ADRENAL   GLANDS 

gland  (in  the  cat),  the  mucous  glands  of  the  mouth  and  pharynx,  the 
gastric  but  not  the  pancreatic  glands,  can  readily  be  shown  to  be 
excited.  In  the  case  of  the  kidney  the  immediate  effect  is  a  diminution 
of  the  urinary  flow,  due  to  constriction  of  the  renal  vessels.  It  has  been 
suggested  by  Cow11  that  one  role  of  the  suprarenal  is  to  act  as  a  regula- 
tor of  the  urinary  excretion.  This  observer  has  demonstrated,  by  ana- 
tomical methods,  direct  vascular  communications  between  the  adrenal 
medulla  and  the  kidney.  That  epinephrine  actually  gains  the  kidney 
by  these  channels  was  shown  by  collecting  and  testing  the  blood  after 
its  circulation  through  them.  Blood  collected,  while  the  gland  was  ex- 
cited reflexly  by  sciatic  stimulation,  exhibited  marked  pressor  action. 
The  work  of  Addis12  and  others  shows  that  the  excretion  of  urea  is  in- 
creased under  the  influence  of  epinephrine  in  certain  dilutions  so  that 
though  the  urine  may  be  diminished  in  quantity,  its  concentration  is 
raised. 

From  these  results  as  a  whole,  it  is  evident  that  the  effect  of  epineph- 
rine on  muscles  and  glands  is  exactly  the  same  as  that  which  would  be 
produced  by  stimulation  of  their  sympathetic  nerve  supply.  This  paral- 
lelism of  action  between  epinephrine  and  the  sympathetic  nervous  sys- 
tem becomes  still  more  evident  when  we  consider  certain  of  the  changes 
in  metabolism  that  follow  administration  of  epinephrine.  Injection  of 
epinephrine  excites  glycogenolysis  in  the  liver  so  that  hyperglycemia 
and  glycosuria  become  established,  results  which  are  also  obtained  by 
stimulating  the  great  splanchnic  nerve.  Intravenous  injection  of  epineph- 
rine causes  the  clotting  time  of  the  blood  discharged  from  the  liver 
to  be  very  materially  shortened,  an  effect  also  produced  by  stimulating 
the  splanchnic  nerve.13 

As  in  the  case  of  the  blood  vessels,  the  above  results  are  obtained  even 
after  the  sympathetic  nerves  to  the  part  have  been  allowed  to  undergo 
degeneration,  from  which  it  is  concluded  that  the  tissues  elaborate  some 
substance  which  reacts  with  epinephrine.  This  substance  may  be  pro- 
duced either  at  the  junction  between  the  nerve  and  muscle — the  myo- 
neural  junction, — or  perhaps  throughout  the  protoplasm  itself.  It  is 
called  the  receptor  substance  of  Langley,  and  is  believed  to  react  not 
only  with  epinephrine,  but  also  with  various  drugs.  The  receptor  sub- 
stance seems  to  increase,  if  not  in  amount,  at  least  in  sensitivity  after 
the  removal  of  the  nerve  control. 

Ergotoxin,  which  is  an  amine  obtained  from  ergot  and  also  from  cer- 
tain of  the  products  of  histidine,  has  an  action  on  the  receptor  substance 
which  is  inhibitory  and  therefore  antagonistic  to  that  of  epinephrine. 

The  antagonistic  action  of  ergotoxin  affects  the  excitatory  but  not 
the  inhibitory  actions  of  epinephrine.  By  using  this  drug  we  are  en- 
abled to  show  that,  although  the  main  effect  of  epinephrine  on  the  tissue  is 


THE   ENDOCRINE   ORGANS,    OR   DUCTLESS   GLANDS  777 

excitatory,  a  less  marked  inhibitory  influence  may  be  simultaneously 
developed.  The  inhibitory  effect  may  also  sometimes  be  evoked  by 
doses  of  epinephrine  very  much  smaller  than  those  used  to  produce 
excitatory  effects.  These  facts  are  well  illustrated  in  the  case  of  the 
muscle  fiber  of  the  blood  vessels.  With  an  ordinary  dose  of  epinephrine 
constriction  occurs;  after  ergotoxin  the  same  dose  of  epinephrine  causes 
dilatation.  This  latter  result  may  also  be  obtained  by  administer- 
ing to  a  normal  animal  quantities  of  epinephrine  that  are  very  much 
smaller  than  the  usual  quantity.  The  coexistence  of  inhibitory  and  ex- 
citatory influence  is  also  well  noted  in  the  case  of  the  uterus.  In  some 
animals  the  effect  of  epinephrine  on  this  organ  is  to  augment  its  rhythmic 
contractions,  in  others  to  inhibit  them.  In  the  former  case,  however,  if 
ergotoxin  is  first  of  all  administered,  epinephrine  in  its  usual  dosage  will 
invariably  produce  an  inhibitory  effect.  The  ergotoxin  no  doubt  acts  on 
the  receptor  substance,  and  similar  effects  have  also  been  produced  with 
apocodeine. 

It  was  first  noted  by  Moore  and  Purinton14  that  the  usual  rise  of  blood 
pressure  which  followed  the  injection  of  epinephrine  was  replaced  by 
a  depressor  effect  when  the  dose  was  very  small.  Later  it  was  shown  that 
this  was  not  an  isolated  instance  of  a  reversed  action  of  epinephrine 
when  employed  in  high  dilutions;  the  intestinal  tone  is  augmented  by 
minute  doses  (1  part  in  500  million  or  more  according  to  Hoskins)15  aiid 
the  contractions  of  the  pregnant  uterus  inhibited. 

The  nature  of  the  vasomotor  effects  differs  not  only  in  accordance  with 
the  dosage,  but  it  is  of  dissimilar  sign  in  different  vascular  areas,  though 
the  dilution  of  the  drug  be  kept  constant.  Hartman16  has  shown  that 
epinephrine  in  high  dilution  causes  dilatation  of  the  peripheral  vessels 
simultaneously  with  vasoconstriction  in  the  splanchnic  area.  These  con- 
clusions were  drawn  from  blood  pressure  records  taken  in  two  series  of 
experiments  in  which  the  splanchnic  and  the  peripheral  vessels,  respec- 
tively, were  excluded  from  the  circulation.  In  the  former  series  a  fall 
in  pressure  was  effected,  in  the  latter  a  pressor  response  was  obtained. 
Hoskins,  Gunning  and  Berry17  went  further  and  found,  by  means  of 
plethysmographic  records,  that  all  the  vessels  of  the  peripheral  circula- 
tion did  not  respond  alike  to  a  given  dose,  those  of  the  muscles  being 
dilated,  while  those  of  the  skin  were  constricted  with  high  dilutions. 
The  variations  in  limb  volume  and  of  blood  pressure  would  then  depend 
upon  which  of  these  effects  predominated  at  the  time.  Neither  are  all 
parts  of  the  splanchnic  area  affected  similarly,  for,  though  the  spleen 
and  kidney  both  show  vasoconstriction  with  all  dilutions,  the  intestinal 
vessels  are  constricted  by  small  doses,  but  dilated  by  large.  (Hartman). 
The  vasodilator  responses  to  epinephrine  are  not,  as  is  the  case  with  the 
constrictor  effects,  mediated  by  the  myoneural  junction.  The  vasodilator 


778  THE   ADRENAL   GLANDS 

mechanisms  for  the  intestine  are  located  in  the  sympathetic  ganglia,  those 
for  the  limbs  are  contained  in  the  sympathetic  as  well  as  the  posterior 
root  ganglia.  These  mechanisms  are  of  comparatively  late  development; 
in  newborn  mammals  (with  the  exception  of  rodents)  administration  of 
epinephrine  in  all  dilutions  produces  universal  vasoconstriction,  and  it  is 
not  until  the  animal  is  several  weeks  old  that  dilator  effects  can  be  ob- 
tained, peripheral  dilatation  is  the  first  to  appear,  somewhat  later  dila- 
tation of  the  intestinal  vessels  may  be  elicited. 

Although  it  is  especially  on  plain  muscular  fiber  having  a  sympathetic 
nerve  supply  that  epinephrine  unfolds  its  action,  yet,  according  to  Can- 
non, Gruber,18  and  others,  it  increases  the  contracting  power  of  volun- 
tary muscle  and  diminishes  the  tendency  to  fatigue. 


CHAPTER  LXXXV 
THE  ADRENAL  GLANDS   (Cont'd) 

Variations  in  Physiological  Activity 

Since  it  is  clearly  established  that  the  adrenal  glands  are  indispensable 
to  life  and  that  extracts  of  them  have  a  very  pronounced  physiological  ac- 
tion, it  remains  to  consider  whether  the  glands  produce  this  internal  secre- 
tion within  the  body,  and  if  so,  whether  it  is  essential  for  the  well-being 
of  the  animal  or  is  required  only  under  certain  conditions.  We  must  also 
endeavor  to  find  out  upon  which  of  the  bodily  functions  of  the  intact 
animal  the  internal  secretion  acts.  These  problems  have  been  attacked 
by  three  methods  of  investigation:  (1)  by  comparing  the  epinephrine 
content  of  similarly  prepared  extracts  of  the  resting  gland  and  of  one 
removed  after  a  period  of  supposed  increased  activity;  (2)  by  collecting 
the  blood  as  it  flows  into  the  vena  cava  from  the  adrenal  vein  and  ex- 
imining  it  for  epinephrine  by  physiological  tests.  These  consist  in  observ- 
ing the  behavior  of  some  tissue  that  is  sensitive  to  the  action  of  epineph- 
rine, such  as  the  intestine  or  uterus,  after  applying  the  blood  or  serum 
to  it,  or  by  injecting  the  blood  or  serum  intravenously  into  another  ani- 
mal and  looking  for  epinephrine  effects;  and  (3)  by  allowing  the  blood 
of  the  adrenal  vein  to  be  discharged  under  certain  conditions  through 
the  vena  cava  into  the  blood  vessels  of  the  same  animal,  and  observing 
the  effect  produced  on  certain  physiological  processes  which  in  one  way 
>r  another  have  been  sensitized  toward  the  influence  of  epinephrine. 
s  autoinjection  method  has  recently  been  used  successfully  by  Stew- 
art and  Rogoff,19  their  favorite  structure  upon  which  to  observe  the 
epinephrine  effect  being  the  denervated  pupil. 

Assaying  the  Epinephrine  Content  of  the  Gland 

With  regard  to  the  first  mentioned  of  the  methods,  either  chemical  or 
physiological  means  may  be  employed  to  assay  the  strength  of  the  ex- 
tracts. The  best  chemical  method  is  that  of  Cannon,  Folin  and  Denis,10 
the  principle  of  which  has  already  been  described.  The  physiological 
method  yielding  most  satisfactory  results  is  that  of  Elliott,20  which  con- 
sists in  injecting  a  portion  of  the  extract  intravenously  into  animals 
from  which  the  influence  of  the  nerve  centers  on  the  heart  and  blood 
vessels  has  been  removed  by  decapitation.  The  rise  in  arterial  blood 

779 


780  THE   ENDOCRINE   ORGANS,    OR   DUCTLESS   GLANDS 

pressure  produced  by  the  injection  is  then  a  very  fair  measure  of  the 
amount  of  epinephrine  contained  in  it.  It  has  been  shown  that  the  re- 
sults obtained  by  the  chemical  method  agree  very  closely  with  those  obtained 
by  the  physiological,  but  it  should  be  remarked  that  it  is  difficult  to  see  how 
the  physiological  method  could  be  accurate  in  all  cases,  since  it  has  been 
shown  that  with  great  dilution  of  epinephrine  a  reversed  effect — a  vaso- 
dilatation — may  be  obtained.  Attempts  to  assay  the  strength  of  an 
epinephrine  solution  by  investigating  the  effects  which  it  produces  on 
other  preparations,  such  as  isolated  loops  of  intestine  or  uterus,  or  the 
enucleated  eyeball  of  the  frog,  are  not  always  successful,  since  the  effects 
are  not  alone  dependent  on  the  concentration  of  epinephrine  in  the 
extract.  When  such  preparations  are  used  for  quantitative  purposes, 
the  strength  of  the  extract  may  be  judged  by  finding  the  extent  to  which 
it  can  be  diluted  and  still  remain  active. 

Quite  apart  from  the  foregoing  possible  sources  of  error,  it  must  be 
remembered  that  the  results  merely  give  us  an  idea  of  how  much  epineph- 
rine may  have  been  contained  in  the  gland  at  the  time  of  its  excision. 
They  can  not  tell  us  how  much  epinephrine  the  gland  was  secreting.  Prior 
to  excision  as  much  of  this  hormone  might  have  been  undergoing  a  process 
of  manufacture  in  the  gland  as  was  being  discharged  from  it,  so  that  the 
assayed  amount  would  represent  merely  the  balance  of  production  and  loss 
of  hormone  by  the  gland.  We  might  quite  well  find  that  the  amount  of 
epinephrine  in  the  excised  gland  was  normal  under  conditions  where 
there  had  been  an  excessive  discharge  of  it  into  the  blood;  that  is  to  say, 
loss  and  production  might  have  been  equal.  Where,  however,  a  marked 
deficiency  was  found  to  exist,  it  would  probably  indicate  that  exhaustion 
of  the  power  of  producing  epinephrine  was  taking  place. 

The  Epinephrine  Content  of  the  Blood, — The  second  method,  in  which 
blood  from  one  animal  is  tested  for  its  epinephrine  effect  by  intravenous 
injection  into  another  animal  or  by  applying  it  to  some  isolated  prepara- 
tion on  which  epinephrine  acts,  has  yielded  important  results.  Since 
serum  contains  all  the  epinephrine  of  blood,  it  can  be  conveniently  used 
for  the  tests  (Stewart  and  Eogoff).  The  isolated  physiological  prepara- 
tions that  have  been  used  in  testing  for  epinephrine  in  the  animal  fluids 
are  as  follows: 

1.  A  segment  of  the  small  intestine  of  a  rabbit,  suspended  in  oxygen- 
ated Locke's  solution  at  body  temperature. 

2.  A  segment  of  the  uterus  of  a  nonpregnant  rabbit  similarly  prepared. 

The  apparatus  used  for  observing  the  contractions  of  either  prepara- 
tion consists  of  a  small  glass  chamber  furnished  below  with  a  hook  to 
which  one  end  of  the  segment  is  attached,  the  other  end  being  connected 
.to  a  muscle  lever,  so  that  the  regular  rhythmic  contractions  can  be  regis- 
tered on  a  drum  (Fig.  192). 


THE   ADRENAL    GLANDS 


781 


Epinephrine  inhibits  the  contractions  of  the  intestine  but  stimulates 
those  of  the  uterus  of  most  animals,  the  intestine  preparation  being  the 
more  sensitive  (Fig.  193).  Indeed,  it  is  said  that  the  inhibition  in  this 
case  may  be  obtained  with  a  solution  containing  1  part  of  epinephrine  in 
20,000,000  of  solution.  In  using  this  method,  however,  great  care  and 
judgment  must  be  exercised  in  drawing  conclusions,  because  other  sub- 
stances present  in  the  blood  are  liable  to  affect  the  contractions;  thus, 
certain  substances  in  blood  serum  which  have  been  produced  by  the  act 
of  blood  clotting  may  cause  augmentation  of  the  beat  in  both  the  intes- 


Alr  vent 


Mete/  waterbath 

38'c. 

Harvard  muscle 
armer  with 
aduated  scale 


Fig.  192. — Arrangement  of  apparatus  for  recording  contractions  of  a  uterine  strip,  intestinal 
strip,  or  ring,  etc.  The  metal  water-bath  is  made  of  a  cheap  metal  water-pail  with  a  heating  rod 
soldered  through  the  side  at  the  bottom.  A  short  metal  tube  is  soldered  into  a  1-inch  opening  in 
the  bottom  to  receive  a  perforated  cork  for  connecting  with  the  Harvard  muscle-warmer  inside. 
(From  Jackson.) 

I 


tinal  and  the  uterine  preparations.  A  certain  amount  of  epinephrine  in 
Locke's  solution  is  consequently  more  likely  to  cause  inhibition  of  the 
intestine  than  a  similar  amount  added  to  blood  serum,  because  in  the  lat- 
ter case  the  pressor  substance  will  neutralize  the  depressor  effect  of  the 
epinephrine.  On  the  uterine  preparation,  both  the  blood  serum  and  the 
epinephrine  have  pressor  effects.  As  has  been  pointed  out  by  G.  N. 
Stewart,21  if  both  preparations  are  employed  for  testing  a  solution  sup- 
posed to  contain  epinephrine,  little  chance  of  error  is  likely  to  be  in- 


782 


THE   ENDOCRINE    ORGANS,    OR    DUCTLESS    GLANDS 


curred ;  that  is,  if  the  solution  produces  inhibition  of  the  intestine  along 
with  augmentation  of  the  uterus,  it  must  contain  epiiiephrine. 

3'.  The  fresh  carotid  artery  of  the  sheep.  A  ring  cut  from  the  artery 
is  suspended  in  oxygenated  Locke's  solution  and  attached  below  to  a 
small  hook  and  above  to  a  loaded  muscle  lever,  by  which  the  contraction 


Fig.  193. — Tracing  showing  the  effect  of  epinephrine  on  the  intestinal  contractions  and  on  the 
arterial  blood  pressure.  (The  preliminary  addition  of  barium  to  the  nutritive  fluid  may  be  disre- 
garded.) (From  Jackson.) 

of  the  muscle  fibers  can  be  magnified.  Epinephrine  causes  the  muscle  to 
contract,  but  the  test  is  not  so  sensitive  as  the  foregoing,  especially  in 
the  presence  of  blood  serum,  because  the  pressor  substances  therein  con- 
tained also  cause  contraction.  Blood  plasma  does  not  contain  the  pres- 
sor substances,  so  that  oxalated  plasma  should  be  used  in  place  of  serum 


THE    ADRENAL    GLANDS 


783 


in  applying  the  test.     To  increase  the  sensitiveness  of  the  muscle,  the 
artery  ring  should  be  slightly  stretched  by  loading  the  lever. 
4.  The  blood  vessels  of  a  frog.    This  method  depends  on  the  same  prin- 


Funnel,  or 
ll  pressure 
boHle 


Hook  through 
lower  jaw 

Cannula  In 
one  aorta 


Fig.    194. — Arrangement    of    apparatus    for    perfusion    of    the    vessels    of    a  -brainless    frog.      (From 

Jackson.) 

ciple  as  in  that  just  described.  The  fluid  supposed  to  contain  epinephrine 
is  added  to  Locke's  solution,  which  is  meanwhile  being  perfused  under 
constant  pressure  through  the  blood  vessels  and  the  rate  of  outflow 


784  THE   ENDOCRINE    ORGANS,    OR    DUCTLESS    GLANDS 

noted  (Fig.  194).  If  the  fluid  added  to  the  inflowing  fluid  contains  epi- 
nephrine, the  outflow  will  become  diminished.  This  is  a  very  satisfactory 
method,  although  it  is  somewhat  limited  in  scope  unless  large  frogs  are 
procurable,  because  of  the  difficulty  of  getting  the  necessary  cannulae 
into  the  vessels  (aorta  and  abdominal  vein). 

5.  The  pupil  of  the  enucleated  eye  of  the  frog.    Extremely  small  traces 
of  epinephrine  are  observed  to  cause  a  dilatation. 

6.  The  denervated  iris.    The  fluid  to  be  tested  is  placed  in  the  conjunc- 
tival  sac  of  an  animal  from  which  the  superior  cervical  ganglion  of  the 
corresponding  side  has  been  removed  some  days  previously.    Under  such 
conditions,  if  epinephrine  is  present  in  the  fluid,  dilatation  of  the  pupil 
occurs.    Both  of  the  preceding  methods  we  owe  to  Meltzer.22 

It  should  be  emphasized  that,  although  each  of  these  methods  is  in 
itself  very  sensitive  for  the  detection  of  epinephrine  without  being  al- 
ways specific,  yet  the  result  should  not  be  considered  conclusive  unless 
definite  effects  have  been  secured  by  at  least  two  methods  that  are  as 
far  as  possible  independent  of  each  other. 

As  an  outcome  of  investigations  by  these  methods  it  has  been  found  that 
when  blood  was  taken  from  the  inferior  vena  cava  at  the  level  of  the  adrenal 
veins,  i.  e.,  blood  with  a  relatively  high  concentration  of  adrenal  secretion, 
the  presence  of  epinephrine  could  be  revealed  after  splanchnic  stimulation 
or  massage  of  the  glands.  Such  methods  which  depend  upon  the  removal 
from  the  animal  of  the  blood  to  be  tested,  are  open  to  the  objection  that  the 
blood  so  obtained  may  become  altered  in  the  process  of  shedding  or  defib- 
rination.  As  a  matter  of  fact  it  has  been  shown  that  shed  blood,  very  rap- 
idly develops  vasoconstrictor  substances.  On  this  account  conclusions  re- 
garding epinephrine  content,  based  upon  the  behavior  of  such  samples,  are 
not  wholly  reliable.  The  method  about  to  be  described  is  preferable. 

The  Autoinjection  Method. — Such  a  method  was  first  of  all  success- 
fully used  by  Asher,  who  employed  an  animal  from  which  all  the  abdom- 
inal viscera  had  been  removed.  On  stimulation  of  the  great  splanchnic 
nerve  a  rise  in  arterial  blood  pressure  occurred  provided  the  adrenal 
veins  were  open,  but  not  so  if  the  adrenal  veins  were  clamped.  By  re- 
moving the  viscera,  the  effect  of  splanchnic  stimulation  on  the  abdom- 
inal blood  vessels  themselves  is  eliminated,  and  any  constriction  which 
occurs  in  the  blood  vessels  of  the  rest  of  the  body  must  obviously  be  due 
to  the  action  of  epinephrine. 

The  most  satisfactory  modification  of  this  method  is  that  employed  more 
recently  by  Stewart,  Kogoff  and  Gibson.23  Blood  from  the  adrenals  was  col- 
lected in  a  pocket  of  the  inferior  vena  cava,  which  was  made  by  applying 
clamps  to  this  vein  above  and  below  the  level  of  the  adrenal  veins.  An 
animal  in  which  the  iris  had  been  sensitized  towards  the  action  of  epineph- 
rine by  prior  removal  of  the  superior  cervical  ganglion  was  employed 


THE   ADRENAL    GLANDS  785 

(page  784).  It  was  found  that  after  the  pocket  had  been  allowed  to  fill 
with  blood  removal  of  the  upper  clamp  caused  the  pupil  to  dilate.  Fur- 
thermore, the  latent  period  of  the  response  coincided  with  the  time  which 
the  wave  of  concentrated  blood  was  calculated  to  take  in  traveling  from 
the  pocket  to  the  eye.  This  reaction  time,  consequently,  varied  inversely 
with  the  rate  of  blood  flow.  Stimulation  of  the  splanchnics  or  massage  of 
the  gland  was  without  effect  upon  the  pupil  so  long  as  the  upper  clamp 
remained  in  position,  but  the  usual  response  ensued  when  the  clamp  was 
removed.* 

When  the  adrenals  were  not  artificially  excited  in  any  way  the  con- 
tents of  the  pocket,  after  removal  of  the  upper  clamp  produced  the  char- 
acteristic reaction  upon  the  pupil,  thus  demonstrating  the  spontaneous 
liberation  of  epinephrine  from  the  glands.  The  capacity  of  the  pocket, 
together  with  its  time  of  filling,  having  been  determined,  the  rate  of 
flow  through  the  adrenal  veins  was  readily  arrived  at.  The  degree  of 
concentration  of  the  pocketed  blood  was  determined  indirectly  by  noting 
the  precise  extent  of  the  pupillary  response  following  the  removal  of 
the  upper  clamp,  and  subsequently  reproducing  this  reaction  by  the  intra- 
venous injection  of  an  equal  quantity  of  epinephrine  solution  of  known 
concentration.  It  is  clear  that  the  product  of  the  rate  of  blood-flow 
through  the  veins  and  the  degree  of  concentration  in  epinephrine  of  the 
blood  in  the  pocket  will  give  the  amount  of  epinephrine  liberated  from  the 
glands  in  a  given  time.  This  was  found  to  vary  between  .0003  and  .001 
mg.  per  kilo  of  body  weight  per  minute. 

The  splanchnic  fibers  concerned  in  the  secretion  of  epinephrine  seem 
to  come  from  a  nerve  center  situated  relatively  low  down  in  the  spinal 
cord.  Section  of  the  cord  at  the  level  of  the  last  cervical  segment  does 
not  affect  the  spontaneous  secretion,  but  this  disappears  when  the  sec- 
tion is  made  below  the  third  thoracic  segment.  (Stewart  and  Rogoff). 

In  connection  with  these  observations  it  is  of  interest  to  note  that 
during  stimulation  of  the  splanchnic  nerve  in  a  normal  animal,  the  conse- 
quent rise  in  blood  pressure  shows  two  peaks  (see  Fig.  29,  p.  137).  The 
first  is  no  doubt  due  to  direct  stimulation  of  the  splanchnic  vasoconstric- 
tors, and  the  second  to  the  outpouring  of  epinephrine  into  the  blood,  the 
justification  for  this  conclusion  being  that  the  latter  rise  fails  to  appear 
after  removal  of  the  adrenal  glands.  In  many  cases  a  well-marked 
"dip"  is  seen  between  the  two  rises.  This  is  explained  as  being  due  to 
initial  minute  amounts  of  epinephrine  passing  into  the  blood  streamf  (see 
page  777). 

*It  does  not  seem  to  be  possible  to  exhaust  the  adrenal  gland  of  its  supply  of  active  material 
by  _  stimulating  the  splanchnic — a  fact  which  would  seem  to  throw  considerable  doubt  on  the  relia- 
bility of  the  conclusions  arrived  at  by  the  use  of  those  methods  in  which  extracts  of  the  gland  are 
assayed  (see  page  779). 

tA  great  part  of  the  work  done  by  clinical  observers  purporting  to  show  that  in  such  conditions 
as  nephritis  and  arteriosclerosis  there  is  an  increase  of  epinephrine  in  the  blood,  has  been  found 
by  Stewart  and  Rogoff  to  be  unproved. 


THE   ENDOCRINE   ORGANS,    OR   DUCTLESS   GLANDS 


That  epinephrine  is  being  constantly  liberated  in  certain  minute 
amounts  is  probably  true,  but  whether  this  amount  is  a  factor  in  the 
maintenance  of  normal  arterial  tone,  or  is  concerned  in  lowering  the 
resistance  of  the  sympathetic  endings,  is  another  question.  Experimental 
investigation  does  not  sustain  the  so-called  "tonus"  hypothesis.  In  the 
first  place,  in  the  experiments  already  cited  (page  785),  the  amount  of 
epinephrine  secreted  spontaneously  would  be,  when  diluted  with  the  mass 
of  blood  of  the  entire  circulation,  quite  inadequate  to  have  any  effect 
upon  blood  pressure;  in  the  second  place  if  any  effect  upon  the  vessels 
did  occur  with  these  minute  doses  it  would  be  one  not  of  constriction 
but  of  dilatation,  on  many  vessels  at  least  (page  777).  No  effects  were 
observed  on  the  general  health  or  the  blood  pressure  of  animals  in 
which  the  adrenal  of  one  side  was  removed,  and  the  nerve  control  of  the 
opposite  gland  severed,  although  under  the  conditions  it  is  evident 
that  very  little  epinephrine  could  have  been  present  in  the  blood  (not 
more  than  1  part  in  400  million  parts  of  blood).  Experiments  performed 
by  Vincent  and  others  gave  similar  results.  Hoskins  and  McClure24  at- 
tacked the  problem  in  a  different  way,  but  arrived  at  a  like  conclusion. 
They  found  that  the  amount  of  injected  epinephrine  necessary  for  the  pro- 
duction of  a  certain  predetermined  response  was,  after  adrenalectomy, 
but  slightly  in  excess  of  that  required  to  be  injected  into  the  same  ani- 
mal with  intact  glands.  This  excess,  which  represented  the  tonic  secre- 
tion of  the  glands,  was  far  below  the  threshold  for  vasoconstrictor  stim- 
ulation. Finally,  epinephrine  is  not  present  in  the  sera  of  patients  suf- 
fering from  vascular  hypertonus  in  sufficient  concentration  to  be  detected 
by  any  of  the  biological  tests  at  our  disposal.  (Stewart.)25 

Since  the  "tonus"  hypothesis  of  the  adrenal  function  is  untenable, 
another,  or  emergency  hypothesis  has  been  brought  forward.  According 
to  this,  epinephrine  is  considered  to  be  secreted  into  the  blood  in  super- 
normal amounts  when  certain  emergencies  arise,  such  as  asphyxia  or  con- 
ditions of  extreme  emotion  such  as  fright  or  anger.  An  experimental  hy- 
persecretion  of  an  analogous  character  is  also  said  to  occur  during  stimu- 
lation of  the  central  end  of  large  sensory  nerves  such  as  the  sciatic. 
The  chief  exponent  of  this  hypothesis  is  Cannon,26  and  he  has  supported 
it  by  a  seemingly  incontrovertible  mass  of  experimental  evidence.  In  the 
earlier  researches  which  appeared  in  1911  the  blood  was  removed  from  the 
vena  cava  opposite  the  openings  of  the  adrenal  veins,  by  pushing  a  cath- 
eter up  to  this  level  through  a  slit  in  the  femoral  vein,  and  blood  was 
tested  for  the  presence  of  epinephrine  by  observing  its  effect  on  the 
beating  of  an  isolated  strip  of  intestine.  It  was  found  that  whereas  the 
blood  of  a  normal  male  cat  did  not  give  evidence  of  the  presence  of  epine- 
phrine, it  did  so  in  a  cat  that  had  previously  been  frightened  by  allowing  a 
to  bark  at  it.  Such  results  were  not  obtained  after  the  removal  of  the 


THE    ADRENAL   GLANDS  787 

adrenal  glands,  or  in  a  female  cat,  which  is  usually  indifferent  to  such  a 
method  of  frightening.  Cannon  also  thinks  that  many  of  the  other  adap- 
tations which  take  place  in  an  animal  in  this  condition  are  associated  with 
the  presence  of  an  excess  of  epinephrine  in  the  blood.  The  three  most  im- 
portant of  these  are:  (1)  increased  discharge  of  sugar  from  the  liver 
into  the  blood;  (2)  increased  efficiency  of  muscular  contraction;  (3)  di- 
minished clotting  time  of  the  blood — all  of  which  are  adaptations  ena- 
bling the  animal  either  to  conquer  the  source  of  the  fear  or  to  be  in  a 
better  position  to  recover  from  any  bodily  injury,  which  he  might  suffer, 
involving  a  loss  of  blood. 

It  has  been  pointed  out  by  Stewart  and  Rogoff,27  however,  that  there 
are  several  serious  sources  of  error  in  the  methods  adopted  by  Cannon 
in  the  earlier  investigations,  particularly  the  uncertainty  as  to  the  ex- 
act source  of  the  blood  collected  through  the  catheter,  the  chances  for 
pressor  substances  developing  in  the  shed  blood,  the  unreliability  of  using 
only  one  test  object  for  the  detection  of  epinephrine  in  blood,  (page 
784)  and  the  unknown  rate  of  blood  flow  through  the  adrenal  glands 
during  the  removal  of  the  blood.  These  authors,  as  a  matter  of  fact  have 
not  been  able  to  secure  any  results  which  would  confirm  Cannon's  con- 
clusions, either  by  repetition  of  the  catheter  method  employed  by  this 
worker,  or  in  other  observations  in  which  blood  was  collected  from  a 
pocket  of  vena  cava  (page  784)  or  in  which  the  pupillary  reaction  was 
employed.  Neither  could  Stewart28  and  Rogoff  obtain  any  evidence  that 
an  increased  secretion  of  epinephrine  bears  any  relationship  to  the  hyper- 
glycemia  that  is  induced  by  ether  or  by  asphyxia  or  by  piqure  (page  705). 
They  did  not  find  that  animals  in  which  the  adrenal  had  been  excised  on 
one  side  and  the  nerve  supply  of  the  remaining  gland  cut,  responded  to 
emotional  conditions  in  any  way  differing  from  normal  animals. 

These  criticisms  have  prompted  Cannon29  to  repeat  his  earlier  observa- 
tions by  the  use  of  a  method  which  would  not  entail  the  removal  of  blood, 
that  is,  by  an  autoinjection  method.  He  chose  as  the  test  object  for  ex- 
cess of  epinephrine  in  the  blood,  a  denervated  heart  which  Levy,30  Gas- 
ser31  and  Meek  had  shown  to  respond  by  a  quickened  beat  to  extremely 
small  concentrations  (for  example  0.007  mgm.  per  kg.  of  "adrenalin"  in- 
jected intravenously  per  minute  increases  the  heart  rate  by  as  much  as  28 
beats  per  minute).  The  denervation  of  the  heart  was  effected  by  section 
of  the  vagi  and  removal  of  the  stellate  ganglia,  and  in  such  animals  it  was 
found  that  stimulation  of  the  sciatic  nerve,  asphyxia  and  emotional  states 
caused  decided  acceleration.  It  would  be  rash  to  venture  a  final  verdict 
at  the  present  stage  of  this  most  interesting  controversy,  but  it  appears 
to  the  author  that  Cannon's  evidence  is  very  strong,  provided  it  can 
be  proved  that  the  heart  is  really  thoroughly  denervated  and  that  sub- 


788  THE   ENDOCRINE   ORGANS,    OR   DUCTLESS   GLANDS 

stances  in  the  blood  other  than  epinephrine  may  not  be  responsible  for 
the  cardiac  changes. 

Of  interest  with  regard  to  the  action  of  epinephrine  as  part  of  a  pro- 
tective  mechanism,  is  the  fact  that  the  contractile  pigment  cells  pos- 
sessed by  certain  types  of  lizards  and  whereby  the  hue  of  these  creatures 
is  varied  in  accordance  with  the  shade  of  the  surroundings,  are  stimu- 
lated by  epinephrine ;  the  latter  contracts  such  cells,  and  nervous  excite- 
ment in  these  animals  has  a  similar  influence  (Redfield32).  It  is  scarcely 
necessary  to  point  out  that,  until  it  is  definitely  established  by  experi- 
mental investigation  that  epinephrine  may  be  discharged  in  excessive 
amounts  under  certain  conditions,  it  is  irrational  to  assume  that  such  may 
occur  in  disease.  The  surgical  removal  of  the  adrenal  gland  is  certainly  not 
warranted  under  any  circumstances. 

The  Association  of  the  Adrenal  with  Other  Endocrine  Organs 

We  have  at  present  very  little  accurate  and  reliable  information  on  the 
association  of  the  adrenal  with  other  endocrine  organs.  That  epinephrine 
has  an  influence  on  many  diverse  organs  and  glands  is  an  undoubted 
fact,  but  this  is  more  probably  to  be  attributed  to  an  activating  influence 
on  sympathetic  nerve  endings  than  to  any  specific  relationship  between 
the  adrenal  glands  and  the  particular  gland  in  question.  The  most  impor- 
tant of  the  results  that  have  been  obtained  are  the  following : 

1.  With  the  Thyroid  and  Parathyroid. — Cannon  and  Cattell,  after  con- 
firming Bradford's  discovery  that  an  electric  current  of  action  is  set  up  in 
the  salivary  gland  when  it  is  excited  to  activity,  proceeded  to  investigate 
the  occurrence  of  such  a  current  in  the  thyroid  gland.33  By  placing  one 
nonpolarizable  electrode  on  the  gland  itself  and  the  other  on  the  neigh- 
boring subcutaneous  tissues  or  on  the  trachea,  a  current  was  found  to  be 
set  up  by  stimulation  of  the  sympathetic  nerve  supply  of  the  thyroid,  by 
intravenous  injection  of  epinephrine,  or  by  stimulation  of  the  great 
splanchnic  nerve  before  it  reaches  the  adrenal  gland.  This  last  result, 
which  is  the  most  important  in  the  present  connection,  was,  however,  not 
observed  when  the  blood  of  the  inferior  vena  cava  was  prevented  by  the 
application  of  a  clamp  from  getting  to  the  heart,  but  immediately  ap- 
peared, after  stimulation,  when  the  clamp  was  removed.  This  experiment 
taken  alone  does  not,  however,  justify  the  conclusion  that  there  is  any 
direct  relationship  between  the  adrenal  glands  and  the  thyroid,  because 
there  are  in  the  thyroid  gland  structures  such  as  the  muscle  fibers  in  the 
blood  vessels,  which  a  hypersecretion  of  epinephrine  might  affect.  Before 
any  direct  relationship  between  the  two  glands  could  be  claimed  to  exist, 
it  would  be  necessary  to  show  that  the  thyroid  action  current  is  obtained 
with  a  concentration  of  epinephrine  in  the  blood  lower  than  that  affecting 
the  blood  vessels. 


THE   ADRENAL   GLANDS  789 

2.  With  the  Sexual  Glands. — As  mentioned  above   (page  768),  a  very 
direct  relationship  exists  between  the  development  of  the  sexual  glands 
and  that  of  the  suprarenals,  particularly  the  cortex  of  the  glands.    In  ad- 
dition to  the  evidence  already  furnished,  it  may  be  mentioned  that,  in  hyper- 
plasia  of  the  adrenals  changes  occur  in  the  testicles,  particularly  in  their 
interstitial  cells. 

3.  With  the  Liver. — Of  the  many  functions  of  this  gland  that  which  is 
most  directly  associated  with  epinephrine  is  the  production  of  glucose 
from  glycogen — the  glycogenolytic  process  (see  page  701).     The  injection 
of  epinephrine  causes  an  immediate  discharge  of  such  an  excess  of  glucose 
into  the  blood  that  hyperglycemia  and  glycosuria  immediately  follow. 
This  result  is  most  striking  when  the  injection  is  made  in  glyco gen-rich 
animals.    In  animals  from  which  all  the  glycogen  of  the  liver  has  been 
removed  by  starvation,  the  injection  of  large  amounts  of  epinephrine 
causes  glycogen  to  accumulate  in  the  -liver  cells — a  result  which  it  is 
difficult  to  interpret. 

In  the  light  of  the  fact  that  stimulation  of  the  great  splanchnic  nerve 
causes  a  demonstrable  increase  of  epinephrine  in  the  blood,  a  natural  con- 
clusion is  that  the  glycosuria  and  hyperglycemia  which  are  known  to  re- 
sult from  stimulation  of  the  splanchnic  nerve  or  of  its  center  in  the 
medulla,  must  be  dependent  upon  a  hypersecretion  of  epinephrine. 
Evidence  supporting  this  hypothesis  seemed  to  be  furnished  by  the  obser- 
vation that,  after  the  removal  of  the  adrenal  glands,  stimulation  of  the 
splanchnic  or  of  the  so-called  "diabetic"  center  in  the  fourth  ventricle 
no  longer  produced  glycosuria  even  in  a  glycogen-rich  animal.  But  it  is 
difficult  to  see  how  such  an  important  physiological  process  as  that  of  the 
nerve  control  of  the  production  of  sugar  by  the  liver  should  be  dependent 
on  the  hypersecretion  of  the  adrenal  gland,  especially  since  the  epineph- 
rine would  have  to  be  carried  by  the  blood  around  a  considerable  part  of 
the  circulation  before  it  arrived  at  the  place  on  which  it  was  to  act.  More- 
over, it  has  been  shown  that  stimulation  of  the  previously  cut  hepatic 
nerve  plexus  (around  the  hepatic  pedicle)  in  a  normal  animal  produces 
hyperglycogenolysis,  in  which  case  there  can  be  no  question  of  a  hyper- 
secretion  of  epinephrine. 

No  doubt  the  adrenal  glands  have  some  important  relationship  to  the 
nerve  control  of  the  glycogenolytic  process,  for,  in  animals  from  which  the 
adrenal  glands  have  been  removed,  stimulation  of  the  hepatic  plexus  does 
not  produce  hyperglycemia.  From  this  result  it  would  appear  that  the 
presence  of  a  certain  amount  of  epinephrine  in  the  blood  i&  necessary  for 
the  proper  transmission  of  the  nerve  impulse  from  the  sympathetic  nerve 
fibers  to  the  liver  cell.  When  the  nervous  system  is  stimulated  in  such 
a  way  as  to  excite  the  glycogenolytic  process,  two  effects  both  operat- 


790  THE    ENDOCRINE    ORGANS,    OR    DUCTLESS    GLANDS 

ing  in  the  same  direction  with  regard  to  the  glycogenic  function  are 
developed:  the  one,  a  hypersecretion  of  epinephrine,  which  activates 
the  sympathetic  nerve  endings,  the  other,  the  transmission  of  the  nerve 
impulse  to  the  liver  cell  (Macleod  and  E.  G.  Pearce).34 

4.  With  the  Pancreas. — The  function  of  the  pancreas  here  concerned 
is  that  of  its  supposed  internal  secretion  from  the  Isles  of  Langerhans. 
Since  epinephrine  readily  produces  glycosuria,  and  since  excision  of 
the  pancreas  has  the  same  effect,  it  has  been  natural  to  inquire  whether 
any  relationship  exists  between  the  two  glands,  and  some  observers 
have  obtained  results  which  they  interpret  as  indicating  that  there  does. 
Certain  observers  even  state  that  glycosuria  does  not  occur  after  the 
injection  if  at  the  same  time  extract  of  pancreas  is  injected.  It  is  al- 
most certain,  however,  that  these  results  are  not  trustworthy.  Thus, 
removal  of  the  adrenal  glands  in  an  animal  suffering  from  pancreatic 
diabetes  does  not  restore  any  of  the  lost  power  of  utilizing  glucose 
during  the  few  hours  that  the  animal  remains  alive.34  That  some  rela- 
tionship may,  however,  exist  is  indicated  by  the  fact  that  epinephrine 
causes  dilatation  of  the  pupil  when  it  is  dropped  into  the  eye  of  a  per- 
son suffering  from  diabetes,  whereas  it  has  no  such  effect  in  the  normal 
individual. 


CHAPTER  LXXXVI 

THE  THYROID  AND  PARATHYROID  GLANDS 
Structural  Relationships 

The  thyroid  and  parathyroid  glands  are  intimately  associated,  anatomically,  in  most 
animals.  The  thyroid  is  present  in  all  the  vertebrates,  but  the  parathyroids  do  not 
occur  below  the  amphibia.  The  thyroid  exists  as  two  lateral  lobes  joined  over  the  trachea 
by  the  so-called  isthmus.  The  parathyroids  are  very  much  smaller,  being  four  in  num- 
ber and  located  in  pairs  on  the  posterior  aspect  of  the  thyroid  lobes.  The  two  upper 
parathyroids  are  usually  more  or  less  embedded  in  the  thyroid  tissue,  where  as  lower  ones 
are  much  more  loosely  attached  to  the  thyroid;  indeed,  in  some  animals,  particularly  the 
herbivora,  they  are  quite  separate  from  it  and  may  be  located  at  a  distance,  as  in  the 
mediastinum.  Accessory  thyroid  and  parathyroid  glands  are  sometimes  present  in  the 
tissues  of  the  neck,  or  in  the  anterior  mediastinum,  accessory  parathyroids  being  common 
in  the  rabbit  and  rat,  and  parathyroid  tissue  being  present  in  the  thymus  in  5  per  cent 
of  dogs  (Marine35).  Before  these  anatomical  relationships  were  thoroughly  worked 
out,  there  was  much  confusion  in  the  interpretation  of  the  results  following  removal  of 
one  or  the  other  gland. 

In  their  histologic  structure  and  embryological  derivation,  the  two  glands  are  very 
different.     The  parathyroids  are  developed  as  an  outgrowth  from  the  third  and  fourth 
branchial  pouches,  and  they  are  composed  of  masses  of  epithelial-like  cells,  sometimes 
more  or  less  divided  up  into  lobules  or  trabeculse  by  bands  of  connective  tissue.     The 
cells  contain  granules,  some  of  which  are  of  a  fatty  nature.     Sometimes  colloid-like  ma- 
terial is  found  between  the  cells,  or  it  may  be  enclosed  in  small  vesicles  not  unlike  those 
of  the  thyroid,  although  usually  considerably  smaller.     The  blood  vessels  are  extremely 
numerous,  and  form  sinus-like  capillaries,  which  come  into  close  relationship  with  the 
epithelial  cells  of  the  glands.     Nerves  also  are  abundant  and  pass  both  to  the  vessels 
and  to  the  secreting  cells.    The  blood  vessels  are  derived  from  the  inferior  thyroid  artery. 
The  thyroid  is  developed  by  immediate  outgrowth  from  the  entoderm  lining  the  floor 
of  the  pharynx,  at  a  level  between  the  first  and  second  branchial  pouches.     ^Represented  at 
first  by  a  solid  column  of  cells,  there  very  soon  occurs  a  division  at  the  lower  end  into 
two  lateral  portions,  and  the  original  solid   column  becomes  hollowed   out.     The  two 
lateral  branches  of  the  original  column  divide  again  and  again  so  as  to  form  a  system  of 
hollow  tubes  lined  with  epithelium.     These  afterward  become  cut  up.  so  as  to  form  the 
closed  vesicles  characteristic  of  the  gland.     Each  vesicle  is  more  or  less  spheroidal  in 
shape,  and  has  no  basement  membrane,  but  its  walls  are  formed  by  a  layer  of  epithelial 
cells,  which  may  be  columnar,  cubical,  or  flattened  in  shape.     Each  vesicle  is  filled  with 
the  so-called  colloid  material,  which  is  peculiar  in  containing  iodine,  and  between  the 
vesicles  is  a  layer  of  connective  tissue  often  containing  small  cells,  some  of  which  are 
not  unlike  those  of  the  parathyroid.     The  connective  tissue  also  contains  the  blood  ves- 
sels, which  are  very  numerous — indeed,  the  thyroid,  in  proportion  to  its  size,  receives 
more  than  five  times  as  much  blood  as  the  kidneys,  the  only  tissue  that  surpasses  it  in 
this  regard  being  the  medulla  of  the  adrenal  gland   (see  page  211).     The  nerves  arise 
from  both  the  vagus  and  the  sympathetic  systems  and  have  been  traced  to  the  secreting 
epithelial  cells.     The  above  description  applies  to  a  strictly  normal  gland. 

791 


792  THE   ENDOCRINE   ORGANS,    OR   DUCTLESS   GLANDS 

THE  THYROID  GLAND 

Condition  of  the  Gland 

In  the  crowded  communities  of  the  Great  Lakes  Basin  of  this  conti- 
nent, it  has  been  found  that  in  most  animals  the  thyroid  gland  is  more  or 
less  abnormal.  In  Cleveland,  for  example,  Marine  has  found  this  to  be 
the  case  in  well  over  90  per  cent  of  the  dogs  brought  to  the  laboratory.36 
The  condition  usually  goes  under  the  name  of  simple  goiter,  which  in- 
cludes all  thyroid  enlargements  except  those  of  exophthalmic  goiter. 
In  man  the  goiter  originates  usually  about  the  age  of  adolescence  and 
more  frequently  in  girls  than  in  boys.  It  may  sometimes  pass  over  into 
the  exophthalmic  type.  The  exact  pathological  changes  in  the  goitrous 
gland  vary  with  the  species  of  animal  and  with  the  duration  of  the  dis- 
ease. In  man,  besides  the  cystic  or  colloid  goiter  an  adenomatous  type 
is  very  common  although  rare  in  other  animals. 

From  the  numerous  observations  that  have  been  made  on  the  glands  of 
domestic  animals,  it  has  been  clearly  established  that  the  very  earliest 
sign  of  goiter  is  a  diminution  in  the  iodine  content  of  the  gland;  fol- 
lowed by  an  increase  in  the  epithelial  cells  and  in  the  blood  supply  and  a 
decrease  in  the  colloid.  Such  hyperplasia  may  be  induced  in  what  re- 
mains after  removal  of  a  large  part  of  a  normal  gland  (compensatory 
hyperplasia),  or  if  a  similar  operation  be  performed  early  in  pregnancy, 
the  young  when  born  will  be  found  to  have  hyperplastic  thyroids.  A 
certain  degree  of  hyperplasia  exists  as  an  accompaniment  of  pregnancy, 
and  it  can  be  produced  in  certain  normal  animals  (particularly  rats)  by 
placing  them  on  an  excessive  meat  diet.  Important  observations  bearing  on 
this  point  have  been  made  by  Marine37  on  brook  trout,  in  which  it  has  been 
found  that  the  so-called  carcinoma  that  develops  when  the  fish  kept  in 
hatcheries  are  fed  with  unsuitable  food  and  overcrowded,  is  really  a 
typical  hyperplasia.  In  its  second  stage  this  develops  into  what  is  known 
as  colloid  goiter  which  is  produced  by  a  deposition  of  colloid  material 
between  the  rows  of  cells  so  as  to  cause  an  opening  out  again  of  the 
vesicles  (Fig.  195),  with  a  consequent  tendency  to  a  reversion  to  the 
normal  histological  structure,  so  far  as  this  is  possible.  The  vesicles  in 
such  a  gland  are  of  enormous  size,  and  the  lining  epithelium,  low  cubical, 
or  almost  flat  in  shape. 

The  outstanding  characteristic  feature  of  the  colloid  material  is  that 
it  contains  iodine,  which  exists  in  combination  with  a  nonprotein  nitrog- 
enous base,  and  is  usually  called  iodothyrin.  In  the  gland  itself  the 
iodothyrin  may  be  in  combination  with  protein,  forming  iodothyro- 
globulin.  E.  C.  Kendall38  has  recently  succeeded  in  isolating  a  pure  crys- 
talline substance  of  perfectly  constant  composition  and  containing  over  60 


THE    THYROID    AND    PARATHYROID    GLANDS 


793 


per  cent  of  iodine.  It  is  called  thyroxin  and  has  been  identified  as  an  indole 
compound  and  has  been  made  synthetically.  In  extremely  minute  dosage  it 
greatly  affects  the  energy  metabolism,  and  is  said  to  induce  symptoms  like 
exophthalmic  goiter.  Its  therapeutic  value  in  cases  of  thyroid  deficiency  is 
remarkable.  Kendall  believes  this  substance  to  be  the  active  constituent  of 
the  thyroid  and  to  be  associated  with  the  metabolism  of  amino  acids.  For 


S. 


B. 


Fig.   195.— Microphotographs  of  thyroid  gland  of  dog.      A,   normal   gland;   B,   active  hyperplasia-    C 
colloid  goiter.      (From   Marine  and  Lenhart.) 

instance  when  given  combined  with  amino  acids  its  effects  are  increased 
several  fold. 

The  importance  of  the  relationship  between  the  function  of  the  thyroid 
and  the  iodine-containing  material  is  indicated  by  the  changes  which 
occur  in  the  percentage  of  iodine  in  the  glands  under  varying  condi- 
tions of  activity.  Marine  observed  that  the  amount  of  iodine  is  inversely 
proportional  to  the  degree  of  hyperplasia  of  the  gland,  and  when  the 


794  THE   ENDOCRINE   ORGANS,    OR   DUCTLESS   GLANDS 

hyperplastic  condition  becomes  fully  developed,  scarcely  a  trace  of 
iodine  is  contained  in  the  gland.  Later,  when  the  hyperplasia  gives 
place  to  colloid  goiter,  the  iodine  increases  again,  both  absolutely  and 
relatively.  Moreover,  it  has  been  found  that  if  iodide  is  administered 
to  an  animal  suffering  from  hyperplasia,  the  hyperplastic  condition  very 
quickly  disappears  and  the  animal  becomes  normal.  Thus,  in  brook 
trout,  the  poor  nutritive  condition  of  the  fish  when  hyperplasia  has 
developed  can  be  immediately  remedied  by  placing  them  in  larger  quan- 
tities of  running  water  or  by  adding  small  traces  of  iodide  to  the  water. 
The  administration  of  small  amounts  of  iodine  as  in  ordinary  salt  from 
salt  deposits  also  prevents  goiter  in  farm  stock,  this  having  been  first 
noted  in  the  State  of  Michigan,  where  prior  to  the  discovery  of  salt 
deposits  sheep  breeding  was  an  entire  failure.  The  importance  of  admin- 
istering small  doses  of  iodides  to  school  children  living  in  goitrous  dis- 
tricts has  recently  been  emphasized  by  Marine  and  Kimball.39  As  small 
a  dose  as  0.001  gin.  at  weekly  intervals  prevents  goiter  in  puppies  sus- 
ceptible to  it. 

Feeding  experiments  carried  out  by  Gudernatsch40  and  subsequently  by 
Kogoff  and  Marine,41  indicate  that  the  thyroid  hormone  has  a  powerful 
influence  upon  the  development  of  the  body.  Tadpoles  fed  upon  thyroid 
substance  showed  a  striking  acceleration  of  the  normal  metamorphosis. 
Those  fed  with  the  glandular  material  grew  less  rapidly  than  the  con- 
trols fed  upon  ordinary  diet,  but  the  tails  of  the  former  showed  more 
rapid  involution  and  the  arm  buds  developed  prematurely. 

Experimental  Thyroidectomy 

A  correct  interpretation  of  the  functional  changes  and  symptoms  which 
follow  upon  partial  or  complete  removal  of  the  thyroid  gland,  or  from 
its  disease,  has  proved  a  very  difficult  problem,  partly  because  sufficient 
care  has  not  been  taken  to  note  how  much  parathyroid  tissue  was  re- 
moved along  with  the  thyroid,  and  partly  because  the  fact  has  been  over- 
looked that  the  effects  produced  by  thyroidectomy  and  parathyroid- 
ectomy  are  often  very  different  in  animals  of  the  same  kind  at  dif- 
ferent ages.  Speaking  generally,  it  may  be  said  that  the  influence  of  the 
parathyroid  is  focused  mainly  on  the  nerve  centers  and  only  to  a  second- 
ary degree  on  the  metabolic  functions,  whereas  the  reverse  is  the  case 
with  the  thyroid,  its  main  effect  being  on  metabolism,  although  it  prob- 
ably also  exercises  a  secondary  effect  on  the  nerve  centers.  More  so 
than  in  the  case  of  any  other  endocrine  organ,  our  knowledge  concerning 
the  function  of  the  thyroid  has  been  gained  by  clinical  experience,  and 
it  is  difficult  to  say  whether  the  clinical  or  the  experimental  method  has 
contributed  the  greater  amount  of  information. 


THE   THYROID   AND   PARATHYROID   GLANDS  795 

The  results  of  experimental  extirpation  of  the  thyroid  vary  accord- 
ing to  the  age  of  the  animal,  and  frequently  they  are  by  no  means 
marked,  provided  sufficient  parathyroid  tissue  has  been  undamaged. 
The  symptoms  are  in  general  thickening  and  drying  of  the  skin,  with  a 
tendency  to  adiposity  and  a  loss  of  tone  of  the  muscles.  The  body  tem- 
perature is  low  and  the  sexual  functions  become  subnormal.  Nervous 
symptoms  in  the  direction  of  mental  dullness  and  lethargy  are  also 
usually  present.  Surgical  removal  of  the  thyroid  in  man  produces  the 
condition  known  as  cachexia  strumipriva.  The  symptoms  may  first  of 
all  become  apparent  a  few  days  after  the  operation,  or  they  may  remain 
latent  for  years,  and  then  develop  so  as  to  produce  the  condition  known 
as  myxedema.  When  nervous  symptoms  are  prominent  in  cachexia 
strumipriva,  it  is  usually  taken  as  evidence  that  an  excessive  amount 
of  parathyroid  tissue  has  been  destroyed.  Kocher  states  that  after  com- 
plete loss  of  the  thyroid,  life  is  impossible  for  more  than  seven  years, 
and  that  to  prevent  ultimate  ill  effects,  at  least  one-fourth  of  the  organ 
should  be  left  intact. 

Disease  of  the  Thyroid 

The  symptoms  of  diseased  conditions  of  the  thyroid  may  be  inter- 
preted as  the  consequence  of  increased  or  diminished  functioning  of  the 
gland.  Sometimes,  however,  the  less  active  gland  is  really  increased  in 
bulk,  this  increase  being  caused  by  the  accumulation  in  it  of  very  large 
quantities  of  colloid  material  accompanied  by  an  attenuated  condition 
of  the  vesicular  cells  (see  page  793).  When  the  gland  is  atrophied  at 
birth,  the  condition  of  cretinism  soon  becomes  developed  (Fig.  196).  The 
characteristic  features  of  cretinism  are:  (1)  An  arrest  of  growth,  espe- 
cially of  the  skeleton,  accompanied  by  incomplete  ossification  of  the  long 
bones  and  a  delay,  often  of  several  years,  in  the  closure  of  the  fontanelles. 
The  disturbance  in  growth  of  the  long  bones  occurs  along  the  epiphyseal 
line,  but  the  deposition  of  new  bone  beneath  the  periosteum  proceeds, 
more  or  less,  normally.  The  consequence  is  that  the  bones  increase  in 
thickness  but  fail  to  develop  properly  in  length.  (2)  Poor  development 
of  the  muscular  system.  (3)  An  unhealthy,  swollen  condition  of  the  skin, 
so  that  it  is  yellowish  in  color,  the  face  being  pale  and  puffy.  (4)  An 
abnormal  development  of  the  connective  tissues  causing  a  shapeless  con- 
dition of  the  surface;  the  abdomen  is  always  swollen,  the  hands  and 
feet  are  shapeless,  and  the  root  of  the  nose  depressed.  (5)  The  nerv- 
ous system  also  fails  to  develop  properly,  so  that  at  the  age  of  puberty 
or  over,  the  child  remains  like  an  infant  in  his  mental  behavior,  idiocy 
being  common.  Indeed,  the  whole  clinical  picture  is  so  character- 
istic that  once  having  seen  a  case  no  one  can  fail  afterward  to 


796  THE   ENDOCRINE   ORGANS,    OR   DUCTLESS   GLANDS 

recognize  the  disease.  Besides  being  due  to  congenital  absence  of  the 
thyroid  (sporadic  type),  cretinism  may  also  occur  as  a  result  of  goitrous 
degeneration  of  the  gland.  This  forms  the  so-called  endemic  variety  of 
the  disease,  and  is  more  commonly  seen  in  goitrous  districts,  being  not 
infrequently  associated  with  disease  of  the  parathyroid,  in  which  case 
the  nervous  symptoms  are  very  prominent. 

The  occurrence  of  thyroid  deficiency  in  adults  produces  clinical  mani- 


Fig.  196. — Cretin,  nineteen  years  old.     The  treatment  with  thyroid  extract  started  too  late  to  be  of 
benefit.      (Patient   of   Dr.    S.   J.    Webster.) 

festations  allied  to  those  of  cretinism,  but  necessarily  modified  by  the  fact 
that  the  patient  has  attained  full  stature  and  sexual  maturity.  Though 
the  skeletal  changes  are  absent,  the  metabolic  disturbances  are  if  anything 
more  pronounced.  This  adult  form  of  the  disease,  which  is  known  as  myxe- 
dema,  may  occur  spontaneously  from  atrophy  of  the  gland,  or  follow  the  sur- 
gical removal  of  the  latter,  when  the  term  cachexia  strumipriva  or  operative 
myxedema  is  applied  to  the  condition.  The  symptoms  are  very  character- 
istic (Fig.  197).  The  skin  is  dry  and  thick,  with  a  deposition  of  connective 


THE    THYROID    AND    PARATHYROID    GLANDS 


797 


tissue  often  containing  fat  in  its  deeper  layers ;  the  hands  and  feet  become 
unshapely;  the  lips  are  thick  and  the  tongue  somewhat  enlarged,  so  that 
when  the  person  attempts  to  speak,  it  appears  as  if  the  tongue  were  too 
large  for  the  mouth ;  the  hair  falls  out ;  there  is  a  low  body  temperature, 
and  it  can  be  shown  that  the  basal  metabolism  is  greatly  depressed,  as 
can  be  shown  by  the  measurement  of  oxygen  consumption.  It  is  said  the 
person  can  take  a  larger  quantity  of  sugar  than  an  ordinary  individual 
without  the  development  of  glycosuria,  but  the  depression  of  the  metabolic 
function  causes  the  patient  to  take  sparingly  of  food,  in  spite  of  which, 
however,  the  body  weight  may  steadily  increase.  The  sexual  function  be- 
comes depressed,  and  there  is  involvement  of  the  nervous  system  as  shown 
by  mental  dullness  and  lethargy. 
Although  the  thyroid  gland  is  much  atrophied  in  myxedema,  symptoms 


A.  B. 

Fig.  197. — A,  Case  of  myxedema;  B,  Same  after  seven  months'  treatment.     (From  Tigerstedt.) 

that  are  very  similar  may  also  occur  when  the  gland  is  enormously  en- 
larged. As  already  explained,  however,  this  enlargement  is  due  merely 
to  an  accumulation  of  colloidal  material  and  is  really  an  atrophic  con- 
dition. A  patient  suffering  from  endemic  goiter  may  at  first  exhibit 
symptoms  which  are  usually  attributed  to  a  hypersecretion  of  thyroid 
material  into  the  blood  (the  symptoms  will  be  described  immediately), 
but  later  these  give  place  to  symptoms  not  unlike  those  of  myxedema. 
It  is  concluded  that  the  above  conditions  are  due  to  deficiency  of 
thyroid  function,  or  hypothyroidism,  because:  (1)  the  gland  is  atrophied, 
and  (2)  similar  symptoms  to  those  exhibited  by  the  clinical  conditions 


798  THE   ENDOCRINE    ORGANS,    OR    DUCTLESS    GLANDS 

can  be  produced  experimentally  by  the  removal  of  the  gland  in  animals. 
By  observations  on  the  effect  of  administration  of  thyroid  extract  to 
cretinous  or  myxedematous  patients,  prompt  amelioration  of  the  symp- 
toms occurs,  which  certainly  suggests  that  the  real  cause  is  the  absence 
of  an  internal  secretion.  There  is  probably  nothing  more  striking  in 
the  whole  domain  of  therapeutics  than  this  effect  from  the  administration 
of  thyroid  extract  or,  more  so  still,  of  thyroxin.  If  the  treatment  is 
started  early  enough,  the  cretinous  child  from  being  an  ill-developed 
idiot  quickly  catches  up  with  children  of  his  own  age  and  becomes  in 
every  respect  normal.  Even  if  this  treatment  is  not  undertaken  until 
the  child  is  several  years  of  age,  it  is  remarkable  how  quickly  the  benefit 
may  show  itself.  In  myxedema  and  cachexia  strumipriva  also,  the 
symptoms  very  quickly  disappear  and  the  person  becomes  perfectly  nor- 
mal by  the  treatment.  In  all  these  conditions,  however,  the  thyroid 
extract  must  be  administered  continuously  in  order  to  prevent  the  reap- 
pearance of  symptoms. 

Quite  distinct  from  the  above  described  conditions  of  hypothyroidism 
are  those  produced  by  an  excess  of  thyroid  autacoid  in  the  blood,  namely, 
hyperthyroidism.  Such  a  condition  can  be  produced  experimentally  in 
normal  animals  by  the  administration  of  thyroid  extract  or  of  thyroxin 
(Kendall).  In  man  its  continuous  administration  is  soon  followed  by  great 
quickening  of  the  pulse  with  some  irregularity,  flushing  of  the  skin,  in- 
creased perspiration,  tremor  in  the  limbs,  emaciation,  and  marked  nervous 
excitability.  Along  with  these  symptoms,  metabolic  investigations  have 
shown  that  the  energy  output  per  square  meter  of  surface  is  greatly  in- 
creased, being  sometimes  nearly  doubled ;  that  the  nitrogen  excretion  is  ex- 
cessive; and  that  alimentary  glycosuria  is  very  commonly  present.  The 
body  temperature  is  not,  however,  as  a  rule  increased,  because  although 
metabolism  is  excited,  yet  heat  loss  is  correspondingly  increased.  Ex- 
ophthalmos  is  said  to  develop  very  occasionally  after  such  administra- 
tion, but  this  is  doubtful.  Lastly,  there  are  usually  digestive  disturb- 
ances, although  the  appetite  is  likely  to  be  increased.  The  pulse  is  quick- 
ened after  administration  of  thyroxin  only  when  protein  food  is  also  taken. 
This  is  believed  by  Kendall  to  be  due  to  the  association  between  th^fhyroid 
hormone  and  the  metabolism  of  the  amino  acids.  It  has  been  shown  that 
a  single  large  dose  of  thyroxin  has  little  demonstrable  effect,  whereas 
minute  doses  administered  over  a  prolonged  period  produce  decided,  toxic 
manifestations,  and,  if  the  administration  is  persisted  in,  death  results. 
These  facts  are  explained  on  the  hypothesis  that  thyroxin  acts  in  the  body 
as  a  catalyst  and  hastens  certain  metabolic  processes  which  are  responsi- 
ble for  the  symptoms,  and  that  they  are  not  due  to  the  action  of  thyroxin 
per  se.  (Kendall.)42 

The  symptoms  following  the  injection  of  the  extract  are  very  similar 


THE    THYROID    AND   PARATHYROID    GLANDS  799 

to  those  of  the  disease  known  as  exophthalmic  goiter.  Indeed,  the  symp- 
toms are  so  much  alike  in  the  two  conditions  that  it  is  scarcely  neces- 
sary to  describe  them  specially  for  the  disease  except  to  mention  that 
in  the  former  exophthalmos  generally  does  not  occur. 

Like  simple  goiter  this  variety  is  from  three  to  four  times  more  fre- 
quent in  women  than  in  men,  a  fact  of  significance  when  we  recall  the 
evidence  of  association  between  the  thyroid  gland  and  the  generative 
organs.  It  is  said  that  the  disease  is  usually  coupled  with  persistence  of 
the  thymus  gland.  The  thyroid  gland  in  exophthalmic  goiter  is  enlarged, 
sometimes  in  one  lobe;  it  is  hard  and  pulpy,  and  on  auscultation  a  mur- 
mur is  heard.  Histologically  the  gland  presents  a  picture  very  like 
that  which  lias  been  described  above  as  hyperplasia ;  that  is  to  say,  the 
vesicles  have  a  deficiency  of  colloid  material;  their  epithelium  is  colum- 
nar and  folded  up  into  the  vesicles;  and  the  interstitial  tissue  between 
the  vesicles  is  very  markedly  increased. 

Exophthalmic  goiter  is  generally  claimed  to  be  due  to  hyper- 
secretion  of  the  thyroid,  because:  (1)  the  symptoms  of  the  disease  are  not 
unlike  those  produced  by  excessive  administration  of  thyroid  to  a  normal 
individual;  and  (2)  they  are  in  general  opposite  in  character  to  the  symp- 
toms found  in  cases  where  the  thyroid  gland  is  atrophied.  The  blood  of 
a  person  with  exophthalmic  goiter  when  injected  into  mice  increases  their 
resistance  to  the  toxic  action  of  acetonitrile,  which  is  also  the  case  after 
thyroid  extract  has  been  injected.  In  many  cases  of  exophthalmic  goiter 
partial  removal  of  the  gland  is  said  to  ameliorate  the  symptoms.  Other 
clinicians,  however,  state  that  if  the  patient  is  given  proper  medical 
treatment,  rest,  and  diet,  equally  beneficial  results  can  be  obtained. 

Certain  investigators,  however,  deny  that  it  has  yet  been  conclusively 
demonstrated  that  exophthalmic  goiter  is  due  to  hypersecretion  of  the  thy- 
roid (Marine).43  It  is  pointed  out  that,  if  hypersecretion  were  the  cause  of 
the  disease,  one  would  expect  that  the  injection  into  animals  of  the  blood 
of  patients  suffering  from  it  would  produce  symptoms  similar  to  those 
following  the  injection  of  thyroid  extract.  The  results  of  such  experi- 
ments, however,  have  been  extremely  confusing  and  very  indecisive,  since 
it  is  difficult  to  recognize  in  laboratory  animals  many  of  the  characteristic 
symptoms,  especially  those  affecting  the  skin  and  eyes  and  the  general 
bodily  nutrition.  Another  difficulty  in  accepting  the  hypersecretion  hypoth- 
esis is  the  fact  that  an  extract  of  a  gland  removed  from  an  exophthalmic 
patient  has  no  different  physiological  action  on  a  normal  animal  from  an 
extract  of  a  normal  gland  containing  the  same  percentage  of  iodine. 
The  evidence  is  by  no  means  conclusive  one  way  or  the  other,  and  it  may 
well  be  that  the  observed  changes  in  the  thyroid  gland  are  not  the  cause 
of  the  symptoms  of  exophthalmic  goiter,  but  merely,  like  the  other  symp- 


800  THE   ENDOCRINE   ORGANS,    OR   DUCTLESS   GLANDS 

toms  of  this  disease,  a  result  of  some  condition  elsewhere.  In  this  con- 
nection it  is  of  interest  to  note  that  degenerative  and  pigmentary  changes 
in  the  ganglion  cells  of  the  cervical  sympathetic  have  been  found  by  Wil- 
son44 in  cases  of  exophthalmic  goiter  and  which  are  believed  to  be  dis- 
tinctive of  this  condition.  On  this  account  disease  of  the  sympathetic 
is  suggested,  by  some,  as  the  possible  cause  of  the  cardiac  and  ocular 
symptoms,  as  well  as  of  the  thyroid  hyperactivity,  the  latter  producing 
secondarily,  it  is  supposed,  the  metabolic  phenomena  characteristic  of 
the  disease. 

The  Relationship  of  the  Thyroid  with  Other  Endocrine  Organs 

1.  With  the  Generative  Organs. — Evidence  of  an  association  between 
the  female  generative  organs  and  the  thyroid  is  very  strong;  thus,  the 
thyroid  becomes  enlarged  at  puberty,  during  the  menses,  and  during 
pregnancy,  and  in  thyroidectomized  young  animals  the  sexual  glands 
fail  to  develop  properly. 

2.  With  the  Adrenal  Glands.— (See  page  788.) 

3.  With  the  Pituitary  Body. — After  removal  of  the  thyroid,  the  pitu- 
itary becomes  greatly  altered  and  enlarged,  particularly  the  pars  an- 
terior, in  which  it  is  not  uncommon  to  find  that  a  certain  amount  of 
vesicles  containing  colloid,  not  unlike  those  of  the  thyroid,  become  devel- 
oped.   This  colloid  material,  however,  does  not  contain  iodine.    It  is  said 
that  this  increase  of  the  pituitary  after  thyroidectomy  does  not  occur  if 
thyroid  extract  be  administered.     Increased  activity  of  the  pars  inter- 
media of  the  pituitary  is  also  quite  plain.     These  facts  would  at  first 
sight  seem  to  indicate  that  the  pituitary  and  the  thyroid  can  act  vica- 
riously, but  this  is  very  doubtful,  for  it  has  not  been  found  that  pitu- 
itary extract  has  any  beneficial  effect  in  the  treatment  of  goiter  and  myx- 
edema.    Nevertheless  the  association  in  function  of  the  two  glands  must 
be  more  or  less  close,  not  alone  for  the  above  reasons,  but  also  because  they 
are  both  associated  to  much  the  same  degree  with  the  sexual  organs, 
and  both  act  on  the  higher  functions  of  the  nervous  system  in  much  the 
same  manner. 

4.  With  the  Thymus  Gland. — The  persistence  of  the  thymus  in  ex- 
ophthalmic goiter,  as  well  as  the  anatomical  and  embryological  relationship 
between  thymus  and  thyroid,  is  taken  to  indicate  some  close  relationship. 

THE  PARATHYROIDS 

Experimental  Parathyroidectomy 

Experimental  parathyroidectomy  yields  results  which  vary  in  dif- 
ferent groups  of  animals,  undoubtedly  because  of  the  fact  that  in  some, 
such  as  the  rat  and  rabbit,  accessory  parathyroids  may  exist.  In  gen- 


THE    THYROID    AND    PARATHYROID    GLANDS  801 

eral,  however,  it  has  been  found  that  if  more  than  two  of  the  four 
parathyroids  be  removed,  very  definite  and  pronounced  nervous  symp- 
toms soon  supervene  and  if  all  four  glands  be  removed,  a  quickly  fatal 
result  is  inevitable.  The  most  acute  symptoms  are  exhibited  by  the 
carnivora.  They  may  not  be  apparent  for  a  day  or  two  after  the  opera- 
tion, although  during  the  period  the  animal  is  in  a  depressed  state,  re- 
fusing food  and  losing  weight  rapidly.  The  muscles  are  also  more  or  less 
stiff  during  this  stage.  When  more  definite  symptoms  appear,  they  con- 
sist of  a  marked  abnormality  of  muscular  contraction,  leading  to  the 
occurrence  of  fibrillar  contractions,  or  tremors  and,  later,  to  cramp-like 
and  clonic  contractions.  When  spontaneous  movements  are  made,  a 
peculiar  shaking  of  the  foot,  like  that  made  by  a  normal  animal  to  shake 
water  off  its  pads,  is  a  characteristic  symptom.  The  slightest  stimulation 
of  the  peripheral  nerves  is  sufficient  to  induce  one  of  these  attacks,  which 
recur  with  ever  increasing  frequency,  becoming  at  the  same  time  more 
pronounced  and  accompanied  by  other  disturbances,  such  as  diarrhea, 
profuse  salivation  and  rapid  pulse.  In  addition  to  the  clonic  seizures, 
there  appears  a  tonic  contraction  of  the  extensor  muscles  of  the  limbs  and 
in  a  certain  percentage  of  dogs  (but  not  of  cats)  spasm  of  the  adductor 
muscles  of  the  larynx  (laryngismus  stridulus)  occurs.  In  this  latter  con- 
dition owing  to  the  consequent  narrowing  of  the  rima  glottidis  the  res- 
pirations are  noisy,  difficult  and  high  pitched  in  tone.  In  cases  that  are 
not  quickly  fatal  the  hair  tends  to  be  shed  and  the  teeth  to  be  improperly 
calcined  (in  young  animals).  Where  a  certain  amount  of  parathyroid  tis- 
sue has  been  left — for  example,  one  of  the  four  lobes — the  symptoms  may 
not  appear  except  under  conditions  of  special  strain  to  the  animal  econ- 
omy, such  as  pregnancy  or  improper  diet.  Thus,  in  a  bitch  from  which 
three  of  the  four  glands  had  been  removed,  no  symptoms  of  tetany  oc- 
curred until  she  became  pregnant.  Under  the  same  conditions  it  has 
been  found  that  a  diet  of  flesh  is  much  more  apt  to  bring  about  the  con- 
dition than  one  of  vegetables  or  milk. 

Injury  or  Disease  of  the  Parathyroids  in  Man 

Tetania  parathyreopriva,  as  the  condition  described  in  the  foregoing 
paragraph  is  called,  may  become  developed  also  in  man  as  the  result 
of  surgical  removal  of  the  parathyroids.  This  was  a  common  enough 
sequela  to  operations  for  goiter  a  few  years  ago,  before  the  significance 
of  these  bodies  was  recognized  or,  indeed,  even  their  existence  known. 
It  was  the  result  of  accident  rather  than  of  design,  were  the  parathyroids 
not  removed  along  with  the  thyroid.  A  similar  condition  (idiopathic 
tetany)  occurs  spontaneously,  in  children  more  particularly,  but  also  in 
adults  when  it  may  be  associated  with  gastrointestinal  disorders,  infec- 
tious diseases,  or  pregnancy.  The  clinical  phenomena  resemble  closely 


802 


THE    ENDOCRINE    ORGANS,    OR    DUCTLESS    GLANDS 


those  described  above  as  appearing  in  laboratory  animals,  with  the  dif- 
ference that  the  clonic  movements  and  the  extensor  spasm  are  more  or  less 
replaced  by  a  tonic  spasm  of  the  flexor  muscles,  which  produces  charac- 
teristic attitudes  of  the  hands  and  feet.  Associated  with  the  carpopedal 
spasm  generalized  convulsions  or  laryngismus  stridulus  may  occur.  Laryn- 
geal  spasm  may,  indeed,  be  the  sole  manifestation  of  parathyroid  de- 
ficiency and  it  is  also  believed  that  many  cases  of  convulsions  occurring 
in  young  children  really  depend  upon  a  deranged  function  of  these  glands. 
In  brief,  tetany,  infantile  convulsions,  and  laryngismus  stridulus  are  proba- 
bly but  different  manifestations  of  the  same  condition. 

It  has  been  suggested  that  certain  obscure  nervous  diseases  of  adults 
such  as  paralysis  agitans  and  Thomsen's  disease  are  dependent  upon 
lesions  of  the  parathyroids.  Chorea,  epilepsy,  and  eclampsia  likewise  have 
been  ascribed  to  disease  of  these  bodies,  but  no  cogent  evidence  has  been 
adduced  to  connect  the  parathyroids  with  any  of  these  conditions.  That, 
on  the  other  hand,  the  belief  in  the  association  of  idiopathic  tetany  and 
parathyroid  disease  is  well  founded  is  evidenced  by  the  close  resemblance 
between  the  nervous  symptoms  of  the  two  conditions.  In  the  case  of 
monkeys  especially,  are  the  symptoms  of  the  experimental  condition  often 
strikingly  similar  to  those  of  the  idiopathic  disease.  In  these  animals 
the  muscular  spasms  following  parathyroidectomy  may  imitate  almost 
unerringly  those  of  infantile  tetany,  so  that  tonic  flexor  spasms  pro- 
ducing the  characteristic  carpopedal  attitudes  of  the  idiopathic  condi- 
tion, appear. 

With  regard  to  the  nature  of  the  disturbances  set  up  ~by  parathyroid  de- 
ficiency. Noel  Paton,  Findlay  and  Watson45  have  recently  shown  that  the 
clonic  spasms  are  not  primarily  dependent  upon  the  cerebrum  or  cere- 
bellum, since  they  persist  after  ablation  of  these  parts  of  the  nervous 
system ;  in  fact,  removal  of  the  hemispheres  or  suppression  of  their  usual 
functions  by  light  anesthesia  increases  the  severity  of  the  clonus.  This 
does  not  imply  that  secondary  involvement  of  the  cerebrum  may  not 
occur;  on  the  contrary,  the  epileptiform  convulsions,  observed  in  the  se- 
verer types  of  tetany,  indicate  considerable  cerebral  mischief.  Division 
of  the  cord  does  not  remove  the  spasms  below  the  site  of  section,  nor 
have  section  and  degeneration  of  the  posterior  roots  any  influence  upon 
them;  but  they  disappear  after  division  of  the  anterior  roots.  These 
observations  show  that  the  seat  of  origin  of  the  spasms  cannot  lie  in  the 
peripheral  nerves  or  in  the  muscles.  This  indicates  that  the  efferent 
neurone  within  the  cord  is  the  structure  affected. 

The  other  nervous  disturbance  following  parathyroidectomy,  namely, 
tonic  spasm  of  the  extensor  muscles  has  been  shown  to  depend  upon  the 
cerebellar  arc.  The  hypertonus  is  uninfluenced  by  decerebration,  whereas 
the  removal  of  cerebellar  impulses  by  severance  of  the  spinal  cord  abol- 


THE    THYROID    AND    PARATHYROID    GLANDS  803 

ishes  this  symptom  below  the  transection.  In  the  severer  cases  other 
more  marked  evidences  of  cerebellar  involvement  may  appear,  e.  g.,  dis- 
turbances of  equilibrium  and  forced  movements  of  a  circling  or  rotatory 
nature. 

Though  the  foregoing  ascribes  a  central  origin  to  the  eminent  nervous 
symptoms  the  peripheral  nerves  are  not  entirely  unaffected  as  has  been 
shown  by  Noel,  Paton  and  his  co-workers.  These  investigators  compared 
the  response  of  muscle  and  nerve  to  electrical  stimulation  in  nor- 
mal and  in  parathyroidectomized  animals,  and  found  that  though  there 
were  considerable  variations  in  the  responses  of  a  normal  animal,  they 
were  very  definitely  exaggerated  in  experimental  tetany  when  either 
the  motor  nerve  or  the  muscle  itself  was  stimulated.  This  increased 
electrical  excitability  is  uninfluenced  by  the  central  nervous  system, 
since  it  persists  after  section  of  the  nerves,  and  though  it  is  manifested 
by  direct  stimulation  of  the  muscle  it  does  not  depend  upon  any  change 
in  the  myal  structures,  for  degeneration  of  the  nerves  or  the  administra- 
tion of  curare  in  sufficient  dosage  to  block  nervous  impulses,  abolishes  it ; 
it  is  concluded  that  the  nerve  ending  is  the  part  of  the  neural  structure 
affected.  Idiopathic  tetany  shows  a  similar  exaggeration  of  electrical 
excitability,  the  excitability  to  mechanical  stimuli  is  increased  to  an  even 
greater  degree  in  this  condition,  a  fact  most  valuable  in  the  diagnosis  of 
latent  disease ;  tapping  over  the  facial  nerve  is  the  common  method  em- 
ployed for  its  elicitation.  Though  these  changes  in  the  excitability  of  the 
peripheral  nerves  are  useful  in  diagnosis,  neither  in  the  experimental 
nor  in  the  idiopathic  condition  can  they  be  taken  as  a  measure  of  the  se- 
verity of  the  process,  for  they  may  be  no  more  marked  in  instances  where 
there  is  involvement  of  the  cerebral  hemispheres  (causing  epileptiform 
convulsions)  than  in  milder  cases. 

The  parathyroid  gland,  besides  influencing  the  nerve  centers,  has  also 
an  influence  on  metabolism.  The  symptoms  produced  by  parathyroidec- 
tomy  are;  (1)  rapid  emaciation  and  failure  to  grow;  (2)  a  tendency  to 
the  production  of  glycosuria,  often  detected  by  finding  that  the  assimi- 
lation limit  for  carbohydrate  is  lowered  (page  685)  ;  and  (3)  most  defi- 
nitely of  all,  an  interference  with  calcium  metabolism,  as  illustrated 
by  the  failure  of  the  teeth  and  bones  to  calcify  properly. 

When  the  tetany  is  the  result  of  a  complete  extirpation  of  all  parathyroid 
tissue,  the  symptoms  can  be  combated  by  a  successful  transplantation  or 
graft  of  parathyroid  tissue  made  from  an  animal  of  the  same  species.  In- 
deed, it  has  been  found  that  the  success  of  a  graft  of  parathyroid  is 
assured  only  when  the  graft  is  derived  from  the  same  kind  of  animal  as 
that  from  which  the  parathyroid  has  been  removed.  Implantation  into 
the  subcutaneous  tissue  of  a  tetany  patient  of  parathyroid  tissue  ob- 
tained fresh  from  the  deadhouse  has  been  performed  with  beneficial  out- 
come. 


804. 


THE   ENDOCRINE   ORGANS,    OR   DUCTLESS   GLANDS 


As  to  the  cause  of  the  symptoms,  many  possibilities  have  to  be  considered, 
in  the  first  place,  no  direct  relationship  exists  between  the  thyroid  and 
parathyroid  in  this  connection.  One  cause  might  be  the  absence  of 
some  substance  which  checks  the  activity  of  the  nervous  system,  some 
chalone  in  Schafer's  sense.  It  was  previously  thought  by  W.  G.  Macal- 
lum46  that,  since,  nervous  symptoms  like  those  of  tetany  could  be  pro- 
duced by  deficiency  of  calcium  in  the  body  and  the  symptoms  of  parathy- 
roidectomy  were  relieved  by  the  administration  of  this  cation,  calcium 
deficiency  was  the  cause  of  the  symptoms.  The  defective  calcification  of 
the  bones  and  teeth  following  parathyroid  deprivation  together  with  the 
frequent  association  of  rickets  (a  condition  characterized  by  a  modified 
calcium  metabolism)  enhanced  the  plausibility  of  such  an  hypothesis. 
On  the  other  hand,  that  no  view  can  be  correct  which  takes  as  its  basis 
the  absence  or  deficiency  of  some  one  or  other  substance  which  is  sup- 
posed, normally,  to  influence  the  activity  of  nervous  tissues  is  indicated 
by  the  fact  that  blood-letting  or  the  transfusion  of  normal  saline  imme- 
diately removes  the  symptoms,  and  keeps  them  in  abeyance  for  some  time. 
Moreover,  such  a  view  does  not  adequately  explain  the  metabolic  dis- 
turbances, which  may  continue  when  the  nervous  symptoms  are  slight  as, 
for  example,  after  the  administration  of  calcium.  The  most  probable  ex- 
planation of  the  beneficial  effect  of  calcium  upon  the  nervous  symptoms  is 
that  it  behaves  merely  as  a  sedative,  reducing  the  excitability  of  the 
nervous  system,  an  action  which  it  is  known  to  possess. 

While  not  denying  that  calcium  ions  may  have  some  minor  relation- 
ship to  the  symptoms,  Noel  Paton  ascribes  them  chiefly  to  intoxication 
by  guanidine  (page  640).  The  evidence  is  as  follows:  (1)  Guanidine 
or  methyl  guanidine  administered  to  normal  animals  produces  symp- 
toms that  are  identical  with  those  following  parathyroidectomy.  (2) 
No  drug,  other  than  guanidine,  which  can  effect  a  decided  increase  in 
the  excitability  of  the  motor  nerve  endings  to  the  constant  current,  has 
been  found.  (3)  There  is  a  marked  increase  in  the  amount  of  these  sub- 
stances in  the  blood  and  urine  of  parathyroidectomized  dogs,  and  in 
the  urine  of  children  suffering  from  idiopathic  tetany.  It  is  also  true 
that  while  creatine  (which  contains  the  guanidine  nucleus  and  is  a  prob- 
able source  of  this  substance)  is  absent  from  the  urine  of  healthy  adults, 
it  is  normally  present  in  the  urines  of  children  between  the  ages  of  12 
and  15  years,  a  period  during  which  the  incidence  of  tetany  is  most 
frequent.  Under  6  months  creatinuria  does  not  usually  occur,  tetany 
also  is  extremely  rare  at  this  age.  These  facts  taken  in  conjunction  with 
the  other  evidence,  seem  to  have  more  than  a  coincidental  bearing  upon 
the  genesis  of  tetany.  (4)  In  certain  cases  the  serum  of  parathyroidecto- 
mized dogs  acts  upon  the  muscles  of  the  frog  similarly  to  weak  solutions 
of  guanidine.  (5)  There  is  a  striking  similarity  in  the  relative  amounts 
of  the  nitrogenous  metabolites  in  the  urine  of  parathyroidectomized  dogs 


THE    THYROID    AND   PARATHYROID    GLANDS  805 

and  normal  animals  injected  with  guanidine,  in  either  instance  the  total 
nitrogen  is  increased  and  the  proportion  of  urea  diminished. 

It  is  concluded  that  the  parathyroids  control  the  metabolism  of  guani- 
dine "by  preventing  its  development  in  undue  amounts.  In  this  way 
they  probably  exercise  a  regulative  action  upon  the  tone  of  the  skeletal 
muscles." 

Though  the  evidence  of  these  observers  is  most  formidable,  it  seems 
that  the  question  has  not  yet  reached  finality,  for  Howland  and  Mar- 
riott47 still  insist  that  a  lowered  calcium  content  of  the  blood  is  responsi- 
ble for  idiopathic  tetany.  This  contention  is  supported  by  a  mass  of 
analytical  data  from  which  the  fact  is  brought  out  that  the  blood  of  chil- 
dren suffering  from  tetany  shows  a  reduction  of  calcium,  to  the  extent 
of  40  per  cent  in  many  instances.  The  question  whether  this  deficiency 
is  merely  an  accompaniment  of  the  condition  or  the  causative  factor 
does  not  appear  to  have  been  fully  investigated.  It  is  possible  that  neither 
of  these  factors — guanidine  formation  or  calcium  deficiency — is  the  pri- 
mary cause  of  tetany,  but  that  one  or  perhaps  both  may  be  secondary  to 
some  condition  as  yet  unrevealed. 

BIBLIOGRAPHY 

Grant  and  Goldman :     A  Study  of  Forced  Respiration :     Experimental  Production  of 
Tetany.     Am.  Jour.  Physiol.,  Hi,  209. 


CHAPTER  LXXXVII 
THE  PITUITARY  BODY 

Structural  Relationships 

Situated  at  the  base  of  the  brain  and  lying  in  the  sella  turcica,  the  pituitary  body 
in  man  does  not  weigh  much  more  than  half  a  gram.  It  is  connected  with  the  brain  by 
a  funnel-shaped  stalk,  the  infundibulum.  On  account  of  a  natural  cleft,  which  runs 
across  the  gland  in  an  oblique  plane,  it  is  an  easy  matter  to  split  it  into  two  portions, 
an  anterior,  or  pars  glandularis,  and  a  posterior,  or  pars  nervosa.  This  cleft  in  the 
case  of  man  is  usually  found  to  be  more  or  less  broken  up  into  isolated  cysts  containing 
a  colloid-like  material,  and  it  represents  the  remains  of  the  original  tubular  structure 
from  which  the  pars  glandularis  is  developed;  namely,  a  pouch  growing  out  from  the 
buccal  ectoderm. 

On  histologic  examination  it  will  be  found  that  the  pars  glandularis  consists  of  masses 
of  epithelial  cells  with  large  sinus-like  blood  capillaries  lying  between  them.  These 
blood  vessels  are  very  numerous,  so  that  in  an  injected  gland  this  portion  of  the  pituitary 
stands  out  very  prominently.  The  vessels  are  derived  from  about  twenty  small  arterioles 
that  converge  toward  the  pituitary  from  the  circle  of  Willis,  and  enter  the  gland  by  the 
infundibulum  or  stalk  by  which  the  gland  is  connected  with  the  base  of  the  brain.  Three 
types  of  cell  can  be  differentiated:  nonstaining  (chromophobe)  and  granular  (chroma- 
phil),  of  which  latter  there  are  cells  with  acid-staining  and  others  with  base-staining 
granules,  the  former  being  by  far  the  more  numerous  (Schafer).  In  some  animals  such 
as  the  cat,  the  cells  of  the  pars  anterior  are  arranged  around  the  blood  sinuses  in  rows 
as  in  a  columnar  epithelium.  The  cells  with  acid-staining  granules  are  said  to  become 
much  increased  in  number  in  pregnancy  and  also  in  the  enlarged  gland  of  acromegaly 
(see  page  816).  After  thyroidectomy  it  has  been  observed  that  colloid-like  masses  ac- 
cumulate in  the  pars  glandularis,  the  cells  sometimes  arranging  themselves  around  these 
masses  as  in  the  thyroid  gland.  The  colloid,  however,  contains  no  iodine. 

The  posterior  part  of  the  gland,  or  pars  nervosa,  is  composed  almost  entirely  of 
neuroglia,  cells,  and  fibers,  usually  with  some  hyaline  or  granular  material  lying  be- 
tween them,  particularly  in  the  neighborhood  of  the  infundibulum,  into  which  it  may  be 
traced.  It  is  believed  that  the  active  principle  of  the  gland  is  represented  by  this  ma- 
terial. The  blood  supply  of  the  pars  nervosa  is  relatively  scanty. 

Between  the  pars  nervosa  and  the  intraglandular  cleft  above  referred  to  is  a  layer 
of  cells  differing  from  those  of  either  the  anterior  or  the  posterior  lobe.  This  layer  of 
cells  constitutes  the  so-called  pars  intermedia.  The  cells  are  somewhat  like  those  of  the 
pars  glandularis,  except  that  they  are  distinctly  granular,  the  granules  being  of  the  neu- 
trophile  variety,  that  is  to  say,  they  stain  with  neither  basic  nor  acid  dyes.  Well-defined 
vesicles,  containing  an  oxyphile  colloid  material  which  is  believed  to  furnish  the 
active  principle  of  the  posterior  lobe,  are  often  found  between  them.  Although  well 
separated  by  the  cleft  from  the  pars  glandularis,  the  pars  intermedia  is  not  well  separated 
from  the  pars  nervosa,  because  many  of  its  cells  extend  for  some  distance  into  the  latter 
between  the  neuroglial  fibers.  Certain  of  the  cells  in  the  pars  intermedia  may  be  seen 
in  various  stages  of  conversion  into  globular  hyaline  bodies,  or  a  granular  mass  of  ma- 

806 


THE    PITUITARY    BODY 


807 


terial  may  appear  in  them.  In  either  case,  the  cells  ultimately  break  down,  setting  free 
the  hyaline  or  granular  material,  which  is  believed  to  be  the  origin  of  the  similar  ma- 
terial already  described  as  existing  between  the  neuroglial  fibers  of  the  pars  nervosa 
and  therefore  ultimately  finding  its  way  by  the  infundibulum  into  the  third  ventricle  of 
the  brain.  As  evidence  that  the  pituitary  secretion  takes  this  course  are  the  facts,  that 
in  the  first  place,  the  active  principle  of  the  gland  may  be  detected  in  the  cerebrospinal 
fluid,  and  secondly,  if  in  the  living  animal  the  infundibulum  be  severed  close  to  its  junc- 
tion with  the  ventricular  floor,  a  subsequent  examination  of  the  gland  shows  an  unusual 
accumulation  of  hyaline  material  in  the  stalk  and  adjacent  portion  of  the  posterior  lobe. 
It  should  be  mentioned,  finally,  that  at  the  margin  of  the  intraglandular  cleft  the  inter- 
mediary and  anterior  portions  of  the  pituitary  come  together,  although  the  cells  of  each 
can  readily  be  distinguished  on  account  of  their  staining  properties.  This  pars  glandu- 


Fig.  198. — Drawing  from  a  photograph  of  a  mesial  sagittal  section  through  the  pituitary  gland 
of  a  human  fetus  (5th  month):  a,  optic  chiasma;  c,  third  ventricle;  d,  pars  glandularis;  e,  iniun- 
dibulum  surrounded  by  epithelial  cells;  f,  pars  intermedia;  g,  intraglandular  cleft;  h,  pars  nervosa. 
(Herring,  from  Howell's  Physiology.) 

laris  et  intermedia  also  extends  as  a  thin  layer  over  part  of  the  pars  nervosa  and  around 
the  neck  of  the  gland  at  the  infundibulum.  These  relationships  are  well  shown  in  the 
accompanying  diagram  (Fig.  198). 

Functions 

Concerning  the  functions  of  the  pituitary,  it  may  be  said  in  general  that 
the  anterior  lobe  has  an  important  relationship  to  the  nutritive  con- 
dition of  the  body  during  growth,  especially  of  the  skeletal  structures, 
and  that  the  posterior  lobe  produces  a  very  active  autacoid  having  to  do 
with  the  physiological  activity  of  unstriped  muscle  fiber.  The  pars  inter- 
media seems  to  be  associated  with  the  posterior  lobe  in  the  production  of 


808  THE   ENDOCRINE   ORGANS,    OR   DUCTLESS   GLANDS 

this  autacoid.     The  function  of  these  two  parts  will  therefore  be  con- 
sidered together. 

Function  of  the  Anterior  Lobe. — The  facts  concerning  the  function 
of  the  pars  glandularis  have  been  gleaned  largely  by  observing  the  ef- 
fects produced  by  partial  or  complete  removal  of  the  entire  pituitary. 
Justification  for  ascribing  the  results  of  this  operation  to  removal  of  the 
anterior  lobe,  rather  than  to  removal  of  the  posterior  is  furnished  by 
control  experiments  in  which  removal  of  the  posterior  lobe  alone  failed 
to  produce  similar  effects. 

Complete  removal  of  the  pituitary  is  almost  invariably  fatal,  the  con- 
dition being  called  apituitarism.  Two  operative  procedures  have  been 
employed  for  the  removal  of  the  gland.  One  of  these,  originated  by 
Paulesco  and  elaborated  by  Gushing  and  his  pupils,48  consists  in  trephin- 
ing the  skull  and  elevating  the  temporal  lobe  of  the  cerebrum  so  as  to 
expose  the  gland.  The  other,  elaborated  by  Horsley,49  consists  in  ap- 
proaching the  gland  through  the  orbital  cavity.  Although  there  is  some 
danger  of  injury  to  nervous  tissues  by  the  intracranial  method,  its  re- 
sults are  more  dependable  since  the  gland  is  actually  exposed  to  view 
before  being  removed. 

Most  hypophysectomized  animals  die  within  two  or  three  days,  unless 
they  are  very  young.  This  longer  survival  of  young  animals  is  ascribed 
to  the  presence  of  accessory  pituitary  material  situated  in  the  dura  mater 
lining  the  sella  turcica.  The  most  extensive  observations  have  been  made 
on  dogs.  On  the  day  following  the  operation  the  animal  appears  about 
normal,  but  it  gradually  becomes  less  active,  refusing  food  and  respond- 
ing slowly  to  stimulation.  It  gradually  gets  weaker  and  weaker;  muscu- 
lar tremors  may  appear,  the  respiration  and  pulse  become  slow,  the  back 
arched,  the  temperature  subnormal;  and,  usually  within  about  forty- 
eight  hours,  coma  develops  and  the  animal  dies  in  this  condition.  Symp- 
toms of  equal  severity  ensue  if  the  anterior  lobe  alone  is  removed.  When 
the  symptoms  are  less  acute  and  death  does  not  occur  so  early,  it  is  be- 
lieved by  Gushing  either  that  small  portions  of  the  gland  have  been  left 
behind  or  that  some  vicarious  activity  of  other  organs  has  developed 
to  replace  that  of  the  pituitary. 

When  only  a  part  of  the  pituitary  is  removed  either  unintentionally 
or  intentionally,  the  symptoms  are  not  nearly  so  acute,  provided  that 
the  portion  remaining  includes  tissue  of  the  anterior  lobe.  The  condition 
is  known  as  hypopituitarism.  It  is  by  a  study  of  this  condition  that 
most  facts  concerning  the  function  of  the  anterior  lobe  have  been 
learned.  When  the  operation  is  performed  on  young  animals,  they 
fail  to  grow  properly;  the  milk  teeth  and  the  lanugo  are  retained; 
the  epiphyses  do  not  ankylose;  the  thyroid  and  thymus  glands  are  en- 
larged; and  the  cortex  of  the  suprarenal  and  the  sexual  organs  fails  to 


THE    PITUITARY    BODY  809 

develop.  The  animal,  though  small,  becomes  very  fat  and  may  therefore  in- 
crease in  weight.  There  is  distinct  evidence  of  mental  dullness.  From  these 
results  it  is  concluded  that  the  anterior  lobe  of  the  pituitary  produces 
autacoids  having  to  do  with  the  development  of  the  skeletal  and  other 
structures  of  the  growing  animal.  That  this  autacoid  is  not  derived  from 
the  posterior  lobe  is  indicated  by  the  fact  that  partial  injury  of  this 
lobe,  or  indeed  its  entire  removal,  is  not  followed  by  similar  symptoms. 

Closer  examination  of  the  metabolic  function  in  hypophysectomized 
animals  has  shown  that  there  is  a  marked  depression  in  the  respiratory 
exchange  of  oxygen  and  carbon  dioxide,  and  that  the  ability  to  metabo- 
lize carbohydrate  becomes  heightened ;  that  is  to  say,  the  animal  can  tolerate 
a  larger  quantity  of  sugar  than  the  normal  animal  without  develop- 
ing glycosuria.  This  effect  on  carbohydrate  metabolism  may  how- 
ever be  associated  not  so  much  with  the  function  of  the  anterior  lobe  as 
with  that  of  the  posterior,  for,  as  we  shall  see  later,  Gushing  and  his 
pupils  have  found  that  extract  of  the  posterior  lobe  has  a  marked  influence 
on  the  assimilation  limit  of  carbohydrate. 

Attempts  have  been  made  to  graft  the  pituitary,  especially  the  anterior 
lobe,  into  various  parts  of  the  body.  It  has  been  found,  however,  that 
within  a  few  days  the  grafts  atrophy  and  disappear  unless  there  has 
been  complete  removal  of  the  pituitary  itself,  in  which  case  the  graft 
may  remain  for  a  month  or  so  and  the  otherwise  fatal  outcome  of  hypophy- 
sectomy  be  warded  off.  Sometimes,  where  the  graft  has  remained  for  a 
longer  time,  it  is  said  that  a  temporary  increase  in  the  growth  of  the 
animal  has  been  noticed. 

Other  observers  have  investigated  the  effects  in  normal  animals  of 
continuous  oral  administration  of  pituitary  substance  or  of  subcutaneous 
injection  of  extract.  The  earlier  results  were  indefinite  and  confusing, 
but  recently  Brailsford  Robertson50  has  succeeded  in  isolating  from  the 
anterior  lobe  a  substance  called  tethelin,  which  accelerates  growth  in 
young  animals  and  is  thought  to  have  a  possible  value  in  hastening  the 
healing  process  in  wounds. 

Tethelin  is  precipitated  by  dry  ether  from  an  alcoholic  extract  of  the 
carefully  isolated  anterior  lobes.  It  contains  1.4  per  cent  of  phosphorus, 
and  nitrogen  in  the  proportion  of  four  atoms  for  every  atom  of  phos- 
phorus, two  of  the  nitrogen  atoms  being  present  as  amino  groups  and 
one  in  an  imino  group.  The  effects  on  growth  of  mice  are  in  every  par- 
ticular like  those  of  the  administration  of  anterior  lobes,  and  consist  in 
retardation  of  the  first  portion  of  the  third  growth  cycle,*  followed  by 

,  *  Robertson  has  contributed  valuable  and  very  extensive  data  on  the  normal  curve  of  growth  of 
white  mice'  kept  under  carefully  controlled  conditions.  Three  growth  cycles  are  present:  the  first 
attains  its  maximum  velocity  between  seven  and  fourteen  days  after  birth;  the  second,  between 
twenty-one  and  twenty-eight  days;  and  the  third  about  six  weeks,  after  which  the  velocity  decreases 
progressively,  until  further  growth  ceases  between  the  fiftieth  and  sixtieth  weeks  succeeding  birth. 


810  THE   ENDOCRINE   ORGANS,    OR   DUCTLESS   GLANDS 

acceleration  of  the  latter  portion  of  this  cycle.  When  fully  grown, 
tethelin-fed  mice  also  differ  from  normal  animals  in  being  smaller  in 
size  but  of  greater  weight,  with  a  distinct  difference  in  the  condition  of 
the  coat.  Normal  animals  at  fourteen  months  of  age  have  "  shaggy, 
staring  and  discolored  coats,"  whereas  tethelin-fed  animals  have  the 
glossy  and  silky  appearance  of  young  animals.  During  growth,  nor- 
mal animals  display  a  greater  variability  in  weight  than  tethelin-fed 
animals. 

Extraordinary  effects  have  been  observed  by  Clark51  to  be  produced 
by  feeding  laying  hens  with  pituitary  gland.  Thus,  by  giving  to  one- 
year-old  hens,  in  addition  to  their  usual  food,  20  milligrams  of  fresh 
pituitary  substance  for  four  days,  it  was  found  that  the  average  daily 
number  of  eggs  laid  by  a  batch  of  655  hens  was  raised  from  273  during 
the  four  days  preceding  the  pituitary  feeding  to  352  during  the  four 
days  of  the  administration,  these  results  being  obtained  at  a  time  of 
year  when  the  natural  egg-production  of  the  hens  was  diminishing.  It 
was  further  observed  that  not  only  is  the  output  of  eggs  greatly  increased 
as  a  result  of  the  pituitary  feeding,  but  likewise  their  fertility,  for  in 
another  experiment  in  which  35  hens  were  kept  along  with  two  cockerels 
of  the  same  breed,  not  only  was  the  output  of  eggs  increased  (from  18  up 
to  33),  but  the  fertility  of  the  eggs  was  greatly  enhanced. 

Functions  of  the  Posterior  Lobe  (and  Pars  Intermedia). — As  already 
mentioned,  excision  of  this  part  of  the  pituitary  can  be  tolerably  well  with- 
stood by  the  animal,  so  much  so  indeed  that  from  its  behavior  after  the 
operation  we  can  conclude  little  as  to  the  function  of  the  lobe.  On  the 
other  hand,  extracts  of  the  posterior  lobe  injected  into  normal  animals 
produce  effects  that  are  very  striking,  indicating  that  the  main  function 
of  this  lobe  is  the  production  of  an  autacoid.  The  extracts  have  more  or  less 
an  epinephrine-like  action.  Such  extracts,  rendered  protein-free  and  steril- 
ized, are  obtainable  on  the  market  under  the  various  names  of  pituitrin, 
hypophysin,  etc.  From  them  a  crystallizable  material  has  been  obtained, 
but  this  is  probably  a  mixture  of  various  substances.  In  discussing  the 
functions  of  these  various  extracts,  it  must  be  remembered  that  the  inter- 
mediary part  (pars  intermedia)  is  included  with  the  posterior  lobe  in 
their  preparation. 

Although  the  effect  of  pituitary  extract  on  plain  muscle  fiber  (and  on 
glandular  tissue)  appears,  on  first  sight,  to  be  very  like  that  produced 
by  epinephrine,  it  has  been  found  on  closer  examination  that  the  two 
substances  really  act  in  different  ways.  The  rise  in  blood  pressure  pro- 
duced by  pituitary  autacoid  is  likely  to  be  more  prolonged  than  that 
produced  by  epinephrine.  It  stimulates  increased  cardiac  activity,  but 
after  the  vagi  have  been  cut  or  sufficient  atropine  administered  to  para- 


THE    PITUITARY   BODY  811 

lyze  them,  the  pituitary  autacoid  continues  to  stimulate  the  strength  of 
the  heartbeat  without  producing  the  acceleration  noted  with  epinephrine. 
Whereas  epinephrine  has  little  or  no  action  on  the  coronary  vessels  (page 
268)  or  on  those  of  the  lungs,  pituitary  autacoid  usually  produces  constric- 
tion of  both  types  of  vessel ;  and  on  the  renal  arteries  the  actions  of  the  two 
autacoids  are  entirely  different,  for  epinephrine  has  a  marked  constric- 
ing  effect,  while  the  pituitary  autacoid  produces  dilatation. 

Another  striking  difference  in  the  extracts  from  the  two  glands  is  re- 
vealed by  repeating  the  injection  after  the  effect  of  a  previous  one  has 
completely  passed  off.  With  epinephrine  the  original  effect  is  repro- 
duced; with  pituitrin,  on  the  other  hand,  the  effect  of  the  second  injec- 
tion is  very  often  the  reverse  of  that  of  the  first;  that  is  to  say,  the  blood 
pressure,  instead  of  rising,  may  fall,  or  the  rise  be  very  much  less 
marked.  Whether  this  effect  of  the  second  dose  is  caused  by  the  action 
of  an  autacoid  having  a  chalonic  rather  than  a  hormonic  influence,  or 
whether  it  is  due  to  a  reversed  effect  of  the  same  hormone,  it  is  impos- 
sible at  present  to  say.  The  chalonic  effect  in  any  case  is  much  more 
evanescent  than  the  hormonic,  and  it  is  not  caused  by  cholin,  as  some 
have  suggested.  The  effect  of  epinephrine,  it  will  be  remembered,  is 
abolished  by  ergotoxin  and  apocodeine.  These  drugs,  on  the  other  hand, 
have  no  influence  on  the  action  of  pituitrin.  The  difference  in  action 
between  the  two  autacoids  is  usually  explained  by  assuming  that  the 
epinephrine  acts  on  the  receptor  substance  associated  in  some  way  with 
terminations  of  the  sympathetic  nerve  fibers  in  involuntary  muscle, 
whereas  pituitrin  acts  directly  on  the  involuntary  muscle  fibers  themselves. 
Other  types  of  involuntary  fiber  are  also  acted  upon  by  pituitrin.  The 
uterine  contractions,  for  example,  are  stimulated  (Fig.  199),  this  effect 
being  unconditioned  by  the  state  of  the  uterus. 

A  similar  effect  is  produced  upon  the  musculature  of  the  intestine 
and  bladder  (in  contrast  to  the  inhibitory  effect  of  epinephrine)  and 
upon  the  muscle  of  the  ureter.  Pupillary  dilatation  of  the  excised  frog's 
eye,  but  not  of  the  mammal's,  is  produced  by  pituitrin.  The  effect  of  this 
substance  upon  the  bronchioles  is  shown  in  Fig.  200. 

The  glands  upon  which  pituitrin  has  the  most  pronounced  action  are  the 
mammary  glands  and  the  kidneys.  It  has  no  influence  upon  the  salivary 
secretion.  The  effect  on  the  kidney  is  evidenced  by  the  remarkable  increase 
in  the  urinary  flow  following  injection  of  the  pituitrin.  This  diuresis  might 
of  course  be  due  merely  to  the  vasodilatation  that  we  have  seen  such  extracts 
produce — a  vasodilatation  which  is  all  the  more  marked  because  the  vessels 
elsewhere  in  the  body  undergo  constriction.  But  pituitrin  continues  to  cause 
increased  urinary  outflow  in  the  absence  of  any  demonstrable  vascular 
change;  it  also  acts  after  the  administration  of  atropine,  so  that  it  is  con- 
sidered by  some  observers  to  act  on  the  excretory  epithelium  of  the  convo- 


812 


THE   ENDOCRINE   ORGANS,    OR   DUCTLESS   GLANDS 


luted  tubules  and  to  constitute  a  renal  hormone  which  affects  the  epi- 
thelium of  the  kidney  in  a  manner  analogous  to  that  by  which  the 
pancreatic  cells  are  stimulated  by  secretin.  Another  reason  for  believ- 


Fig.    199. — Tracing  showing  the   action  of  pituitrin  on  the  uterine  contractions  and  blood   pressure 
in  a  dog.     Made   by   Barbour's  method.      (From  Jackson.) 

ing  that  the  secretory  hormone  is  independent  of  that  producing  vaso- 
dilatation  of  the  renal  vessels  is  the  fact  that  a  repeated  dose  of  pituitrin, 
although,  as  we  have  seen,  usually  has  a  depressor  action  on  the  blood 


THE    PITUITARY    BODY 


813 


vessels,  still  produces  a  stimulating  effect  on  the  excretion  of  urine. 

The  work  of  Knowlton  and  Silverman/'8  on  the  gaseous  exchange  of  the 
kidney  during  pituitrin  diuresis  is  against  this  view.  These  observers 
could  detect  no  increased  oxygen  consumption  accompanying  the  in- 
creased urinary  flow,  and  ascribe  the  latter  effect  purely  to  augmented 
blood  flow.  The  value  of  pituitriii  as  a  diuretic  in  clinical  practice  is  now 
well  recognized. 

The  work  of  Cow52  upon  the  secretory  activity  of  the  kidney  in  rela- 
tion to  pituitrin  administration  indicates  that  the  hypophysis  normally, 


Fig.    200. — Tracing   showing   the    constricting   action    of    pituitrin    on    the    bronchioles    and    its    effect 
on  blood  pressure   in   a  spinal  dog.      (From  Jackson.) 

is  part  of  a  mechanism  for  the  control  of  the  urinary  flow  its  action 
being  opposed  to  that  of  the  adrenal  medulla.  It  is  asserted  that  ingested 
fluid  taken  up  by  the  gastrointestinal  mucosa  absorbs  a  substance  of  a 
hormonic  nature  contained  therein,  which  passing  into  the  general  blood 
stream  calls  forth  the  diuretic  principle  from  the  pituitary  body. 

The  effect  on  milk  secretion  is  best  demonstrated  by  placing  a  cannula 
in  the  mammary  ducts  so  that  the  milk  may  freely  flow  out.  By  observ- 
ing the  rate  of  outflow  during  the  injection  of  pituitrin,  it  will  be  found 
that  a  remarkable  increase  occurs.  After  this  increased  secretion  has 
ceased,  however,  the  injection  of  more  pituitrin  has  no  further  effect, 
indicating  that  the  influence  of  the  first  injection  must  have  been,  not  so 


814 


THE    ENDOCRINE    ORGANS,    OR    DUCTLESS    GLANDS 


much  to  stimulate  the  secretion  of  milk,  as  to  accelerate  the  outflow  of 
that  which  previously  had  been  secreted  and  had  collected  in  the  alveoli 
and  ducts.  This  effect  explains  why  the  pituitary  galactagogue  should 
have  very  little  if  any  effect  on  the  total  production  of  milk  or  on  the 
total  amount  of  fat  and  other  constituents  contained  in  it.  Histological 
examination  of  sections  of  a  resting  mammary  gland  and  of  the  same 
gland  after  administration  of  the  pituitrin,  bears  out  the  above  interpre- 
tation of  the  action.  Alveoli  in  the  resting  state  will  be  found  largely 
distended  with  milk  and  the  epithelium  flattened  against  the  basal  mem- 
brane, whereas  alveoli  from  the  gland  after  pituitary  activity  show  small 
shriveled-up  alveoli,  containing  little  milk,  and  with  epithelium  that  is 
well  marked  and  stands  out  prominently  from  the  basal  membrane. 

These  facts  taken  together  indicate  that  pituitrin  stimulates  the  mus- 
cular fibers  of  the  ducts  of  the  mammary  glands,  thus  squeezing  out  the 
milk  contained  in  them.  Muscular  fibers  have  been  described  as  existing 
between  the  basal  membrane  and  epithelial  cells,  much  in  the  same  way 
as  they  do  in  the  case  of  the  sweat  glands.  At  least  Schafer  has  suc- 
ceeded in  demonstrating  in  this  position  rod-shaped  nuclei  which  prob- 
ably belong  to  muscular  fibers.3  By  their  contraction,  the  milk  in  the 
alveoli  is  expelled  into  the  ducts.  The  observation  of  Maxwell,53  namely, 
that  the  alveolar  contour  of  a  lactating  gland  failed  to  show  any  change 
when  irrigated  with  pituitrin,  is  opposed  to  the  foregoing  view.  It  has  also 
been  found  that  pituitrin  stimulates  the  secretion  of  cerebrospinal  fluid 
and  that  this  stimulation  is  independent  of  a  rise  in  blood  pressure. 

Eecently  Abel  and  Kuboto54  have  brought  forward  evidence  to  show  that 
the  depressor  effect  of  pituitrin  is  not  specific,  but  is  due  to  the  presence  of 
histamine  (/?-iminazolethylamine)  a  substance  we  have  seen  to  be  produced 
by  the  decarboxylation  of  histidine  (page  536).  These  authors  have  isolated 
the  depressor  and  the  plain-muscle  stimulant  principle  from  the  posterior 
lobe  of  the  pituitary  in  the  form  of  a  di-picrate.  With  regard  to  crystalline 
form,  solubility,  melting  point  and  the  method  of  its  isolation,  this  sub- 
stance is  identical  with  the  di-picrate  of  histamine ;  since  the  physiological 
actions  of  the  two  substances  are  also  the  same  their  unity  is  believed  to  be 
established. 

Pituitrin  has  a  distinct  effect  on  carbohydrate  metabolism.  After  its 
intravenous  or  subcutaneous  injection,  a  marked  lowering  in  the  toler- 
ance for  sugar  is  observed  (page  685),  usually  to  such  an  extent  that 
glycosuria  becomes  established.  Gushing  and  his  pupils  have  concluded 
that  the  posterior  lobe  contributes  an  autacoid  which  influences  the  utili- 
zation of  sugar  in  the  body.  Confirmatory  evidence  for  this  view  is  fur- 
nished by  the  observation  that  mechanical  stimulation  of  the  posterior 
lobe,  such  as  is  produced  by  puncturing  it  with  a  needle,  is  followed  by 


THE    PITUITARY    BODY 


815 


a  temporary  glycosuria,  which  is  said  to  be  as  pronounced  as  -that  fol- 
lowing puncture  of  the  diabetic  center  (page  704),  provided  glycogen  is 
present  in  the  liver.  The  production  of  this  carbohydrate  autacoid  would 
appear  to  be  under  the  control  of  the  sympathetic  nervous  system,  for  it 
has  been  found  by  Gushing  and  others  that  stimulation  of  the  superior 
cervical  ganglion,  which  has  been  known  for  many  years  to  be  fre- 
quently followed  by  glycosuria,  has  this  effect  only  provided  the  posterior 
lobe  of  the  pituitary  is  intact.  Even  surgical  manipulation  of  the  pitui- 
tary may  excite  a  hypersecretion  of  pituitrin,  which  would  account  for 
the  glycosuria  often  observed  after  experimental  excision  or  partial 


A. 


B. 


Fig.    201. — A,    To    show    the    appearance    before    the    onset    of    acromegalic    symptoms;    B,    The    ap- 
pearance after  seventeen  years  of  the  disease.      (After  Campbell  Geddes.) 

destruction  of  the  pituitary.  A  similar  irritation  may  be  set  up  in  disease 
of  the  gland. 

The  glycosuria  which  is  usually  observed  after  partial  hypophysectomy 
soon  passes  off,  to  be  followed  by  a  permanent  condition  of  increased 
tolerance  for  sugar,  because  now  less  pituitrin  is  being  produced.  It  is 
said  that  during  the  stage  of  increased  tolerance  diabetes  can  not  be  pro- 
duced even  by  excision  of  the  pancreas.  The  glycosuria  produced  by 
irritation  of  the  posterior  lobe  is  accompanied  by  a  marked  polyuria  (dia- 
betes insipidus),  which  may  outlast  the  glycosuria. 

The  extract  of  the  pars  intermedia  has  an  action  similar  to  but  not 
identical  with  that  of  the  posterior  lobe,  some  of  the  effects  of  which  it 
lacks,  for  example,  it  possesses  no  pressor  action  or  influence  upon  the 
kidney,  and,  though  it  exhibits  galactogogue  and  oxytocic  qualities,  these 


816  THE    ENDOCRINE    ORGANS,    OR    DUCTLESS    GLANDS 

are  considerably  less  potent  than  in  the  case  of  extracts  of  the  pars  nervosa. 
The  active  principle  of  the  pars  intermedia,  on  account  of  these  differences, 
is  looked  upon  by  Herring55  as  representing  an  immature  stage  in  the  manu- 
facture of  the  active  principle  of  the  gland,  the  final  product  of  which  is 
represented  by  the  extract  of  the  posterior  lobe.  The  fact  that  the  cells 
of  the  pars  intermedia  are,  apparently,  the  ultimate  source  of  the  pituitary 
autacoid  (see  page  806)  supports  this  view. 

Clinical  Manifestations  of  Deranged  Pituitary  Function 

Because  of  their  importance  from  a  physiological  standpoint,  we  shall 
now  proceed  to  review  briefly  some  of  the  more  important  facts  that  have 
so  far  been  brought  to  light  by  clinical  observations.  The  pathological 
condition  most  frequently  observed  affecting  the  pituitary  is  an  adenom- 
atous  growth  particularly  located  in  the  anterior  lobe.  Besides  pro- 
ducing general  symptoms  of  pressure,  such  as  diminution  of  the  visual 
field  and,  perhaps,  headache,  a  shadow  can  usually  be  observed  when  the 
patient  is  examined  by  means  of  the  x-rays.  General  symptoms,  com- 
monly ascribed  to  a  hypersecretion  of  the  autacoid  of  the  anterior  lobe  of 
the  pituitary — hyperpituitarism — begin  sooner  or  later  to  show  them- 
selves. These  symptoms  are  almost  exactly  opposite  in  character  to  those 
observed  in  animals  after  removal  of  this  portion  of  the  gland.  Thus, 
the  bones  of  the  extremities  become  stimulated  to  increased  growth, 
so  that  if  the  patient  is  young,  and  the  epiphyses  therefore 
not  ossified,  remarkable  elongation  of  the  long  bones  occurs,  pro- 
ducing the  condition  known  as  gigantism.  On  the  other  hand,  if  the  dis- 
ease does  not  develop  until  after  ossification  is  complete,  its  effects  be- 
come most  marked  in  the  bones  of  the  face,  the  lower  jaw  becoming 
enormously  hypertrophied  and  the  supraorbital  ridges  very  prominent. 
The  long  bones  also  become  enlarged  at  their  extremities,  and  there  may 
be  some  increase  in  length  of  the  vertebral  column,  although  the  stature 
does  not  increase  because  of  kyphosis  (bowing  of  the  spine).  The 
condition  is  called  acromegaly.  Nutritive  disturbances  of  the  skin  and 
hairs  also  become  marked,  causing  the  skin  to  become  dry  and  yellowish, 
and  the  hairs  to  undergo  abnormal  increase  over  the  body.  An  early 
symptom  of  the  condition  is  a  failure  of  the  sexual  power  (Figs.  201  and 
202.) 

After  a  time  the  disease  begins  to  affect  the  pars  intermedia  et  nervosa, 
and  disturbances  in  carbohydrate  metabolism  come  to  be  observed,  con- 
sisting usually  in  a  diminished  tolerance  accompanied  by  glycosuria,  in 
the  early  stages  of  the  disease,  followed  by  increased  tolerance  in  the 
later  stages.  The  glycosuria  is  usually  accompanied  by  marked  polyuria. 

It  should  be  observed  that  sometimes  tumor  of  the  pituitary  has  been 


THE    PITUITARY   BODY  817 

found  to  exist  postmortem  though  none  of  the  above  symptoms  had  been 
recorded  during  life.  In  these  cases  it  is  probable  that  the  disease  from 
the  start  had  been  of  such  a  nature  as  to  produce  a  tendency  to  hypo- 
pituitarism  rather  than  hyperpituitarism,  for  the  symptoms  are  very  like 
those  observed  in  animals  after  partial  or  complete  removal  of  the  gland. 
If  the  condition  commences  before  adolescence,  the  body  fails  to  grow, 
although  the  child  may  continue  to  increase  in  weight  because  of  the 


Fig.  202. — Hand  of  a  person  affected  with  acromegaly. 

remarkable  deposition  of  fat  in  the  tissues.  Sexual  development  is  strik- 
ingly interfered  with,  and  the  secondary  sexual  characteristics  fail  to 
show  themselves.  In  boys,  for  example,  the  pubic  hairs  fail  to  extend  up 
to  the  umbilicus;  and  the  hairs  on  the  chin  do  not  develop,  whereas  the 
hair  of  the  scalp  grows  profusely.  The  bones  remain  of  the  female  type, 
and  a  broad  pelvis,  rounded  limbs,  small  feet  and  hands  are  often  ob- 
served. In  these  cases  there  is  usually  excessive  tolerance  for  carbohy- 
drates, which  may  explain  the  adiposity,  sugar  being  converted  into  fat. 
In  the  light  of  the  experimental  results,  the  effect  on  carbohydrate 


818 


THE   ENDOCRINE    ORGANS,    OR    DUCTLESS    GLANDS 


metabolism  may  be  explained  as  due  to  involvement  of  the  posterioi 
lobe.  Mental  development  is  retarded,  and  psychic  derangements  ar< 
sometimes  observed. 

Where  the  hypopituitarism  does  not  develop  until  after  adolescence, 
some  of  the  above  symptoms  will  of  course  be  missed,  but  many  will 
observed,  such  as  dryness  of  the  skin,  loss  of  hair,  and  the  tendency  ri 
the  male  to  adopt  certain  of  the  female  characteristics,  particularly  witl 
regard  to  the  growth  of  hair.  Obesity  and  increased  tolerance  for  sugai 
are  also  evident,  and  pigmentation  of  the  skin,  something  like  that  ol 
Addison's  disease,  is  said  often  to  be  a  prominent  feature.  These  clini< 
types  of  hypopituitarism  (both  the  preadolescent  and  the  postadolescent] 
were  first  described  as  entities  by  Frohlich,  and  are  grouped  under  th( 
term  dystrophia  adiposo-genitalis.  They  are  due  undoubtedly  to  involv( 
ment  of  both  lobes  of  the  pituitary. 

In  contrast  to  the  foregoing,  a  form  of  infantilism  associated  with  hypopi- 
tuitarism occurs,  in  which  the  subjects  are  not  obese  but  rather  the  revers( 
There  is  a  markedly  retarded  development  of  the  skeleton  and  the  sexual 
organs,  while  the  patient  presents  to  the  casual  observer  the  appearam 
of  an  ill-nourished  child.    When  stripped,  however,  it  is  seen  that  he  01 
she,  is  in  reality,  except  for  the  sexual  immaturity,  a  man  or  a  woman  ii 
miniature.     The  form  possesses  the  lineaments  of  the  adult,  the  relative 
bodily  proportions  of  the  child  being  absent.    This  type,  which  is  usually 
known  as  that  of  Lorain,  is  probably  due  to  disease  affecting  chiefly  th( 
anterior  lobe.     Operative  interference  in  the  early  stages  in  many  cas( 
of  hypopituitarism  as  well  as  of  hyperpituitarism  is  of  undoubted  benefit, 
as  is  shown  by  the  brilliant  work  of  Harvey  Gushing,  to  which  the  reader 
referred  for  further  information. 

The  Relationship  of  the  Pituitary  Gland  with  Other  Endocrine 

Organs 

The  relationship  of  the  pituitary  gland  with  other  endocrine  organs 
seems  to  be  an  intimate  one. 

1.  With  the  Thyroid  and  Parathyroid  Glands. — That  enlargement  oJ 
the  pituitary  occurs  after  thyroidectomy  in  man  has  been  known  for 
considerable  number  of  years.     The  enlargement  affects  more  particu- 
larly the  pars  anterior,  although  changes  are  also  described  in  the  pai 
intermedia  et  nervosa.     Accompanying  the  enlargement  of  the  anterioi 
lobe,  vesicles  containing  colloid-like  material  often  become  developed  ii 
it,  but  even  after  the  hypertrophy  has  proceeded  to  a  considerable  d< 
gree,  this  colloid  does  not  contain  iodine,  nor  does  an  extract  have  th< 
same  physiological  effect  as  one  of  the  thyroid  gland.    It  can  not  replac< 
thyroid  extract  in  the  treatment  of  patients  with  goiter  or  myxedema, 


THE    PITUITARY    BODY  819 

or  ameliorate  the  symptoms  produced  in  animals  by  the  removal  of  the 
thyroid  gland.  Deposition  of  colloid-like  material  in  the  pars  anterior 
also  occurs  in  myxedema.  Histological  changes  in  the  pars  intermedia  et 
nervosa,  although  less  pronounced  than  in  the  pars  anterior,  are  never- 
theless said  to  be  perfectly  distinct  following  thyroidectomy,  and  to  con- 
sist in  an  increase  in  the  hyaline  and  granular  masses  which  have  already 
been  described  as  present  to  a  certain  extent  in  the  normal  gland. 

Less  direct  evidence  of  an  association  in  function  between  the  pituitary 
and  the  thyroid  is  furnished  by  the  similarity  of  the  effects  produced  on 
the  sexual  functions  and  on  the  general  development  of  young  animals 
by  the  removal  of  either  gland.  In  both  cases  the  animals  fail  to  grow 
properly;  the  sexual  organs  remain  undeveloped;  and  the  mental  func- 
tions are  infantile  in  type.  In  hypophysial  deficiency,  however,  extreme 
adiposity  is  likely  to  be  more  marked  than  is  the  case  in  cretinism. 

2.  With  the  Sexual  Organs. — That  the  pituitary  gland  has  much  to  do 
with  the  development  of  the  sexual  organs  has  already  been  shown.    Fur- 
ther evidence  of  a  relationship  between  the  sexual  glands  and  the  pitui- 
tary is  furnished  by  the  following  observations.     After  castration  en- 
largement occurs  in  the  pituitary,  and  on  histological  examination  the 
gland  is  found  to  contain  a  large  number  of  oxyphile  cells,  particularly 
in  the  pars  anterior.    This  influence  of  the  sexual  glands  on  the  pituitary 
is  believed  to  depend  on  the  interstitial  cells  present  in  them,  for  it  has 
been  found  that  if  the  ovary  or  testis  is  transplanted  into  other  parts  of 
the  body  after  the  castration,  the  changes  in  the  pituitary  do  not  occur, 
although,   as  we   shall   see,   the   transplanted   gland   becomes   entirely 
atrophied  except  for  the  interstitial  cells.    The  enlargement  of  the  pitui- 
tary during  pregnancy — an  enlargement  which  often  brings  it  to  two  or 
three  times  its  normal  weight — is  further  evidence   of  its   association 
with  the  ovary. 

3.  With  the  Suprarenals. — Association  of  function  is  suggested  in  this 
case  by  the  fact  that  extracts  of  suprarenal  and  pituitary  have  very  much 
the  same  effects  on  involuntary  muscular  fiber  and  glandular  structures, 
and  it  is  said  that  the  two  extracts  mutually  facilitate     each  other's 
action  in  this  regard.    It  should  be  remembered,  however,  that  pituitrin 
and  epinephrine  do  not  appear  to  act  on  exactly  the  same  peripheral 
mechanism  (see  page  811). 

4.  With  the  Isles  of  Langerhans. — Since  pituitrin  affects  carbohydrate 
metabolism,  which  is  thought  to  be  primarily  controlled  by  the  Isles  of 
Langerhans,  it  is  claimed  by  some  observers  that  a  relationship  also 
exists  between  the  pituitary  and  these  structures.    Injections  of  duodenal 
extracts  are  also  said  to  cause  a  hypersecretion  of  pituitrin  into  the- 
cerebrospinal  fluid. 


CHAPTER  LXXXVIII 
THE  PINEAL  GLAND,  THE  GONADS,  AND  THE  THYMUS 

THE  PINEAL  GLAND 

This  peculiar  structure  lies  between  the  anterior  corpora  quadrigem- 
ina,  and  weighs  about  two-tenths  of  a  gram.  It  is  largest  in  the  early 
years  of  life,  and  undergoes  retrogressive  changes  after  puberty.  Micro- 
scopically it  consists  of  epithelial  cells  arranged  loosely  in  trabeculae, 
with  large  sinus-like  capillaries  between  them;  neuroglia  and  sometimes 
muscle-fiber  cells  are  also  present.  Curious  globules  of  calcareous  mat- 
ter (brain-sand)  are  also  found,  especially  in  the  pineal  gland  of  man. 
The  gland  is  developed  from  an  evagination  of  the  third  ventricle,  and 
it  is  homologous  with  the  so-called  median  eye  of  reptiles. 

The  functions  of  the  pineal  gland  are  obscure.  In  cases  where  its 
extirpation  has  been  successfully  accomplished  (in  the  fowl),  it  has  been 
found  that  the  body  growth  is  stimulated  and  that  the  sexual  characteris- 
tics develop  more  quickly.  This  result  would  seem  to  indicate  that  the 
clinical  observation  that  tumors  of  the  pineal  gland  associated  in 
young  boys  with  abnormal  growth  of  the  skeleton  and  with  early 
development  of  the  secondary  sexual  characteristics,  depends  on  the 
fact  that  a  new  growth  produces  destruction  of  the  gland  with  consequent 
hypopinealism.  The  immediate  effects  of  the  injection  of  extract  of  pineal 
gland  are  not  characteristic,  consisting  merely  of  a  fall  in  blood  pressure, 
which  is,  however,  obtainable  when  an  extract  of  practically  any  cellular 
organ  is  injected.  Prolonged  administration  of  an  extract  to  growing  ani- 
mals is  said  to  accelerate  the  growth  and  to  bring  about  a  precocious  develop- 
ment of  the  sexual  organs;  but  this  result  is  somewhat  difficult  to  inter- 
pret, for,  as  we  have  just  seen,  similar  changes  occur  after  experimental 
removal  of  the  gland.  It  is  stated  by  McCord  and  Allen56  that  the  pig- 
ment cells  (melanophores)  of  tadpoles  become  contracted  after  pineal 
feeding.  As  the  receptors  of  the  reflex  governing  such  color  reactions  of 
various  animals  are  situated  in  the  retina,  these  investigators  give  signi- 
ficance to  their  observations  by  correlating  them  with  the  fact  that  the 
pineal  gland,  as  stated  above,  is  the  representation  of  a  reptilian  eye. 

820 


THE    PINEAL    GLAND    AND    THE    GONADS  821 

THE  GONADS  OR  GENERATIVE  ORGANS 

The  Generative  Glands  of  the  Male 

The  structures  which  are  responsible  for  the  well-known  influence  of 
the  testicles  on  the  development  of  the  male  sexual  characteristics  are 
the  so-called  interstitial  cells  of  Leydig,  which  consist  of  polygonal- 
shaped  epithelial-like  cells,  with  well-marked  nuclei  and  nucleoli.  Lipoid 
granules,  staining  black  with  osmic  acid,  are  also  present  in  the  cyto- 
plasm. The  degree  of  development  of  the  interstitial  cells  varies  in  dif- 
ferent animals,  being  marked  in  the  cat  and  man  and  ill-marked  in  the 
rat  and  rabbit.  In  animals  which  show  seasonal  changes  in  sexual  activ- 
ity, the  cells  are  most  prominent  between  the  periods  of  sexual  activity, 
when  the  semeniferous  epithelium  is  less  evident.  They  also  become 
prominent  in  cases  where  the  semeniferous  epithelium  is  atrophied, 
either  as  a  result  of  disease  or  following  ligation  of  the  vas  def erens  done 
in  such  a  way  that  the  artery  and  nerves  to  the  testicles  are  not  included 
in  the  ligature.  When  the  testicle  or  a  portion  of  it  is  grafted  into 
another  part  of  the  body,  the  semeniferous  epithelium  degenerates,  but 
the  interstitial  cells  remain  alive  and  become  quite  prominent.  It  is 
believed  that  the  interstitial  cells  are  responsible  for  the  production  of 
an  autacoid  that  has  to  do  with  the  development  of  accessory  sexual 
characteristics. 

T~he  effects  of  castration  are  not  significant  in  animals  below  the  verte- 
brata.  In  all  of  these,  however,  they  are  very  pronounced.  The  cas- 
trated male  frog  fails  to  show  development  of  the  thumb  pad,  but  this 
development  immediately  ensues  if  portions  of  testis  from  another  frog 
be  placed  in  the  dorsal  lymph  sac.  In  birds  the  results  are  more  pro- 
nounced; m  the  castrated  male  chick  the  comb,  spurs,  wattles,  etc.,  fail  to 
develop,  but  will  usually  do  so  if  some  testis  from  another  bird  is  trans- 
planted into  its  tissues.  In  mammals  the  effects  are  most  striking  in 
animals  that  develop  marked  male  characteristics,  such  as  the  growth 
of  antlers  in  stags.  These  fail  to  develop  properly  and  are  prematurely 
shed  after  castration.  In  man  also,  as  is  well-known  from  a  study  of 
eunuchs,  castration  has  a  very  profound  effect.  Hair  fails  to  grow  on  the 
face;  the  larynx  remains  undeveloped;  the  epiphyses  are  a  long  time  in 
ossifying,  so  that  the  stature  may  become  great,  but  at  the  same  time 
the  limb  bones  may  be  more  delicate  than  usual ;  the  sutures  of  the  skull 
are  slow  in  closing ;  and  the  whole  architecture  of  a  castrated  male  comes 
to  be  very  like  that  of  the  female.  Confirmatory  evidence  of  the  influ- 
ence of  the  testicles  on  the  development  of  secondary  sexual  character- 
istics is  afforded  by  the  observation  that  malignant  tumors  of  the  testes 
in  boys  are  associated  with  the  premature  development  of  the  secondary 


822 


THE   ENDOCRINE   ORGANS,    OR   DUCTLESS   GLANDS 


sexual  characteristics,  and  that  these  may  recede  after  the  removal  oJ 
the  tumor. 

As  a  result  of  castration,  interesting  changes  have  also  been  observe* 
in  other  ductless  glands.     Thus,  the  suprarenal  cortex  and  the  thymuj 
become  enlarged,  whereas  the  thyroid  and  pituitary  become  atrophie< 
The  metabolic  functions  also  become  tardy,  as  is  evidenced  by  a  tendency 
to  the  deposition  of  fat. 

When  the  castration  is  performed  on  an  adult  man,  the  above  chang< 
in  the  sexual  characteristics  are  of  course  not  so  evident,  although  the 
prostate,  etc.,  atrophy.     The  effect  on  the  metabolic  functions  is,  how- 
ever, very  marked,  there  being  a  striking  tendency  to  increased  form* 
tion  of  fat.    It  is  interesting  that  accompanying  this  there  should  usual] 
occur  a  lowering  of  the  assimilation  limit  for  carbohydrate,  so  that  glyc< 
suria  is  very  readily  induced.     We  can  not  assume,  therefore,  as  Gush- 
ing has  done  in  the  case  of  hypopituitarism,  that  the  fat  deposition  if 
attendant  upon  an  improper  combustion  of  carbohydrate. 

These  remarkable  effects  of  castration  have  naturally  prompted  ol 
servers  to  study  the  influence  of  injection  of  testicular  extract  on  th( 
development  of  sexual  characteristics  in  different  animals,  but  the  re- 
sults have  in  general  been  considered  to  be  of  a  negative  character. 


The  Female  Generative  Organs 

It  is  well  known  that,  besides  their  function  in  producing  ova,  th< 
ovaries  also  produce  autacoids  that  have  to  do  not  only  with  the  fix* 
tion  of  the  embryo  in  utero,  but  also  with  the  changes  that  occur  during 
pregnancy  in  the  maternal  organism.    It  is  however  at  present' uncertain 
as  to  where  these  autacoids  are  produced  in  the  ovary.     The  two  mos 
likely  sources  are  the  stroma  cells  and  the  corpus  luteum.    In  the  stroma 
of  the  ovary  of  certain  animals,  groups  of  cells  have  been  describe( 
having   a   different   appearance   from   those   of   ordinary   stroma   cell 
They  have  been  called  the  interstitial  cells  of  the  ovary,  and  are  believe< 
to  be  analogous  with  the  similar  structures  found  in  the  testicle.    It  i* 
possible,  however,   that  these  interstitial  cells  are  nothing  more  thai 
cells  derived  from  previous  corpora  lutea.     The  latter  are  formed 
proliferation  of  the  follicular  epithelium  which  remains  after  extrusioi 
of  the  ovum,  and  by  the  ingrowing  into  the  follicle  of  the  so-called  theci 
cells  and  blood  vessels.     The  fully '  developed  corpus  luteum  in  most 
animals  consists  of  cells  arranged  in  trabeculse  converging  toward  th< 
scar  which  formed  at  the  place  where  the  follicle  had  burst.     The  luteal 


THE    PINEAL    GLAND    AND    THE    GONADS  823 

cells,  as  they  are  called,  are  characterized  by  containing  considerable 
quantities  of  lipoid  material. 

That  the  ovary  produces  some  autacoid  is  evidenced  by  both  clinical 
and  experimental  observations.  Thus,  if  both  ovaries  are  removed  in  a 
young  animal  (oophorectomy  or  spaying),  it  is  well  known  that  not 
only  does  the  uterus  fail  to  develop  properly,  but  the  external  changes 
characteristic  of  puberty  in  the  female  fail  to  materialize,  although  act- 
ually the  general  effects  are  not  so  pronounced  as  they  are  in  the  male 
after  castration.  Menstruation  does  not  set  in ;  the  mammary  glands  fail 
to  develop ;  and  there  is  a  tendency  for  the  hair  to  grow  as  in  the  male. 
When  the  operation  is  performed  in  adult  life,  the  changes  are  not  very 
pronounced,  except  that  menstruation  ceases  and  the  uterus  and  mam- 
mary glands  atrophy.  Metabolism  also  becomes  altered,  causing  a 
tendency  to  the  deposition  of  fat,  and  in  the  case  of  the  human  animal  at 
least,  there  is  frequently  evidence  of  mental  disturbance. 

Attempts  to  acquire  more  definite  information  regarding  the  physio- 
logical effects  of  the  ovarian  autacoid  have  recently  been  made  by  Schafer 
and  Itagaki.3  Extracts  were  prepared  from  the  corpus  luteum  or  Graafian 
follicles  or  from  the  hilum  ovariae,  and  observations  were  made  on  the 
effect  produced  on  the  behavior  of  the  chief  forms  of  unstriated  muscle 
by  adding  the  extracts  to  isolated  preparations  of  uterus  or  intestine 
or  by  injecting  the  extracts  into  animals.  Applied  to  the  isolated  prepa- 
rations, extract  of  follicular  tissue  or  of  liquor  folliculi  was  found  to 
increase  the  force  and  rate  of  the  rhythmic  contractions  of  the  uterus  as 
well  as  its  tone,  whereas  inhibition  was  produced  when  extract  of  the 
hilum  was  used.  Extract  of  corpus  luteum,  when  injected  into  the 
veins,  was  found  to  cause  the  uterus  to  increase  its  contraction  or  if 
quiescent  to  begin  contracting.  It  was  further  noted  that  extracts  of  the 
hilum  caused  a  fall  in  arterial  blood  pressure,  whereas  those  of  the  corpus 
luteum  had  little  or  no  effect.  It  would  appear  from  these  observations 
that  the  extracts  contain  two  different  autacoids,  one  having  a  hormonic 
and  the  other  a  chalonic  action  on  plain  muscular  fiber. 

Extract  of  corpus  luteum  when  intravenously  injected  also  stimulates 
the  outpouring  of  the  milk  from  the  mammary  glands,  although  not  so 
markedly  so  as  extract  of  pituitary  gland.  This  pituitary-like  action  is 
not  obtained  with  extracts  of  ovary  that  do  not  contain  corpora  lutea. 
Besides  being  concerned  in  the  outpouring  of  milk,  corpus  luteum  has 
also  been  shown  to  be  related  in  some  way  to  the  development  of  the 
mammary  gland  during  pregnancy.  These  glands  become  developed  in 
young  virgin  rabbits  after  the  continuous  administration  for  a  month 
or  so  of  extract  of  corpus  luteum,  and  they  also  develop  in  unimpreg- 


824  THE   ENDOCRINE   ORGANS,    OR   DUCTLESS   GLANDS 

nated  animals  when  the  corpus  luteum  is  made  to  develop  by  artificial 
means  such  as  puncturing  the  Graafian  follicle.  Furthermore,  destruc- 
tion of  the  corpora  lutea  in  a  pregnant  rabbit  arrests  development  of 
the  mammary  glands.  The  corpus  luteum  has  also  an  important  func- 
tion in  connection  with  the  formation  of  the  uterine  decidua  and  the 
fixation  of  the  embryo.  Thus,  after  destruction  of  the  corpus  luteum  at 
an  early  period  in  pregnancy,  the  embryo  fails  to  become  adherent  to 
the  uterus. 

THE  THYMUS* 

The  structure  of  the  thymus  is  of  a  lymphoid  nature  consisting  of  a 
cortex  composed  of  closely  packed  masses  of  lymphocytes  and  a  medulla 
made  up  of  a  cellular  reticulum,  in  the  meshes  of  which  are  seen  large 
bodies  possessing  a  concentric  configuration — the  corpuscles  of  Hassel. 
The  gland  is  developed  from  outgrowths  of  the  third  branchial  pouch 
on  either  side,  which,  meeting  in  the  midline,  unite  to  form  a  solid  block 
of  cells,  this  later,  becoming  hollowed  out  and  branched.  In  the  walls  of 
the  tubules,  so  formed,  lymph  nodes  appear  which  ultimately  form  the 
cortex.  The  walls  of  the  tubules  themselves  break  up,  their  cellular 
elements  subsequently  forming  the  reticulum  and  concentric  corpuscles 
of  the  medulla.  Though  prominent  in  early  childhood  the  thymus  un- 
dergoes progressive  involution  with  advancing  years,  until  in  adult  life 
it  is  more  or  less  vestigial  in  character.  It  is  still  a  question  whether  this 
body  should  be  included  with  the  organs  of  internal  secretion,  and  though 
many  views,  mostly  of  a  more  or  less  speculative  nature,  have  been  ad- 
vanced to  justify  its  consideration  as  an  endocrine  organ,  the  proof  that 
it  possesses  an  internal  secretion,  in  the  generally  accepted  sense,  is 
wanting.  It  is  wiser  perhaps  to  state  that  its  functions  are  obscure,  and 
that  we  do  not  know  what  role  it  plays  in  the  animal  economy.  The  re- 
sults of  feeding  the  gland  to  animals  or  of  ablation  experiments  are  con- 
flicting and  of  little  help  in  arriving  at  any  conclusion  in  this  regard. 
Attention,  however,  should  be  drawn  to  certain  significant  facts  regarding 
its  behavior.  First,  its  involution  is  arrested  or  retarded  after  castration, 
a  fact  suggestive  of  an  endocrine  function ;  secondly,  it  is  believed  to  be  a 
source  of  the  lymphocytes,  and  possibly  also  of  the  granular  leucocytes. 
Examinations  of  the  blood,  with  a  view  to  the  lymphocytic  counts,  show, 
from  infancy  to  puberty,  a  declining  curve,  the  gradient  of  which  follows 
closely  that  of  thymic  involution.  On  this  account  it  is  believed  by  some 
that  "the  thymus  functions  as  a  lymphoid  organ  in  infancy  and  child- 
hood when  a  large  number  of  lymphoid  cells  and  leucocytes  are  needed 
to  combat  infection."  (Hoskins,  E.  R.). 


'For  a  review  of  the  literature,   the  reader  is  directed  to  a  recent  article  by   Blatz.57 


THE    PINEAL   GLAND   AND    THE    GONADS  825 

DUCTLESS  GLANDS  REFERENCES 

(Monographs) 

i  Vincent,  Swale:     Internal  Secretions  and  the  Ductless  Glands,  Ed.  Arnold,  London. 
sBiedl:     The  Internal  Secretory  Organs,  Wm.  Wood  &  Co.,  1913. 

sSchafer,  Sir  E.  A.:     The  Endocrine  Organs,  Longman's,  Green  &  Co.,  New  York  and 
London,  1916. 

(Original  Papers) 

*Guthrie,  L.,  and  Emery,  W.  d'  E.:     Trans.  Clin.  Soc.,  London,  1907,  xl,  175;  also  Bul- 
lock, W.,  and  Segueira,  J.:     Trans  Path.  Soc.,  London,  1905,  Ivi,  189. 
sMyers:     Trans.  Path,  Soc.,  London,  1898,  xlix,  368. 
e  Wheeler:     Quoted  by  Swale,  Vincent:     Endocrin,  1917,  i,  140. 
7Halle,  W.  L. :  Quoted  by  Schaf er,  E.  A. :     Brit.  Med.  Jour.,  June  6,  1908. 
sEwins,  A.  J.,  and  Laidlaw,  P.  P.:     Jour.  Physiol.,  1910,  xl,  275. 
sBoyd,  W. :     Jour.  Lab.  and  Clin.  Med.,  1918,  iv,  133. 

loFolin,  O.,  Cannon,  W.  B.,  and  Denis,  W. :     Jour.  Biol.  Chem.,  1913,  xiii,  447. 
nCow,  D.:     Jour.  Physiol.,  1915,  xlix,  441. 

32Addis,  T.,  Barnett,  G.  D.,  and  Shevky,  A.  E.:      Am.  Jour.  Physiol.,  1918,  xlvi,   39. 
isCannon,  W.  B.,  and  Gray,  H.:     Am.  Jour.  Physiol.,  1914,  xxxiv,  232;  also  with  Men- 

delhall,  W.  L. :     Ibid.,  243  and  251. 
i^Moore,    B.,    and   Purinton,    C. :     Am.    Jour.    Physiol.,    1900,    iii,    Proc.    Am.    Physiol. 

Soc.  XV. 

isHoskins,  B.  G.:     Am.  Jour.  Physiol.,  1912,  xxix,  363. 

leHartman,  F.  A.,  and  others:     Am.  Jour.  Physiol.,  1915,  xxxviii,  433;  ibid.,  1917,  xliii, 

311;  ibid.,  xliv,  353;  ibid.,  1918,  xlv,  111;  ibid.,  xlvi,  168,  502  and  521;  Endocrin., 

1918,  ii,  122;  ibid.,  1919,  iii,  321;  Jour.  Pharm.  and  Exper.  Therap.,  1919,  xiii, 

417. 

i7Hoskins,  R.  G.,  Gunning,  R.  E.  L.,  and  Berry,  E.  L.:     Am.  Jour.  Physiol.,  1916,  xli, 

513. 

isGruber,  C.  M.,  and  Fellows,  A.  P.:     Am.  Jour.  Physiol.,  1918,  xlvi,  472;  and  Gruber, 
C.  M.:     ibid.,  1914,  xxxiii,  335;  Gruber,  C.  M.,  and  Kretschmer,  O.  S.:     ibid., 
1918,  xlvii,  179. 
isStewart,  G.  N.,  and  Kogoff,  J.  M.:     Jour.  Lab.  and  Clin.  Med.,  1918,  iii,  209.     See 

full  bibliography  by  Rogoff  in  this  paper. 
soElliott,  T.  R. :     Jour.  Physiol.,  1912,  xliv,  374. 

2iStewart,  G.  N. :     Jour.  Exper.  Med.,  1911,  xiv,  377;  ibid.,  1912,  xv,  547;  ibid.,  xvi,  502. 
22Meltzer,  S.  J.:     Deutsch.  Med.  Wchnschr.,  1909,  xiii. 
2^Stewart,  G.  N. :     Rogoff,  J.  M.,  and  Gibson,  F.  S. :     Jour.  Pharm.  and  Exper.  Therap., 

1916,  viii,  205. 

24Hoskins,  R.  G.,  and  McClure,  C.  W. :  Arch.  Int.  Med.,  1912,  x,  343. 
25Stewart,  G.  N.:     Jour.  Exper.  Med.,  1911,  xiv,  377. 
"~mnon,  W.  B.,  et  al:     Am.  Jour.  Physiol.,  1911,  xviii,  64;  ibid.,  1914,  xxxiii,  356;  also 

Bodily  Changes  in  Pain,   Hunger,  Fear  and  Rage,  D.  Appleton  &  Co.,   1915. 
^Stewart,  G.  N.,  and  Rogoff,  J.  M.:     Jour.  Exper.  Med.,  1917,  xxvi,  637;  Jour.  Pharm. 

and  Exper.  Therap.,  1917,  x,  49;  Am.  Jour.  Physiol.,  1917,  xliv,  543. 
Stewart,  G.  N.,  and  Rogoff,  J.  M.:  Am.  Jour.  Physiol.,  1920,  li,  366. 
^Cannon,  W.  B.:     Am.  Jour.  Physiol.,  1919,  1,  399. 

vy,  A.  G.:     Heart,  1913,  iv,  342. 
^Gasser,  H.  S.,  and  Meek,  W.  J.:     Am.  Jour.  Physiol.,  1914,  xxxiv,  63. 
'2Redfield,  A.  C.:     Jour.  Exper.  Zool.,  1918,  xxvi,  275. 
Cannon,  W.  B.,  and  Cattell,  McK.:     Am.  Jour.  Physiol.,  1916,  xli,  74. 
'Macleod,  J.  J.  R.,  and  Pearce,  R.  G.:     Am.  Jour.  Physiol.,  1912,  xxix,  419 
^Marine,  D. :     Personal  communication. 
3Marine,  D. :     Jour.  Exper.  Medv  1914,  xix,  89. 
'^Marine,  D.,  and  Lenhart,  C.  H.:     Jour.  Exper.  Med.,  1910,  xii,  211;  ibid.,  1911,  xiii, 

455;  also  Bull.  Johns  Hopkins  Hosp.,  1910,  xxi,  95. 
ssKendall,   E.   C.:     Boston   Med.   and  Surg.   Jour.,   1916,   clxxv,   557;    also   Proc.   Am. 

Phys.  Soc.,  1918,  xliv. 
^Marine,  D.,  and  Kimball,  O.  P.:      Jour.   Lab.   and  Clin.  Med.,  1917,  iii,   41. 
3Gudernatsch,  J.  F.:     Am.  Jour.  Anat.,  1913,  xv,  431. 

llRogoff,  J.  M.,  and  Marine,  D. :     Jour.  Pharm.  and  Exper.  Therap.,  1916,  ix,  57. 
^Kendall:     Enderin,   1918,  ii,  81;   ibid.,  1919,  3,  156. 

Also  Plummer,  H.  S-:     Am.  Jour.  Physiol.,  1918,  Proc.  Am.   Soc.  Phys.,   1918. 


826 


THE   ENDOCRINE   ORGANS,    OR   DUCTLESS   GLANDS 


43Marine,  D.,  and  Lenhart,  C.  H.:     Arch.  Int.  Med.,  1911,  viii,  265. 

44 Wilson,  L.  B.:     Am.  Jour.  Med.   Soe.,   1916,.  elii,   799  5   ibid.,   1913,  cxlvi,   731;    also 

Wilson,  L.  B.,  and  Durante,  L. :     Jour.  Med.  Kesearch,  1916,  xxxiv,  273. 
45paton,  Noel,  and  Finlay,  J.:     Quart.  Jour.  Exper.  Physiol.,  1916,  x,  203;  also  Paton, 

Noel,  Finlay,  J.,  and  Watson,  A.:     Ibid.,  233,  243,  315  and  377. 
46MacCallum,  W.  G.,  etc.:     Jour.  Exper.  Med.,  1909,  xi,  118;  ibid.,  1913,  xviii,  646;  Jour. 

Pharm.   and  Exper.   Therap.,   1911,   ii,   421. 

47Howland,  J.,  and  Marriott,  W.  McK. :     Bull.  Johns  Hopkins  Hosp.,  1918,  xxix,  235. 
48Cushing,  Harvey:     Pituitary  Body  and  Its  Disorders,  J.  B.  Lippincott  Co.,  1912. 
49Horsley,  V.:     Brit.  Med.  Jour.,  1885,  i,  111. 
soKobertson,  Brailsford,  and  Kay,  L.  A.:     Jour.  Biol.  Chem.,  1916,  xxiv,  347,  363,  385, 

397,  409. 

siClark,  L.  N.:   Jour.  Biol.  Chem.,  1915,  xxii,  485. 
52Cow,  D.:      Jour.  Physiol.,   1914,  xlviii,  443. 
ssMaxwell,  A.  L.  J.:     Jour.  Physiol.,  1915,  xlix,  483. 
54Abel,  J.  J.,  and  Kuboto,  S. :     Jour.  Pharm.  and  Exper.  Therap.,  1919,  xiii,  243.     See 

also  Cow,  D.:     ibid,  1919,  xiv,  275;  Abel,  J.  J.,  and  Nazayama,  T.:     ibid.,  1920, 

xv,  347;  and  Dudley:  •  ibid.,  1919,  xiv,  295. 

soHerring,  P.  T. :     Quart.  Jour.  Exper.  Physiol.,  1914,  viii,  267. 
56McCord,  C.  P.,  and  Allen,  F.  P.:     Jour.  Exper.  Zool.,  xxiii,  207. 
."Blatz,  W.  E.:     Jour.  Lab.  and  Clin.  Med.,  1919,  v,  3. 
ssKnowlton,  J.  P.,  and  Silverman,  A.  C.:     Am.  Jour.  Physiol.,  1918,  xlvil,  1. 


PART  IX 

THE  CENTRAL  NERVOUS  SYSTEM  AND  THE  CONTROL 
OF  MUSCULAR  ACTIVITY 


(Contributed  by  A.  C.  REDFIELD) 
CHAPTER  LXXXIX 

THE  EVOLUTION  OF  THE  NEUROMUSCULAR  MECHANISM 

Disease  of  the  nervous  system  confronts  the  physician  with  a  complex 
group  of  symptoms,  a  syndrome  due  to  more  or  less  sharply  localized 
disturbances  in  its  function.  It  is  the  province  of  physiology  to  analyze 
the  fundamental  activities  of  the  nervous  system  and  assign  to  various 
parts  a  functional  significance,  so  that  the  complicated  picture  presented 
by  disease  may  be  recognized  as  the  logical  result  of  a  lesion  of  definite 
nature,  location,  and  extent.  We  find  the  symptoms  of  nervous  dis- 
ease grouping  themselves  as  disturbances  (1)  of  sensation  (anesthesia, 
etc.)  (2)  of  movement,  both  volitional  and  reflex  (paralysis,  etc.)  (3) 
of  postural  coordination  (muscular  spasms  and  flaccidity,  ataxia,  etc.) 
(4)  of  the  mechanisms  of  integration  in  the  nervous  system  including  the 
higher  mental  functions  of  association,  memory,  and  attention,  etc. 

Corresponding  to  each  of  these  groups  we  can  recognize  a  definite  as- 
pect of  nervous  activity,  the  successful  performance  of  which  depends 
on  the  continuity  of  more  or  less  precisely  known  groups  of  cells  within 
the  nervous  system,  and  disturbances  of  any  of  these  aspects  can  be  as- 
signed to  lesions  affecting  some  part  of  the  group  of  nerve  cells  on  which 
they  depend. 

The  fundamental  function  of  the  nervous  system  is  to  correlate  the 
activities  of  the  body  so  that  its  many  parts  may  act  harmoniously  and 
as  a  unit  in  preserving  the  welfare  of  the  individual.  What  the  basis 
of  this  integration  of  activity  which  manifests  itself  so  remarkably  in 
the  behavior  of  the  higher  animals,  is,  can  best  be  illustrated  by  a  consid- 
eration of  its  evolutionary  development. 

Primitive  Neuromuscular  Mechanisms 

In  the  unicellular  organisms  three  processes  occur  when  a  response  is 
brought  about  by  a  stimulus.  These  are  (1)  excitation,  or  the  setting  up 
of  a  physiological  disturbance;  (2)  conduction,  or  the  spread  of  the  dis- 

827 


828 


CENTRAL  NERVOUS  SYSTEM 


turbance  to  parts  of  the  cell  remote  from  the  point  of  excitation;  and  (3) 
response  on  the  part  of  the  protoplasm  to  which  the  disturbance  has  spread. 
Thus  when  a  paramecium  swims  against  a  hard  object,  an  excitation  is  set 
up  by  the  contact  at  its  anterior  end ;  the  disturbance  so  produced  spreads 
to  other  parts  of  the  cell  and  causes  the  reversal  of  the  direction  of  the 
stroke  of  the  cilia  in  relatively  remote  regions,  with  the  result  that  the 
paramecium  backs  away  from  the  obstacle,  and  then  starts  off  in  another 
direction.  The  three  fundamental  processes  of  excitation,  conduction,  and 
response  occur  whenever  the  neuromuscular  system  of  an  animal  is  brought 
into  play.  The  case  of  multicellular  animals  differs  from  that  cited  above 
only  in  that  the  conduction  is  intercellular,  so  that  the  disturbance  set  up  by 
an  excitation  spreads  from  one  cell  to  another. 

There  exist  in  multicellular  animals  many  examples  of  cells  independent 
of  the  influence  of  nervous  tissue  which  respond  directly  to  stimuli. 
These  are  known  as  independent  effectors.  The  most  primitive  muscle  cells 
known  are  those  which  close  the  terminal  pores  of  sponges,  thus  regulating 
the  flow  of  water  through  these  animals.  Parker1  has  shown  that  these 
muscles  respond  to  a  variety  of  stimuli  in  spite  of  the  fact  that  no  nerve 
cells  can  be  found  in  association  with  them.  Ciliated  epithelial  cells,  such 
as  occur  in  certain  ducts  and  passageways  in  man  are  also  independent  ef- 
fectors, acting  independently  of  nervous  control.  The  ameboid  white  blood 
corpuscles  also  must  be  quite  comparable  in  their  mechanisms  of  response 
to  the  protozoa. 

The  forerunner  of  nervous  conduction  is  seen  in  the  activities  of  these 
independent  effectors.  If  a  field  of  ciliated  epithelium  is  examined  micro- 
scopically, it  is  found  that  the  cilia  are  not  beating  in  a  disorderly  way,  but 
that  definite  waves  are  passing  across  the  field,  each  cilium  beating  a  mo- 
ment later  than  the  preceding  one.  The  appearance  is  quite  like  that  pro- 
duced by  gusts  of  wind  sweeping  across  a  field  of  grain.  In  the  sponges, 
also,  a  stimulus  applied  several  centimeters  from  the  terminal  pore  will 
cause  its  muscles  to  contract  in  spite  of  the  absence  of  nervous  tissue  con- 
necting the  muscles  with  the  point  of  stimulation.  This  type  of  intercel- 
lular conduction  by  nonnervous  tissue  is  called  neuroid  transmission.  It 
illustrates  the  significant  fact  that  conductivity  is  not  a  specific  property 
of  nervous  tissue,  but  is  displayed  by  many  other  tissues  as  well. 

Nervous  tissue  makes  its  first  appearance  in  the  Coelenterates  (Fig. 
203).  A  most  primitive  condition  is  found  in  the  tentacles  which  sur- 
round the  mouth  of  the  sea  anemone.  At  the  base  of  certain  epithelial 
cells  fibrous  processes  are  developed  which  connect  with  underlying  mus- 


EVOLUTION    OF    THE    NEUROMUSCULAR    MECHANISM 


829 


cles.  The  epithelial  cell  serves  as  a  receptor  for  stimuli,  and  transmits 
the  disturbances  set  up  by  them  to  the  muscle  or  effector.  Such  a  mecha- 
nism is  called  a  receptor-effector  system.  The  responses  which  it  brings 
about  are  purely  local,  since  there  is  no  provision  for  conducting  the 
disturbance  to  remote  parts  of  the  animal,  but  the  introduction  of  the 
receptor  serves  a  valuable  purpose  in  increasing  the  sensitivity  of  the 
system.  Moreover,  the  arrangement  is  adequate  for  the  purpose  for 


Fig.  203.  —  The  evolution  of  the  nervous  system.  A,  the  independent  effector  as  illustrated  by 
muscle  cells  of  the  sponge;  B,  a  receptor-effector  system  such  as  occurs  in  the  tentacles  of  sea 
anemones;  C,  the  neuromuscular  mechanism  of  the  trunk  of  the  sea  anemone,  in  which  a  network 
of  nerve  cells  is  interposed  between  receptor  and  effector;  D,  the  nerve  net  surrounding  a  small 
blood  vessel  of  the  frog;  E,  the  nervous  system  of  the  earthworm,  illustrating  a  typical  reflex  arc 
and  the  occurrence  of  association  neurons;  a,  within  the  ganglion;  r,  receptor;  nn,  nerve  net;  an, 
ifferent  neuron;  en,  efferent  neuron.  (Modified  after  Parker,  Prentiss  and  Bayliss.) 


it  is  employed,  which  is  to  cause  the  tentacle  to  bend  toward  a 
irticle  of  food  situated  between  it  and  the  mouth,  so  that  the  currents 
up  by  the  cilia  with  which  the  tentacle  is  covered  may  sweep  the  food 
ito  the  mouth.  An  arrangement  quite  similar  to  the  receptor  effector 
Astern  of  the  Coelenterates  is  found  in  the  axon  reflexes  of  mammals,  in 
which  disturbances  set  up  in  certain  sensory  neurons  spread  directly  through 
collateral  fibers  to  the  vasomotor  muscles  of  the  skin  (page  898). 


830 


CENTRAL    NERVOUS    SYSTEM 


The  Nerve  Net 


In  the  trunk  of  the  sea  anemone  nervous  tissue  assumes  a  much  more 
important  role.  Between  the  receptors  of  the  epithelium  and  the  muscles 
there  is  interposed  a  layer  of  nerve  cells  arranged  as  a  network.  This 
network  can  transmit  disturbances  set  up  in  the  receptors  to  quite  dis- 
tant muscles,  with  the  result  that  a  local  stimulus  may  bring  about  a  gen- 
eralized contraction  of  the  trunk.  The  primitive  nervous  system  is  thus 
seen  to  consist  of  a  network  of  nerve  cells  or  nerve  net.  Its  charac- 
teristic consists  in  the  fact  that  the  nerve  cells  are  joined  together  by 
continuous  fibers  so  that  the  structure  is  essentially  a  syncytium.  No 
cell  membranes  can  be  distinguished  separating  the  fibers  of  the  constit- 
uent nerve  cells.  The  result  of  this  structure  is  that  nerve  impulses  set 
up  in  one  region  can  spread  at  random  to  all  parts  of  the  nerve  net.  The 
responses  produced  by  such  a  mechanism  are  necessarily  diffuse  in  char- 
acter, since  large  groups  of  muscles  will  be  brought  into  play  at  one  time. 
Since  conduction  is  not  limited  to  definite  paths  in  the  nerve  net,  local  in- 
jury will  have  little  effect  on  the  reactions  of  the  organism  because  the 
nerve  impulses  can  pass  around  the  injured  region  through  other  parts 
of  the  nervous  network.  The  rapidity  with  which  impulses  are  conducted 
by  the  nerve  net  is  not  great,  being  only  146  centimeters  a  second,  or  about 
two  hundred  times  less  than  the  velocity  of  the  nerve  impulse  in  the  motor 
nerves  of  the  frog. 

The  nerve  net  is  retained  in  many  parts  of  the  higher  animals.  Wher- 
ever it  occurs  it  is  usually  very  closely  associated  with  the  muscles  which 
it  innervates.  The  most  important  nerve  net  in  man  is  found  in  the 
intestine  (myenteric  plexus).  In  this  structure  an  important  modifica- 
tion in  behavior  has  developed.  While  .the  reactions  of  the  intestine 
maintain  the  sluggish,  diffuse  character  seen  in  the  eoelenterates,  con- 
duction no  longer  proceeds  as  readily  in  all  directions.  Excitation  pro- 
duces a  contraction  of  the  muscles  above  the  point  stimulated  and  relax- 
ation below  it  (the  myenteric  reflex  page  501).  Waves  of  contraction 
travel  along  the  intestine  usually  only  in  one  direction,  from  pyloric  end 
downward.  The  nerve  net  has  developed  a  definite  polarity,  a  property 
which  is  fundamental  in  the  central  nervous  system  of  the  higher  animals. 

The  Central  Nervous  System 

A  typical  central  nervous  system  appears  in  simple  form  in  the  seg- 
mented worms.  The  nerve  cells  of  which  it  is  composed  do  not  form 
a  syncytium,  as  in  the  nerve  net,  but  are  separated  from  one  another  at 
the  points  at  which  their  fibers  meet  by  a  specialized  structure  called 
a  synapse.  A  definite  membrane  may  be  seen  at  this  point  separating 
the  protoplasm  of  one  fiber  from  that  of  the  other.  .The  nerve  cell  con- 


EVOLUTION   OF   THE   NEUROMUSCULAR   MECHANISM 


831 


sequently  acquires  a  certain  individuality,  and  can  become  specialized  for 
special  kinds  of  activity,  and  is  called  a  neuron.  The  neuron  is  the  fund- 
amental unit  of  structure  and  function  in  the  central  nervous  system.  It 
consists  typically  of  a  nerve  cell  body  containing  the  nucleus,  from  which 
extend  numerous  short  fibers,  or  dendrites,  and  one  long  fiber,  or  axon. 
The  axon  may  be  branched,  such  branches  being  called  collaterals. 


Fig.   204. — Normal   cell   from  the  ventral   horn,  stained  to   show   Nissl's  granules,     a,  the   axon. 

(From    Howell.) 

The  arrangement  of  neurons  in  the   central  nervous   system  of  the 
rorms  is  characteristic.    Most  of  the  nerve  cell  bodies  are  collected  to- 
gether in  centrally  located  masses   or  ganglia.     Fibers   pass   from   the 
'eceptors  in  the  epithelium  to  the  ganglion  of  the  same  segment  in  defi- 
nite nerve  trunks,  while  other  fibers  originating  from  nerve  cell  bodies 
within  the  ganglion  pass  in  other  trunks  to  the  muscles.     In  addition 


832 


CENTRAL  NERVOUS  SYSTEM 


fibers  pass  from  one  ganglion  to  the  next  in  trunks  known  as  intergan- 
glionic  connectives. 

In  order  that  a  muscular  response  may  result  from  a  stimulus  applied 
to  the  skin  of  a  worm,  a  disturbance  must  pass  through  the  following 
structures:  (1)  the  receptor  with  its  afferent  fiber,  (2)  a  motor  neuron 
with  its  efferent  fiber,  to  (3)  the  muscle  (or  other  effector).  This  group 
of  structures  is  called  a  reflex  arc,  It  is  the  simplest  anatomical  arrange- 
ment in  the  central  nervous  system,  capable  of  bringing  about  a  signi- 


Fig.  205. — Arborization  of  collaterals  from  the  dorsal  root  fibers  around  the  cells  of  the  posterior 
horn.  A,  ascending  fiber  in  dorsal  columns;  B,  collaterals;  C,  cells  of  dorsal  horn;  E,  synapses. 
(From  Ramon  y  Cajal.) 

ficant  motor  response.     The  activity  produced  by  such  a  mechanism  is 
called  a  reflex. 

The  reflex  arc  as  we  have  described  it  lies  frequently  within  a  single  seg- 
ment of  the  worm.  Consequently  it  can  provide  each  segment  with  a 
great  degree  of  autonomy,  so  that  many  of  its  activities  are  undisturbed 
by  the  removal  of  other  parts  of  the  animal.  No  provision  is  made  by 
such  an  arrangement  for  correlating  the  activities  af  adjacent  segments. 
The  ganglia  of  worms  contain,  as  a  matter  of  fact,  an  additional  type 
of  neuron  which  makes  the  correlation  of  the  activities  of  different  seg- 
ments possible.  These  are  neurons  which  lie  entirely  within  the  central 
nervous  system.  Their  axons  lie  in  the  interganglionic  connectives  and 


EVOLUTION   OF   THE   NEUROMUSCULAR   MECHANISM 


833 


Fig.  206. — Part  of  a  ventral  cornual  cell   from   the   calf's  spinal  cord,   stained  to   show   neurofibrils. 
ax,  axon;  a,  b,  c,  dendrites.      (From  Bethe.) 


Fig.  207. — Schema  of  simple  reflex  arc;   r,  receptor  in  an   epithelial  membrane;  a,   afferent  fiber;  s, 
synapses;  c,  nerve  cell  of  motor  neuron;   e,  efferent  fiber;  m,  effector  organ. 


834 


CENTRAL  NERVOUS  SYSTEM 


serve  to  connect  afferent  fibers  in  one  segment  with  motor  neurons  in  some 
distant  segment.  They  are  called  association  neurons  because  they  asso- 
ciate the  activities  of  remote  parts  of  the  body. 

The  fundamental  characteristics  of  the  central  nervous 
system  as  it  appears  in  the  worms  consists  in  (1)  the 
individuality  of  the  component  nerve  cells  and  their 
specialization  for  certain  functions,  (2)  the  arrangement 
of  the  neurons  in  such  a  way  that  the  impulses  must 
pass  over  definite  paths  or  reflex  arcs  in  order  to  reach 
an  effector,  (3)  the  introduction  of  neurons  specialized 
to  associate  the  activities  of  reflex  arcs  in  remote  parts 
of  the  body,  and  (4)  the  segregation  of  the  greater  part 
of  the  nervous  tissue  into  a  centrally  located  chain  of 
ganglia,  from  which  fibers  pass  to  peripheral  structures 
in  definite  nerve  trunks.  These  characteristics  persist 
in  the  central  nervous  system  in  the  higher  animals,  in- 
cluding man. 

Certain  modifications  of  the  simple  arrangement  found 
in  the  worms  have  been  introduced  into  the  nervous  sys- 
tem as  the  motor  activities  of  organisms  became  more 
precise  and  complex.  Of  minor  importance  may  be  men- 
tioned the  introduction  of  an  afferent  nerve  cell  distinct 
from  the  receptor  between  the  latter  and  the  central 
ganglionic  mass,  (see  the  Evolution  of  Receptors  page 
854)  and  the  introduction  of  an  outlying  neuron  between 
the  termination  of  the  primary  motor  neuron  and  the 
effector  organ  (see  the  autonomic  system  page  894).  Of 
far  greater  importance  is  the  great  increase  in  the  num- 
ber of  association  neurons  which  become  the  salient  fea- 
ture of  the  vertebrate  nervous  system.  In  the  worms  the 
inter-ganglionic  connectives  are  scarcely  more  bulky 
than  the  peripheral  nerves  from  a  single  ganglion, 
whereas  in  the  central  nervous  system  of  man  the  num- 
ber of  the  fibers  extending  from  segment  to  segment  ex- 
ceeds by  many  times  the  number  of  fibers  in  any  single 
pair  of  spinal  nerves.  This  increase  in  the  mass  of  the 
central  portion  of  the  nervous  system  is  not  distributed 
equally  in  all  parts,  but  tends  to  concentrate  itself  par- 
ticularly at  the  anterior  end.  Even  in  the  worms  the  most 
anterior  ganglion,  the  supraesophageal  ganglion,  is  larger  than  the  others, 
while  this  tendency  finds  its  culmination  in  the  great  bulk  of  the  brain  in 
man.  This  condition  is  obviously  correlated  with  the  development 


Fig.  208.— Dia- 
gram of  nervous 
system  of  seg- 
mented inverte- 
brate; a,  supra- 
esophageal g  a  n- 
glion;  b,  subeso- 
phageal  ganglion; 
oe,  esophagus  or 
gullet. 


EVOLUTION    OF    THE    NEUROMUSCULAR    MECHANISM  835 

of  special  sense  organs  at  the  anterior  end  of  the  animal:  the  sense 
of  taste  at  the  mouth,  the  tactile  organs  found  on  the  tentacles  which 
adorn  the  head  of  many  invertebrates,  and  of  special  receptors  for  stim- 
uli originating  at  a  distance,  such  as  the  eye  and  ear.  The  development 
of  association  neurons  for  the  correlation  of  activities  initiated  by  the 
stimulation  of  these  receptors  has  made  this  portion  of  the  central  nervous 
system  the  natural  place  for  the  seat  of  the  higher  mental  functions  as 
they  evolved. 


CHAPTER  XC 

THE  CONDUCTION  OF  THE  NERVOUS  IMPULSE 

We  have  seen  that  the  activity  of  the  neuromuscular  mechanism  in- 
volves the  three  processes  of  excitation,  conduction,  and  response.  These 
processes  may  be  regarded  as  fundamental  properties  of  protoplasm 
which  may  all  be  exhibited  by  a  single  cell.  The  evolution  of  the  cen- 
tral nervous  system  is  the  history  of  a  gradual  specialization  of  cells 
each  for  the  execution  of  one  of  these  processes.  Thus  in  a  reflex  arc 
the  receptor  is  a  cell  primarily  fitted  to  react  to  slight  changes  in  its 
environment,  the  neurons  are  especially  adapted  to  the  conduction  of  im- 
pulses, and  the  effector  is  constructed  for  the  sole  purpose  of  carrying 
out  some  motor  response  or  producing  some  specialized  secretion.  It 
would  appear  as  though  a  single  cell  could  not  develop  the  ability  to 
perform  all  of  these  functions  with  perfection  and  as  a  consequence  a 
high  degree  of  division  of  labor  has  been  established. 

It  should  be  remembered,  however,  that  this  specialization  for  one 
process  has  deprived  the  cells  to  only  a  limited  degree  of  the  ability 
to  be  the  seat  of  the  other  processes.  Thus  although  excitability  is  pri- 
marily a  property  of  the  receptors,  nerve  cells  must  also  retain  the  abil- 
ity to  become  excited  by  disturbances  set  up  in  the  receptors,  and  muscles, 
must  be  able  to  be  excited  by  impulses  reaching  them  from  motor  neurons 
Similarly  conduction  must  occur  not  only  in  nerve  cells,  but  in  receptors, 
so  that  a  disturbance  set  up  at  the  distal  end  of  the  receptor  cell  may 
reach  the  nerve  fibers  which  terminate  about  its  proximal  end.  Muscle 
cells  also  must  be  able  to  conduct  disturbances  set  up  in  the  myoneural 
junction  to  all  parts  of  the  muscle  fiber,  so  that  they  may  contribute  to 
the  response.  It  has  been  seen  that  the  conductivity  of  the  cardiac  mus- 
cle is  of  great  importance  in  the  co-ordination  of  the  action  of  the  heart 
(page  182).  Even  contractility  which  would  appear  at  first  sight  to  be  a 
function  of  the  effector  alone  is  displayed  occasionally  by  the  other  parts 
of  the  reflex  arc.  Thus  embryonic  nerve  fibers  have  been  observed  to 
perform  ameboid  movements  and  the  rods  and  cones  of  the  retina,  which 
are  the  receptors  of  light,  become  shorter  or  longer  in  response  to  changes 
in  illumination. 

While  excitation,  conduction,  and  response  are  seen  to  occur  in  all 
parts  of  the  reflex  arc,  when  we  come  to  study  these  processes  it  is  con- 
venient to  examine  each  in  that  tissue  in  which  it  is  most  highly  developed 
and  where  the  other  processes  will  introduce  a  minimal  complicating  ele- 

836 


THE    CONDUCTION    OF    THE    NERVOUS    IMPULSE  837 

ment.  Thus  excitation  is  best  considered  in  connection  with  the  recep- 
tors and  a  consideration  of  it  may  be  postponed  until  we  are  ready  to 
take  up  the  aspect  of  central  nervous  activity  which  leads  to  sensation 
and  the  phenomenon  of  consciousness.  Response  must  be  studied  in  mus- 
cular tissue  and  its  treatment  may  be  put  off  until  we  have  seen  what 
the  nervous  mechanism  initiating  muscular  activity  consists  of.  Con- 
ductivity is  readily  studied  in  nerve,  and  since  this  process  forms  the 
base  of  all  nervous  activity,  it  must  be  treated  before  the  study  of  the 
activity  of  the  nervous  system  as  a  whole  can  be  undertaken. 

Conduction  in  the  Nerve  Fiber 

When  a  nerve  fiber  supplying  a  muscle  is  stimulated,  the  response  of 
the  muscle  is  so  prompt  that  for  many  years  physiologists  despaired  of 
determining  the  rate  at  which  the  nerve  impulse  traveled  along  the 
nerve.  Helmholtz  succeeded,  however,  in  devising  a  simple  method  by 
which  the  velocity  of  the  impulse  could  be  measured  and  found  that 
in  the  sciatic  nerve  of  the  frog  the  rate  of  propagation  was  about  30 
meters  a  second.  Later  determinations  have  shown  that  in  the  nerves 
of  man  the  velocity  of  the  impulses  is  three  or  four  times  as  great,  a  dif- 
ference which  may  be  attributed  to  the  higher  temperature  of  the  human 
body.  It  is  seen  from  this  that  very  little  time  is  lost  in  the  transmission 
of  impulses  along  nerve  trunks,  and  rapid  responses  to  stimulation  are 
thus  insured.  Although  nerve  fibers  are  closely  bound  together  within  a 
nerve  trunk,  impulses  cannot  spread  in  a  lateral  direction  from  one  fiber 
to  its  neighbor.  Consequently  if  a  branch  of  the  lumbar  plexus  is  stim- 
ulated, contraction  occurs  in  a  more  limited  group  of  muscles  than  if 
the  nerve  trunk  is  stimulated  below  the  junction  of  the  various  parts 
of  the  plexus.  The  response  of  muscles  to  the  artificial  stimulation  of 
a  nerve  trunk  also  differs  in  its  distribution  from  responses  induced 
reflexly  or  volitionally.  These  facts  show  that  the  constituent  fibers 
of  a  nerve  trunk  are  completely  isolated  from  one  another. 

Within  the  single  nerve  fiber  nervous  impulses  may  travel  in  either 
direction  along  its  length  irrespective  of  the  direction  in  which  con- 
duction normally  takes  place.  Thus  if  a  collateral  of  a  motor  neuron 
is  stimulated  close  to  its  termination  in  a  muscle,  the  impulse  will  travel 
up  the  collateral  to  its  point  of  junction  with  a  second  collateral,  and 
down  the  latter  to  cause  a  contraction  of  the  muscles  which  this  in- 
nervates. The  polarity  which  is  such  an  important  feature  of  the  activ- 
ity of  the  reflex  arc  as  a  whole  is  not  exhibited  by  the  conduction  within 
a  single  neuron,  which  thus  preserves  one  of  the  fundamental  proper- 
ties of  the  primitive  nerve  net. 

The  All  or  None  Nature  of  Conduction. — Activity  cannot  occur  in  the 
body  without  the  expenditure  of  energy.  It  is  pertinent  to  inquire  what 


838  CENTRAL    NERVOUS    SYSTEM 

is  the  source  of  the  energy  expended  in  the  conduction  of  a  nerve  im- 
pulse. It  was  perhaps  natural  for  physiologists  to  assume  that  this 
energy  was  derived  from  the  stimulus,  much  as  the  energy  of  a  pro- 
jectile is  derived  from  an  explosion.  That  this  is  not  true  has  been 
shown  by  important  experiments  by  Adrian.2'3  The  intangible  nature 
of  the  nerve  impulse  makes  a  measurement  of  its  strength  difficult.  One 
cannot  use  the  muscular  contraction  produced  by  it  as  a  measure  of 
its  strength,  because  the  degree  of  muscular  response  will  be  determined 
by  the  number  of  nerve  fibers  brought  into  action  as  well  as  by  any 
variation  which  may  occur  in  the  intensity  of  the  nerve  impulse  in  each 
fiber.  Adrian  chose  as  a  criterion  of  the  strength  of  the  nerve  impulse  its 
ability  to  traverse  a  region  of  nerve  fiber  in  which  conduction  had  been  ren- 
dered difficult  by  the  application  of  a  narcotic.  Whether  or  not  a  nerve  im- 
pulse can  emerge  from  such  a  region  depends  on  the  distance  which  the  im- 
pulse must  travel  before  coming  to  the  normal  part  of  the  fiber.  This 
indicates  that  in  passing  through  the  narcotized  area  the  impulse  becomes 
weaker  and  weaker,  and  may  become  completely  extinguished  if  it  fails 
to  emerge  in  time.  If  the  nerve  impulse  derives  its  energy  from 
the  stimulus,  it  should  be  impossible  for  it  to  regain  its  strength  after 
dissipating  its  energy  in  a  region  in  which  conduction  is  difficult.  This 
point  can  be  tested  by  passing  the  impulse  through  two  equal  narcotized 
areas  separated  by  a  region  of  normal  nerve.  If  the  length  of  each  of 
these  areas  be  not  quite  great  enough  to  extinguish  an  impulse,  but  if 
their  combined  length  is  sufficient  for  this  purpose,  and  if  no  recovery 
occurs  in  the  intervening  region  of  normal  tissue,  then  the  impulse 
will  be  unable  to  pass  through  both  areas.  In  passing  the  first  area 
the  intensity  will  be  reduced  in  part ;  on  passing  through  the  normal 
region  there  will  be  no  recovery,  and  in  the  second  area  of  narcosis  the 
strength  of  the  impulse  will  be  reduced  to  extinction.  As  a  matter  of 
fact  Adrian  found  that  the  nerve  impulse  does  not  behave  in  this  man- 
ner. Impulses  which  would  be  complete^  extinguished  by  a  given  area 
of  narcosis  could  pass  through  two  areas  one  half  as  long  if  these  were 
separated  by  a  short  length  of  normal  tissue.  In  passing  through  the 
normal  tissue  the  strength  of  the  impulse  recovered  so  that  it  was  as 
great  on  entering  the  second  region  as  it  was  when  it  came  to  the  first, 
and  consequently  it  was  able  to  pass  through  one  as  well  as  the  other 
(Fig.  209). 

From  this  observation  several  important  conclusions  can  be  drawn.  The 
energy  of  the  nerve  impulse  is  derived  not  from  the  stimulus,  but  from 
the  nervous  tissue  through  which  it  is  passing.  Consequently  the  strength 
of  the  impulse  depends  on  the  condition  of  the  tissue,  and  it  will  vary 
only  as  the  condition  of  the  tissue  varies.  If  a  nerve  conducts  an  im- 
pulse at  all,  it  will  be  of  the  maximum  strength  possible  for  the  -con- 


THE    CONDUCTION    OF    THE   NERVOUS   IMPULSE 


839 


dition  of  the  nerve  at  that  time.  This  conception  is  known  as  the  all 
or  none  law  of  conduction,  because  the  tissue  acts  with  all  its  power  or 
not  at  all.  It  is  quite  comparable  to  the  all  or  none  action  of  cardiac 
muscle  with  which  we  have  already  become  familiar  (page  177). 

The  importance  of  the  conclusion  that  the  energy  of  the  nerve  im- 
pulse is  derived  from  the  nerve  fiber  itself  is  this.  No  matter  in  how 
complex  a  fashion  a  neuron  may  be  subdivided  into  collaterals  or  den- 
drites  an  impulse  set  up  in  it  may  pass  with  undiminished  intensity  along 
each  of  these  subdivisions.  Since  each  collateral  may  be  united  with 
other  neurons,  the  impulse  may  spread  from  the  one  neuron  to  several 
others  without  becoming  attenuated  by  the  multiplicity  of  the  paths 


A 


B 


Fig.  209. — Diagram  illustrating  the  effect  of  areas  of  narcosis  (n)  on  the  strength  of  the  nerve 
impulse.  A  indicates  the  gradual  decline  in  the  strength  of  the  impulse  as  it  penetrates  an  area 
just  long  enough  to  cause  its  complete  extinction.  B  and  C  illustrate  the  two  possible  results  of- 
sending  an  impulse  through  two  shorter  areas,  separated  by  a  length  of  normal  nerve.  If  no  re- 
covery occurs  in  the  normal  tissue,  the  impulse  may  be  extinguished  in  the  second  narcotized  area, 
as  B  indicates.  If  recovery  occurs  in  this  area,  the  impulse  may  reach  the  muscle  in  undiminished 
strength.  Adrain  showed  the  latter  alternative  to  be  true. 

in  which  it  is  traveling.  Hence  the  conception  of  the  older  physiology 
of  the  presence  of  special  reinforcement  centers  in  the  central  nervous 
system  for  the  purpose  of  reinforcing  the  strength  of  the  impulse  as  it 
spreads  may  be  dispensed  with,  since  every  part  of  every  nerve  fiber 
contributes  the  energy  necessary  to  keep  the  impulse  going  as  it  travels 
along. 

The  Refractory  Period. — Although  the  nerve  impulses  induced  by  ar- 
tificial stimulation  may  be  momentary  in  duration  the  activity  of  the 
reflex  arc  brought  about  by  normal  conditions  in  life  is  usually  main- 
tained for  some  time  in  order  to  achieve  continuous  contraction  of  the 


840 


CENTRAL   NERVOUS    SYSTEM 


appropriate  groups  of  muscles.  Such  continuous  activity  on  the  parl 
of  nerve  cells  might  be  due  to  either  (1)  the  passage  of  a  series  of  dis- 
tinct impulses  along  the  nerve  fiber,  or  (2)  to  a  continuously  main- 
tained activity.  Experiment  has  shown  that  the  first  conception  is  th< 
correct  one.  Two  impulses  set  up  in  rapid  succession  in  the  nerv( 
fibers  of  a  nerve  muscle  preparation  from  the  frog  may  cause  a  greater 
contraction  in  the  muscle  than  a  single  impulse.  If  the  interval  betweei 
these  stimuli  is  decreased  to  less  than  0.0025  of  a  second  the  effect  due 
to  the  second  stimulus  disappears  and  it  has  evidently  failed  to  initi- 
ate a  second  nerve  impulse.  This  result  occurs  whether  the  two  stimuli 
are  applied  to  the  same,  or  to  different  parts  of  the  nerve  fiber,  showing 
that  it  is  not  due  to  the  impossibility  of  setting  up  the  process  of  ex- 


100 


50 


•01  -02 

Time  since  previous  stimulus  (seconds) 


•03 


Fig.  210. — The  recovery  of  excitability  in  the  nerve  fiber  after  the  passage  of  a  nerve  impulse. 
After  a  brief  time  in  which  no  second  excitation  is  effective,  the  excitability  gradually  returns  to 
normal,  and  then  becomes  temporarily  greater  than  normal.  The  changes  in  conductivity  following 
the  passage  of  a  nerve  impulse  over  the  nerve  follow  a  similar  course.  (From  Adrain  and  Lucas.) 

citation  in  one  place  twice  in  such  rapid  succession,  but  that  the  nerve 
fiber  is  incapable  of  conducting  a  second  nerve  impulse  until  a  sufficient 
period  of  recovery  has  intervened.  Moreover  by  cooling  the  nerve  be- 
tween the  point  of  stimulation  and  the  muscle,  without  affecting  the 
temperature  in  the  place  at  which  the  process  of  excitation  occurs,  the 
period  of  recovery  may  be  increased  three  fold,  because  at  a  low  tem- 
perature it  takes  longer  for  the  nerve  fiber  to  regain  its  power  to  con- 
duct. This  period  of  recovery  during  which  a  second  impulse  cannot 
pass  along  a  nerve  fiber  is  called  the  refractory  period  of  conduction.  It 
is  quite  analogous  to  the  refractory  period  which  occurs  in  the  heart 
(page  179)  and  like  it  imparts  certain  characteristics  to  the  tissue  in 
which  it  occurs. 


THE    CONDUCTION    OF    THPJ    NERVOUS   IMPULSE  841 

Because  of  the  refractory  period  the  continuous  activity  of  nerve  must 
consist  of  a  series  of  nerve  impulses  occurring  at  brief  intervals.  Nerv- 
ous discharge  consequently  has  a  discontinuous  or  rhythmic  character. 
The  actual  rate  of  this  rhythm  has  not  been  determined  precisely  for 
the  voluntary  movements  of  man,  but  the  length  of  the  refractory  period, 
which  is  shorter  in  the  nerves  of  warm-blooded  animals  than  in  the  frog, 
renders  it  unlikely  that  it  is  greater  than  3000  impulses  per  second,  while 
certain  experiments  indicate  that  it  is  at  least  300  impulses  per  second.22 
The  nerve  fiber  has  been  found  to  be  unfatigued  even  by  continuous  stim- 
ulation for  twenty-four  hours,  a  fact  which  is  explained  by  the  discovery 
that  the  nerve  will  not  conduct  an  impulse  until  it  has  recovered  from 
the  fatiguing  effects  of  the  preceding  impulse.  The  rhythmic  character 
of  nervous  activity  also  suggests  a  way  in  which  nerve  impulses  set  up 
by  different  stimuli  may  differ  from  one  another  and  consequently  bring 
about  different  reactions.  Although  the  all-or-none  law  of  conduction  may 
preclude  the  possibility  of  nerve  impulses  differing  in  strength  or  inten- 
sity, there  is  no  reason  why  the  rate  at  which  impulses  follow  one  another 
in  normal  nervous  activity  may  not  vary  greatly,  and  this  difference  may 
be  a  determining  factor  in  the  spread  of  the  impulses  through  the  spinal 
cord  and  brain. 

Conduction  between  Neurons 

So  far  conduction  has  been  considered  only  with  regard  to  the  spread 
of  a  nerve  impulse  through  a  single  nerve  cell.  In  passing  from  one 
neuron  to  another  the  nerve  impulse  must  pass  through  the  synapse 
which  is  the  structure  uniting  their  respective  fibers.  The  presence  of 
synapses  in  the  path  of  conduction  imposes  certain  characteristics  on 
the  activities  of  the  reflex  arc  which  do  not  appear  in  conduction  within 
a  single  nerve  fiber.  The  key  to  an  understanding  of  reflex  activity  and 
the  higher  mental  processes  by  which  reflex  acts  are  controlled  undoubt- 
edly lies  in  the  physiology  of  the  synapse. 

The  Polarity  of  the  Reflex  Arc. — In  nerve  fibers  it  has  been  seen  that 
impulses  may  spread  in  either  direction  along  the  axon.  In  the  reflex 
arc  as  a  whole  the  passage  of  the  impulse  is  in  one  direction  only,  from 
the  receptor  to  the  effector  organ,  because  a  nerve  impulse  can  pass  in 
one  direction  only  through  the  synapse,  which  acts  as  a  valve  to  prevent 
impulses  passing  back  in  the  opposite  direction.  This  fact  is  demon- 
strated by  the  classic  experiments  of  Bell  and  Magendie,  who  found 
that  no  muscular  response  followed  stimulating  the  central  end  of  the 
cut  ventral  root  of  a  spinal  nerve.  The  motor  neurons  whose  axons 
compose  the  ventral  root  can  transmit  impulses  only  to  the  muscles 
which  they  innervate,  and  in  this  experiment  they  were  separated  by 
the  operation  from  the  point  of  stimulation.  That  impulses  do  not 


842 


CENTRAL    NERVOUS    SYSTEM 


spread  backward  from  the  motor  neurons  to  the  afferent  neurons  can  be 
demonstrated  by  attaching  a  galvanometer  to  the  afferent  nerve,  when 
it  will  be  seen  that  no  action  current  is  set  up  in  the  afferent  neuron 
if  the  stump  of  the  ventral  root  is  stimulated.  Impulses  set  up  in 
these  fibers  can  not  pass  to  other  neurons  within  the  spinal  cord,  be- 
cause the  synapses  will  not  allow  them  to  spread  in  that  direction. 

Thus  it  is  seen  that  the  polarity  which  is  characteristic  of  the  central 
nervous  system  is  imposed  upon  it  by  the  synapse.  In  the  primitive 
nerve  net,  in  which  synapses  can  not  be  demonstrated,  polarity  does 
not  exist. 

Resistance  to  Conduction  due  to  Synapse. — The  synapse  is  also  a  re- 
gion which  offers  some  resistance  to  the  passage  of  the  nerve  impulse 
and  may  prevent  its  passage  altogether.  It  is  usually  impossible  to 
cause  reflex  response  by  applying  a  single  induction  shock  to  a  sensory 
nerve,  although  the  stimulus  may  be  quite  strong  enough  to  excite  a  nerve 
muscle  preparation.  Not  until  the  stimulus  is  repeated  several  times, 
setting  up  a  series  of  nerve  impulses,  will  the  resistance  of  the  synapses 
in  the  reflex  arc  be  overcome  so  that  an  impulse  can  pass  through  to  the 
muscle. 

The  synapses  in  which  the  collaterals  of  a  single  neuron  terminate 
differ  considerably  in  the  resistance  which  they  offer  to  the  passage  of 
the  nerve  impulse.  If  a  series  of  weak  stimuli  are  applied  to  the  foot 
of  a  frog  from  which  the  brain  has  been  removed  a  flexion  of  the  leg 
may  be  induced.  If  the  stimulus  is  increased  in  strength  movements 
of  the  opposite  leg  will  occur,  while  still  stronger  stimuli  will  cause  the 
excitation  to  spread  to  the  muscles  of  the  trunk  and  forelimbs.  This 
observation  indicates  that  the  impulses  set  up  by  a  weak  stimulus  can  pass 
only  through  those  synapses  which  connect  the  afferent  neurons  with 
the  motor  neurons  of  the  same  limb,  while  stronger  stimuli  are  required 
to  set  up  impulses  which  can  pass  to  the  synapses  leading  to  the  motor 
paths  to  more  remote  muscles.  This  graded  synaptic  resistance  is  con- 
sequently an  important  mechanism  in  determining  what  paths  an  im- 
pulse shall  follow  in  its  course  through  the  greatly  branching  systems 
of  nerve  fibers  which  occur  in  the  nervous  system. 

Summation  in  Reflex  Conduction. — The  resistance  presented  to  the 
passage  of  the  impulse  by  the  synapse  suggested  to  Lucas  that  con- 
duction in  a  synapse  is  comparable  to  that  in  a  narcotized  area  of  nerve. 
A  second  point  of  resemblance  is  that  the  impulse  travels  slower  through 
both  synapse  and  through  a  length  of  nerve  treated  with  alcohol.  He 
consequently  studied  with  care  the  conditions  of  conduction  through 
narcotized  nerve  and  discovered  several  facts  which  are  of  value  in 
understanding  the  peculiarities  which  the  synapses  give  to  reflex  conduc- 
tioii.  If  an  area  of  narcosis  is  just  deep  enough  to  check  the  passage 


THE    CONDUCTION    OF    THE    NERVOUS    IMPULSE  843 

of  a  single  nerve  impulse,  it  is  found  that  a  second  impulse  can  pass 
through  it,  provided  it  is  produced  immediately  after  the  termina- 
tion of  the  refractory  period.  For  a  short  interval  after  the  passage 
of  one  impulse  into  a  region  in  which  conduction  is  difficult  the  nar- 
cotized nerve  becomes  better  able  to  conduct  a  second  impulse.  The 
effects  of  two  impulses  added  together  is  thus  able  to  produce  a  re- 
sponse which  a  single  impulse  alone  cannot  accomplish.  This  phenom- 
enon is  known  as  summation  in  conduction.  Such  summation  is  a 
characteristic  of  reflex  conduction,  as  we  have  seen  in  the  experiment 
in  which  stimulation  with  an  induction  shock  fails  to  bring  about  a 
reflex  act  unless  it  is  repeated  several  times.  In  some  cases  as  many 
as  40  or  50  stimuli  must  be  applied  before  reflexes  are  established. 

Two  characteristic  phenomena  of  reflex  conduction  closely  related 
to  summation  which  may  be  explained  on  the  assumption  that  one  im- 
pulse can  alter  the  ease  with  which  a  second  impulse  can  overcome 
the  resistance  at  the  synapse  are  Induction  and  Facilitation. 

Induction  is  the  production  of  a  reflex  response  by  the  application  to 
different  afferent  nerves  of  two  stimuli  each  of  which  alone  is  incapable 
of  setting  up  impulses  which  can  break  through  the  resistance  of  the 
reflex  arc.  Induction  may  occur  when  the  stimuli  are  applied  at  the 
same  time  or  when  one  stimulus  is  commenced  after  the  other  has  been 
discontinued.  Facilitation  resembles  induction  except  that  the  stimuli 
are  each  capable  of  producing  the  response  when  applied  independently. 
Their  combined  effect  is  to  produce  a  greater  response  than  either  can 
elicit  when  acting  alone. 

The  underlying  assumption  in  these  cases  is  that  the  afferent  paths 
over  which  the  impulses  travel  in  to  the  nervous  system  impinge  upon 
a  common  motor  path  in  the  synapses  of  which  summation  in  conduction 
occurs. 

Inhibition. — In  studying  the  heart  we  have  seen  that  nerve  impulses 
traveling  over  the  vagi  may  depress  or  inhibit  the  action  of  the  cardiac 
muscle.  Inhibition  is  also  an  important  process  in  the  action  of  the 
central  nervous  system,  and  is  of  great  importance  because  when  cer- 
tain groups  of  muscles  are  made  to  contract  the  activity  of  opposing 
groups  must  be  depressed  in  order  that  movement  may  be  made  without 
opposition.  Coordination  in  the  nervous  system  depends  011  the  in- 
hibition of  certain  reflex  activities  in  order  that  other  reactions  may 
be  carried  out  without  confusion.  Certain  forms  of  inhibition  can  be 
explained  by  considerations  quite  similar  to  those  employed  in  the  ex- 
planation of  summation.  We  have  seen  that  immediately  after  the  pas- 
sage of  a  nerve  impulse  along  a  nerve  a  period  occurs  during  which 
a  second  impulse  cannot  be  conducted  by  the  nerve  fiber.  This  is  the 
refractory  period  of  conduction.  Later  still  there  is  a  period  during 


844 


CENTRAL   NERVOUS   SYSTEM 


which  the  conductivity  of  the  fiber  is  supranormal,  and  although  the 
first  impulse  has  failed  to  pass  through  a  region  of  resistance  such  as 
a  narcotized  area  or  a  synapse,  the  second  impulse  falling  in  this  period 
of  supranormal  conductivity  may  be  powerful  enough  to  pass  through 
and  excite  the  muscle.  This  is  the  phenomenon  of  summation.  Between 
the  refractory  period  and  the  period  of  supranormal  conduction  the 
nerve  fiber  is  recovering  its  ability  to  conduct.  Impulses  set  up  at 
this  period  will  be  of  subnormal  strength  and  will  be  less  able  to  pene- 
trate regions  in  which  conduction  is  difficult.  Consequently  if  the  rhythm 
of  nervous  discharge  is  such  that  each  impulse  falls  in  the  period  of 
subnormal  conductivity  which  follows  the  passage  of  the  preceding  im- 
pulse, the  discharge  will  be  of  impulses  of  subnormal  strength.  Such 
a  series  of  impulses  may  be  unable  to  pass  through  the  resistance  of  the 
synapse  and  no  activity  can  result.  Whether  a  series  of  impulses  will 
produce  summation  or  inhibition  depends  on  the  relation  between  their 
frequency  and  the  time  required  for  the  conducting  tissue  to  recover 
from  the  effects  of  each  impulse,  that  is,  on  whether  each  impulse  falls 
in  the  period  of  supranormal  or  of  subnormal  conduction  set  up  by  its 
predecessor. 

If  the  synapses  connecting  a  single  afferent  path  with  two  motor 
neurons  have  different  rates  of  recovery,  the  impulses  might  fall  in  the 
period  of  supranormal  conductivity  of  one  synapse  and  be  summated 
and  cause  a  contraction  of  the  corresponding  muscle,  while  they  might 
fall  in  the  period  of  subnormal  conductivity  of  the  other  synapse  and 
be  inhibited,  the  corresponding  muscle  remaining  inactive.  In  this  way 
we  obtain  a  picture  of  how  the  reciprocal  inhibition  of  antagonistic 
groups  of  muscles  may  be  accomplished. 

It  must  be  remembered  that  physiologists  have  just  made  a  beginning 
in  analyzing  nervous  activity  from  this  point  of  view,  and  that  our  present 
ideas  are  no  doubt  crude  and  subject  to  revision.  Also  the  facts  on  which 
our  conception  of  the  nature  of  nervous  conduction  is  based  have  been  made 
out  chiefly  by  a  study  of  the  motor  nerves.  It  is  conceivable  that  the  im- 
pulses conducted  by  sensory  nerves  are  of  a  different  nature  from  those 
motor  impulses,  but  so  far  as  they  can  be  studied  they  appear  to  be  the 
same.  It  is  also  possible  that  the  impulses  set  up  by  electrical  stimulation 
of  motor  nerve  trunks  are  different  from  those  arising  through  voli- 
tional or  reflex  activity. 

Canalization. — The  frequent  use  of  a  path  through  the  nervous  system 
appears  to  lower  permanently  the  resistance  of  the  synapses  along  its 
course.  This  process  is  known  as  canalization,  and  results  in  a  greater 
facility  in  bringing  about  movements  of  the  muscles  to  which  the  path 
leads.  The  bearing  of  canalization  on  the  development  of  skill 
in  mechanical  manipulation  and  in  habit  formation  is  obvious. 


THE    CONDUCTION    OF   THE   NERVOUS   IMPULSE  845 

The  conductivity  of  the  synapse  can  be  altered  not  only  by  the  pas- 
sage of  nerve  impulses  through  it,  but  by  many  other  agents.  Certain 
chemical  substances  such  as  strychnine  and  tetanus  toxine  have  a  selec- 
tive action  upon  the  synapse,  lowering  the  synaptic  resistance,  and  con- 
verting inhibition  into  active  contraction  (see  page  941).  In  those 
invertebrates  which  possess  an  asynaptic  nervous  system,  or  nerve  net, 
strychnine  is  without  such  effect.  Nicotine  has  a  selective  action  upon 
the  synapses  of  the  sympathetic  nervous  system,  increasing  the  resist- 
ance so  that  impulses  are  unable  to  pass  (page  895). 

Eeflex  activity  is  very  easily  abolished  by  lack  of  oxygen,  as  will  be 
indicated  in  the  next  chapter.  In  this  regard  it  differs  from  nerve  trunk 
conduction  to  a  marked  degree.  Since  conduction  can  be  shown  to  be 
quite  independent  of  the  nerve  cell  body,  it  must  be  the  synapses  which 
are  rendered  impassable  by  asphyxia.  Fatigue  occurs  readily  in  re- 
flex conduction,  and  must  also  have  its  seat  in  the  synapse,  since  the 
nerve  trunk  itself  is  quite  indefatigable. 

The  Myoneural  Junction. — The  synapse  is  a  region  of  tissue  at  the 
junction  of  two  nerve  fibers  having  properties  quite  distinct  from  those 
of  the  nerve  fibers  themselves.  The  myoneural  junction,  interposed  be- 
tween nerve  fiber  and  muscle  is  an  analogous  structure,  the  properties 
of  which  are  different  from  both  muscle  and  nerve.  Certain  drugs  have 
a  selective  action  upon  it,  such  as  curare,  which  decreases  the  conductiv- 
ity of  the  myoneural  junctions  of  skeletal  muscles  and  thus  results  in 
their  paralysis.  Curare  is  a  poison  which  is  used  by  certain  savages  on 
their  arrow  heads.  Its  fatal  effects  are  due  to  its  action  in  paralyzing 
the  respiratory  muscles  by  blocking  the  passage  of  nerve  impulses  across 
the  myoneural  junction.  Epinephrine,  the  secretion  of  the  adrenal  glands, 
has  a  specific  affinity  for  the  myoneural  junctions  of  certain  autonomic 
nerves,  exciting  the  junctional  tissue  to  action  similar  to  that  produced  by 
the  nerve  impulses  (see  page  776).  The  most  prominent  characteristic 
of  the  myoneural  junction  is  its  resemblance  to  the  synapse.  Like  it, 
it  is  a  region  in  which  conductivity  is  difficult  and  readily  modified,  so 
that  it  may  be  the  seat  of  summation,  inhibition,  and  fatigue. 


CHAPTER  XCI 
THE  NUTRITION   OF  NERVOUS   TISSUE 

The  Function  of  the  Nerve  Cell  Body 

In  the  preceding  chapter  we  considered  the  physiology  of  the  nerve 
fiber  and  the  synapses  in  which  it  terminates.  We  must  now  inquire 
what  part  the  nerve  cell  body,  containing  the  nucleus  of  the  neuron,  takes  in 
the  conduction  of  the  nervous  impulse.  In  the  crayfish  it  is  possible  to 
remove  the  cell  bodies  from  the  motor  neurons  of  the  antenna  without 
disturbing  the  reflex  connections  of  the  nerve  fibers.  This  can  be  done 
because  the  motor  neuron  possesses  a  single  axon  which  divides  at  some 
distance  from  the  cell  body  into  two  collaterals,  one  connecting  with  the 
afferent  neurons  of  the  reflex  arcs  which  control  the  movements  of  the 
antennas,  the  other  passing  directly  to  the  muscles  of  that  organ.  Cutting 
away  the  part  of  the  cephalic  ganglion  which  contains  the  cell  bodies 
of  these  neurons  does  not  interfere  with  the  reflex  excitation  of  the 
muscles  of  the  antenna?,  provided  that  the  continuity  of  the  collaterals 
is  not  destroyed.  The  nerve  fibers,  deprived  of  their  cell  bodies  are  able 
to  function  normally  for  two  or  three  days.  Conduction  does  not  then 
depend  primarily  upon  the  presence  of  the  nerve  cell  body.  On  the  days 
following  the  operation  the  reflex  is  elicited  with  greater  and  greater 
difficulty,  and  fails  altogether  on  the  third  or  fourth  day.  The  nerve  cell 
body  is  consequently  necessary  for  maintaining  the  conductivity  of  its 
nerve  fibers,  that  is,  it  is  concerned  with  the  nutrition  of  the  outlying  parts 
of  the  neuron. 

Degeneration  and  Regeneration  of  Nerve  Fibers.4 — The  nutritive  func- 
tion of  the  nerve  cell  is  also  illustrated  by  the  phenomena  wrhich  follow 
the  section  of  a  peripheral  nerve  trunk  or  of  the  tracts  of  fibers  in  the 
central  nervous  system.  "When  a  man's  motor  nerve  is  severed,  the 
excitability  of  the  peripheral  part  may  be  increased  for  one  or  two  days, 
but  will  then  decline  rapidly  and  disappear  completely  by  the  end  of 
the  second  week.  Microscopic  examination  reveals  the  fact  that  such 
a  nerve,  the  fibers  of  which  are  cut  off  from  their  cell  bodies,  has  under- 
gone degeneration.  The  fibers  have  broken  up  into  ellipsoid  segments 
of  myelin,  each  containing  a  piece  of  the  axis  cylinder,  and  these  seg- 
ments later  fragment  very  irregularly  into  smaller  pieces  which  are 
eventually  absorbed.  In  animals  such  as  the  rabbit,  in  which  the  process 
occurs  slowly,  it  can  be  seen  that  the  degenerative  changes  begin  at  the 

846 


THE    NUTRITION    OF    NHRVOUS    TISSUE 


847 


wound  and  proceed  peripherally,  although  in  the  dog,  in  which  the  degen- 
eration is  rapid,  it  appears  as  though  the  process  occurred  synchro- 
nously in  all  parts  of  the  fiber. 

In  the  fibers  on  the  central  side  of  the  wound  degeneration  also  oc- 
curs, but  it  is  limited  to  the  several  internodal  segments  which  lie  just 
above  the  point  of  injury.  Nearer  to  the  nerve  cell  body  the  fibers  re- 
main for  the  most  part  unchanged.  An  influence,  howeyer,  is  exerted 


- 


I 


H 
II 


i 


II 


i| 


*\\ 


IV 


VI 


Fig.  211. — Degeneration  and  regeneration  of  a  sectioned  nerve  fiber.  I.  Fibrillation  of  the  axis- 
cylinder  and  swelling  of  the  myelin.  II.  Segmentation  of  the  axis-cylinder,  swelling  and  displace- 
ment of  the  myelin.  Proliferation  of  neurilemma  cells.  III.  Disappearance  of  the  axis-cylinder; 
myelin  bulbs;  proliferated  connective  tissue  cells.  Retrograde  degeneration.  IV.  Formation  of 
granular  bodies;  elimination  of  degenerated  myelin  by  phagocytes.  Soldering  of  fragments  by 
proliferated  connectve  tissue  cells.  Retrograde  degeneration.  V.  Beginning  of  regeneration  in  the 
central  end.  VI.  Progression  of  the  regenerated  axis-cylinder  in  the  empty  sheath  of  the  peripheral 
end.  VII.  Regeneration  of  the  peripheral  segment.  Commencement  of  myelin  reconstruction. 
(After  Tinel.) 


on  the  cell  body  by  the  peripheral  injury.  The  chromatic  substance  of 
Nissl's  granules  becomes  modified  so  that  they  lose  their  staining  power 
(chromatolysis),  the  cell  becomes  swollen,  and  the  nucleus  may  assume 
an  eccentric  position.  Peripheral  to  the  wound  the  destruction  of  the 
tissue  is  complete,  a  fiber  separated  from  its  cell  body  being  unable  to 
continue  to  live.  The  changes  which  occur  on  the  central  side  of  the 
injury  are  usually  of  a  temporary  nature,  and  are  restored  by  the  process 


848  CENTRAL  NERVOUS  SYSTEM 

of  regeneration,  by  means  of  which  the  nerve  cells  reestablish  a  func- 
tional connection  with  the  muscles.  If  such  reestablishment  is  impos- 
sible, as  in  the  case  of  amputation,  disuse  may  be  accompanied  by  an 
atrophy  of  the  neurons  so  that  the  number  of  cells  in  the  ventral  horn 
of  the  cord  decrease  and  their  fibers  degenerate. 

While  degeneration  of  the  nerve  fiber  is  doubtless  influenced  greatly 
by  the  presence  of  the  nerve  cell  body,  a  major  part  in  the  process  is 
attributed  to  the  cells  of  the  neurilemmal  sheath.  The  process  of  re- 
generation occurs  coincidently  with  that  of  degeneration.  It  commences 
with  activity  of  the  nuclei  of  the  neurilemma,  which  divide  rapidly  and 
form  about  themselves  strands  of  protoplasm  which  replace  the  frag- 
ments of  the  degenerated  fiber  as  it  is  absorbed.  While  it  has  been 
claimed  that  the  fibers  of  the  new  nerve  are  actually  formed  by  the  neu- 
rilemma, it  seems  more  probable  that  they  grow  out  along  the  strands 
of  this  tissue  from  the  central  stump  of  the  nerve,  the  neurilemma  fur- 
nishing them  with  guidance,  support,  and  perhaps  nutrition  as  they 
grow.  The  importance  of  the  neurilemma  in  the  process  is  supported 
also  by  the  fact  that  in  the  spinal  cord  and  brain,  where  the  neurilemma 
is  absent,  nerve  fibers  do  not  display  an  ability  to  regenerate.  And  herein 
lies  an  important  principle  in  prognosis,  for  injuries  to  peripheral  nerves 
may  be  repaired  by  regeneration,  whereas  the  severance  of  fibers  in  the 
central  nervous  system  results  in  a  permanent  injury  which  can  be 
corrected  only  by  developing  the  use  of  new  paths  for  the  control  of 
the  functions  which  are  disturbed. 

It  should  be  obvious  that  these  facts  form  the  basis  for  understanding 
the  clinical  treatment  of  peripheral  nerve  injuries.  Although  the  periph- 
eral end  of  a  severed  nerve  is  doomed,  its  neurilemma  will  form  the 
guiding  path  in  the  establishment  of  a  connection  between  the  new  fiber 
and  the  muscle.  It  is  consequently  desirable  to  reunite  the  ends  of  the 
fibers  in  order  to  facilitate  the  regeneration  by  allowing  the  nerve  fibers 
to  establish  a  connection  with  the  neurilemma  of  the  peripheral  stump. 
Even  when  the  stumps  are  not  brought  into  direct  contact  it  is  very 
remarkable  to  observe  with  what  surety  the  new  fibers  grow  out  into 
the  intervening  cicatrix  and  establish  a  relation  with  the  neurilemmse 
of  the  peripheral  trunk. 

The  phenomenon  of  degeneration  has  provided  an  invaluable  tool  for 
the  study  of  the  anatomical  relationships  within  the  nervous  system 
and  the  function  of  its  parts.  By  destroying  the  cells  of  a  nerve  center 
and  observing  which  fibers  degenerate,  one  can  ascertain  the  distribu- 
tion of  the  fibers  which  arise  from  the  center,  while  a  study  of  the 
disturbances  in  the  activity  of  the  animal  produced  by  the  lesion  tells 
us  what  functions  are  dependent  on  the  neurons  which  are  involved. 
Since  degeneration  does  not  extend  beyond  the  synapses  of  the  neuron 


THE   NUTRITION   OF   NERVOUS   TISSUE  849 

affected  by  the  lesion,  it  is  possible  to  learn  by  this  method  just  how 
far  the  axons  from  any  group  of  nerve  cells  extend.  The  atrophic 
changes  which  occur  in  the  nerve  cell  bodies  after  section  of  their 
nerve  fiber  may  also  be  used  to  show  from  what  nucleus  any  tract  of 
fibers  originates.  The  fact  that  regeneration  does  not  occur  in  the  brain 
or  cord  after  degeneration  forms  the  basis  of  a  method  known  as  suc- 
cessive degeneration  by  which  the  anatomical  paths  followed  by  reflexes 
may  be  made  out.  For  example  the  scratch  reflex,  by  means  of  which  the 
dog  relieves  itself  of  irritation  set  up  by  parasites  on  the  skin  may  be 
initiated  through  afferent  impulses  entering  the  cord  in  the  thoracic 
region.  The  problem  is  to  discover  what  neurons  conduct  these  impulses 
to  the  motor  neurons  of  the  leg  which  lie  in  the  lower  segments  of 
the  cord.  Section  of  the  lateral  column  of  the  cord  abolishes  the 
reflex,  but  we  know  that  in  this  column  lie  also  fibers  descending  from 
centers  in  the  cerebrum,  midbrain,  and  medulla,  and  it  is  desirable 
to  differentiate  these  from  the  propriospinal  fibers  whose  cell  bodies 
lie  within  the  cord  itself.  By  making  a  transection  of  the  cord,  above 
the  afferent  path  of  the  reflex,  all  these  fibers  will  be  caused  to  de- 
generate. After  a  year  the  degenerated  fibers  will  have  disappeared 
and  their  paths  will  be  occupied  by  a  neuroglial  scar.  A  section  is  now 
made  of  the  lateral  column  just  below  the  entrance  into  the  cord  of  the 
afferent  path  of  the  reflex.  Degeneration  will  now  set  in  in  those  de- 
scending fibers  whose  cell  bodies  lie  .between  the  primary  and  secondary 
lesion,  and  the  course  of  these  fibers  may  be  traced  to  their  junction  with 
the  motor  neurons.  By  methods  such  as  these  the  paths  followed  by 
the  nerve  impulses  involved  in  the  various  functions  of  the  nervous 
system,  with  which  we  are  to  become  familiar,  have  been  made  out. 

The  nutrition  of  the  nervous  system  is  a  subject  of  great  importance 
because  of  the  fact  that  many  manifestations  of  nervous  disease  are  the 
result  of  nervous  lesions,  secondary  to  some  primary  disturbance  in 
the  circulation  of  the  spinal  cord  or  brain.  Thrombosis  or  hemorrhage 
may  produce  a  mechanical  block  in  the  course  of  vessels  supplying  the 
nervous  tissue,  or  pathological  modifications  of  the  blood  vessel  walls 
may  interfere  with  the  metabolic  exchange  between  blood  and  tissue.  In 
myelitis  and  poliomyelitis  the  nervous  lesions  may  have  a  close  relation 
to  the  distribution  of  the  blood  vessels.  In  this  connection  the  section 
on  the  circulation  of  the  brain  may  be  reviewed  with  profit  (page  254). 
Certain  regions  of  the  central  nervous  system  are  supplied  with  blood 
from  two  sets  of  arteries  so  that  occlusion  of  one  does  not  interfere 
with  the  nutrition  of  the  part.  We  will  see  that  this  is  a  characteristic 
of  the  foveal  part  of  the  visual  center,  which  consequently  is  rarely 
affected  by  the  vascular  lesions  of  civil  life  (page  882).  The  importance 


850  *  CENTRAL  NERVOUS  SYSTEM 

of  the  nervous  system  to  the  existence  of  animals  and  its  limited  power 
of  regeneration  is  correlated  with  the  fact  that  in  prolonged  starvation 
its  metabolism  is  maintained  at  the  expense  of  other  organs  of  the  body 
with  the  result  that,  excepting  the  heart,  it  is  the  organ  which  least  and 
last  undergoes  a  diminution  in  Aveight. 

The  Metabolism  of  the  Nerve  Fiber 

The  all-or-none  nature  of  the  nerve  impulse  has  given  reason  to  be- 
lieve that  the  energy  of  the  nerve  impulse  is  derived  from  processes 
going  on  in  each  part  of  the  fiber  which  it  traverses.  The  refractory 
period  in  conduction  is  occupied  with  processes  which  restore  the  nerve 
fiber  to  its  original  state  of  conductivity.  These  processes  constitute 
the  metabolism  of  activity  in  the  nerve  fiber ;  in  addition  to  them  we  may 
expect  a  certain  amount  of  metabolism  concerned  with  the  maintenance 
of  the  normal  condition  of  the  tissue. 

With  regard  to  the  chemical  exchange  in  nervous  tissue,  practically 
nothing  is  known  except  regarding  the  consumption  of  oxygen,  the 
output  of  carbon  dioxide,  and  the  effects  of  disturbances  in  these  proc- 
esses produced  by  abnormal  conditions  of  circulation  and  respiration. 

Some  uncertainty  exists  regarding  the  production  of  carbon  dioxide 
during  the  activity  of  the  nerve  fiber.  It  is  maintained  by  Tashiro,5 
who  has  used  a  very  sensitive  method  for  its  detection,  that  the  carbon 
dioxide  production  of  nerve  is  distinctly  increased  while  it  is  being 
stimulated.  On  the  other  hand  A.  V.  Hill6  has  failed  to  detect  any  heat 
production  occasioned  by  the  passage  of  nerve  impulses  through  a  nerve, 
although  he  used  a  method  capable  of  detecting  a  change  of  one  hundred- 
millionth  of  a  degree  in  the  temperature  of  the  tissue.  If  any  oxidative 
process  had  occurred  in  the  nerve,  such  as  might  have  resulted  in  the 
liberation  of  carbon  dioxide,  it  should  have  been  accompanied  by  a 
heat  production  readily  detected  by  this  method.  The  presence  of  dis- 
agreement on  this  point  at  least  emphasizes  one  point,  that  the  carbon 
dioxide  production  in  nerve  fibers,  both  at  rest  and  in  activity,  is  small  and 
must  contribute  a  minor  share  to  the  metabolic  requirements  of  the 
body  as  a  whole. 

The  nerve  fiber  is  dependent  on  a  supply  of  oxygen  to  only  a  limited 
degree,  its  requirements  being  apparently  small.  A  nerve  trunk  of 
the  frog  may  retain  its  ability  to  conduct  for  three  to  five  hours  in  an 
atmosphere  of  pure  nitrogen,  but  at  the  end  of  that  time  its  ability 
to  transmit  an  impulse  will  come  to  an  end.  On  supplying  it  with  oxy- 
gen its  conductivity  is  restored  again  in  a  few  minutes.  Oxygen  is 
consequently  necessary  for  the  continued  function  of  the  nerve  fiber, 
which  can,  however,  be  deprived  of  its  oxygen  supply  for  long  periods 
without  losing  its  ability  to  recover. 


THE    NUTRITION    OF    NERVOUS    TISSUE  *851 

Metabolism  of  the  Central  Nervous  System 

The  synapses  are  regions  in  which  conductivity  is  modified  by  a  va- 
riety of  conditions.  It  is  to  be  expected  consequently  that  nutritional 
defects  will  influence  the  ease  with  which  impulses  may  pass  through 
these  regions.  The  cell  body  is  the  nutritive  center  for  the  neuron  as  a 
whole.  In  the  reflex  arc,  of  which  the  synapses  and  nerve  cell  bodies 
form  a  part  it  is  logical  to  expect  that  deficiencies  in  nutrition  would 
show  themselves  more  promptly  than  in  the  isolated  nerve  trunk.  This 
is  indeed,  the  case.  While  a  nerve  trunk  will  retain  its  conductivity 
in  an  atmosphere  of  nitrogen  for  several  hours,  the  reflexes  of  the  frog, 
deprived  of  oxygen  supply,  disappear  in  thirty  minutes.  In  the  warm- 
blooded mammal  all  reflexes  disappear  within  a  few  minutes  after  fail- 
ure of  the  blood  supply,  and  in  man  unconsciousness  may  be  the  im- 
mediate result  of  disturbance  in  the  cranial  circulation  or  of  asphyxia. 

We  have  already  seen  how  dependent  the  activity  of  bulbar  centers, 
which  control  the  heart  beat,  the  blood  pressure,  and  the  movements  of 
respiration,  are  on  certain  conditions,  such  as  the  hydrogen-ion  concen- 
tration of  the  blood,  which  must  be  profoundly  altered  by  disturbances 
in  the  circulation  of  the  brain.  In  the  same  way  the  excitability  of 
the  spinal  centers  concerned  with  reflex  conduction  is  modified  by  asphyx- 
ial  conditions.  Spasmodic  contractions  of  skeletal  muscles,  or  convul- 
sions, commonly  precede  death  from  asphyxia.  These  occur  in  animals 
in  which  the  brain  has  been  removed  and  are  consequently  due  to  the 
activity  of  the  spinal  cord.  In  spinal  animals  in  which  reflexes  may  be 
elicited  with  difficulty  a  mild  degree  of  asphyxia  frequently  causes 
a  reflex  to  appear,  which  could  not  be  produced  previously.  Deeper  as- 
phyxia will  cause  certain  reflexes,  i.  e.,  the  scratch  reflex,  to  take  place 
spontaneously.  When  death  is  threatened,  general  convulsions  of  the 
skeletal  muscles  of  the  trunk  and  limbs  are  invariably  set  up.  These 
effects  show  that  asphyxia  may  increase  the  excitability  of  the  spinal 
centers  of  skeletal  muscle  and  may  result  in  the  spontaneous  contraction 
of  the  muscles  which  they  supply.  The  heightened  excitability  is  of  short 
duration,  however,  if  the  asphyxia  is  complete,  and  passes  into  a 
condition  of  depression,  followed  by  the  complete  failure  of  the  re- 
flexes, which  may  be  restored,  however,  if  the  respiration  of  air  or  oxygen 
is  established  in  time  (Mathison7). 

The  responses  of  the  spinal  centers  for  movement  of  skeletal  muscle 
do  not  differ  fundamentally  from  those  of  the  medulla,  which  are  con- 
cerned with  the  regulation  of  the  circulation  and  respiration.  The  dif- 
ference in  their  behavior  consists  in  the  fact  that  the  bulbar  centers 
react  to  smaller  changes  in  the  condition  of  circulation.  Thus  the  vaso- 
motor  center  reacts  to  thirty  seconds  of  oxygen  lack  or  to  breathing  5  per 
cent  of  C02  whereas  the  spinal  centers  require  two  minutes  of  oxygen 


852  CENTRAL   NERVOUS    SYSTEM 

lack  or  30  per  cent  of  C02.  The  significance  of  the  difference  in  sensi- 
tivity of  the  spinal  and  bulbar  centers  to  changes  in  the  composition 
or  flow  of  the  blood  lies  in  the  fact  that  stimulation  of  the  latter  tends 
to  bring  about  automatically  reactions  which  restore  the  blood  to  its 
proper  condition.  As  a  result  the  spinal  centers  are  rarely  confronted 
in  healthy  life  with  a  circulatory  condition  which  might  modify  their 
activity. 

After  all  activity  of  the  central  nervous  system  has  been  suppressed  by 
anemia,  or  asphyxia,  complete  recovery  may  result  if  the  circulation  is 
restored  to  a  normal  condition  soon  enough.  The  respiratory  reflexes  are 
the  first  to  reappear,  then  the  excitability  of  spinal  reflexes  is  regained, 
and  finally  cerebral  function  is  restored.  Less  prompt  recovery  occurs 
if  the  circulation  remains  inadequate  for  a  longer  period,  manifesting 
itself  chiefly  in  a  failure  of  the  cerebrum  to  regain  its  normal  function 
completely.  A  pregnant  cat,  which  had  been  subjected  to  anemia  of 
the  brain  and  upper  cord  for  10  minutes,  regained  her  ability  to  walk, 
to  clean  her  paws,  and  to  lap  up  water  or  milk,  but  her  movements  were 
poorly  controlled.  On  the  twelfth  day  she  gave  birth  to  kittens.  To  these 
she  paid  no  attention  unless  one  of  them  came  in  contact  with  her 
nose  when  she  would  lick  it  with  her  tongue.  She  allowed  the  kittens 
to  suckle  and  fondled  them  with  her  paws  when  nursing  very  much  as 
a  normal  cat  would  do,  but  if  one  of  them  wandered  away  she  would 
make  no  attempt  to  bring  it  back.  The  picture  was  one  of  the  automatic, 
reflex  aspects  of  motherhood  deprived  of  the  discriminative  attributes 
which  depended  on  cerebral  processes. 

The  central  nervous  system  exhibits  a  difference  in  the  nutritive  re- 
quirements of  its  different  parts.  It  is  interesting  to  see  how  long  dif- 
ferent groups  of  nerve  cells  will  resist  complete  anemia  without  losing 
their  ability  to  revive.  Considerable  variations  occur  in  different  ani- 
mals, but  the  following  figures  may  be  taken  as  typical.  They  represent 
the  time  beyond  which  anemia  cannot  be  extended  without  producing 
changes  in  the  nerve  cells  which  cannot  be  recovered  from. 

Cerebrum,   small   pyramidal   cells 8   minutes 

Cerebellum,  Purkinje  cells 13  minutes 

Medullary  centers   20-30  minutes 

Spinal  Cord  45-60  minutes 

Sympathetic  ganglia   3-3%  hours 

Myenteric  plexus   7-8  hours 

The  great  susceptibility  of  the  cerebral  cells  explains  the  ease  with 
which  consciousness  is  lost  as  the  result  of  circulatory  failure  or  asyphyxia. 
A  prolonged  condition  of  low  blood  pressure  may  result  in  the  failure 
of  the  medullary  centers  because  of  the  insufficiency  of  the  blood  supply. 


THE    NUTRITION    OF    NERVOUS    TISSUE  853 

This  is  perhaps  one  of  the  limiting  factors  in  the  resuscitation  of  patients 
suffering  from  low  blood  pressure  induced  by  hemorrhage  or  secondary 
traumatic  shock.  Bayliss  has  found  that  if  the  blood  pressure  of  the 
cat  is  maintained  at  a  low  level  for  an  hour  or  two  the  vasomotor  center 
loses  its  reflex  excitability  and  the  respiratory  center  fails  to  maintain 
a  ventilation  of  the  lungs  sufficient  to  support  life.  Restoration  of  the 
blood  pressure  by  transfusion  may  come  too  late  to  cause  these  centers 
to  recover.  In  the  cat  the  respiratory  center  loses  its  power  of  revival 
before  the  vasomotor  center,  but  the  relative  susceptibility  no  doubt 
varies  in  different  species  of  animals.  The  cells  of  the  outlying  ganglia 
of  the  sympathetic  system  and,  particularly,  those  of  the  myenteric 
plexus  are  able  to  withstand  a  prolonged  disturbance  in  their  blood  sup- 
ply much  better  than  the  neurons  of  the  central  nervous  system.  For 
this  reason  a  strangulated  loop  of  intestine  which  appears  hopelessly 
damaged,  by  the  prolonged  circulatory  statis  to  which  it  has  been  sub- 
jected, may  recover  its  normal  function  with  remarkable  success.8 
A  close  relation  probably  exists  between  the  distribution  of  the  cap- 
illaries in  the  nervous  system  and  the  nutritional  requirements  of  its 
various  parts.  Measurements  indicate  that  the  grey  matter,  in  which  the 
nerve  cell  bodies  lie,  is  much  more  richly  supplied  with  capillaries  than 
the  white  matter.  The  grey  matter  is  more  adequately  supplied  in  the 
medulla  than  in  the  cord,  and  the  same  relation  holds  true  between  the 
white  matter  in  these  regions.  Among  the  nuclei  of  the  medulla  it 
appears  that  sensory  nuclei  are,  in  general,  more  richly  vascularized  than 
motor  nuclei.  This  relation  is  perhaps  explained  by  the  almost  con- 
tinuous activity  of  the  sensory  neurons  as  contrasted  with  the  more  inter- 
mittent activity  of  the  neurons  concerned  with  motor  acts. 


CHAPTER  XCII 
THE  RECEPTORS 

Having  reviewed  the  fundamental  conditions  of  conduction  in  nerve 
fibers  and  in  the  reflex  arc,  we  are  now  in  a  position  to  consider  the 
arrangements  of  neurons  which  form  the  basis  of  the  principal  aspects 
of  central  nervous  activity.  We  will  consider  the  afferent  part  of  the 
reflex  arc,  the  activity  of  which  gives  rise  to  the  discharge  of  impulses 
over  motor  neurons  in  reflex  activity,  and  to  the  phenomena  of  sensa- 
tion and  discrimination  which  determine  the  nature  of  volitional  acts. 
Disturbances  in  these  arrangements  give  rise  to  the  sensory  symptoms  of 
nervous  disease.  Such  a  consideration  must  start  with  the  study  of  the 
receptors  or  sense  organs. 

The  Evolution  of  Specialized  Receptors 

The  receptor  is  a  cell  specialized  in  such  a  way  as  to  be  excited  by 
minute  changes  in  the  condition  of  its  environment.  As  a  result  of 
such  excitation  reflex  actitity  is  set  up  which  causes  the  animal  to  re- 
spond, usually  in  a  way  which  is  to  its  advantage,  and  sensations  are 
produced  which  give  information  concerning  the  nature  and  position  of 
the  stimulus  and  its  probable  consequences.  The  primitive  type  of  re- 
ceptor, which  appears  in  the  coelenterates  and  occurs  generally  in  most 
invertebrates  consists  of  an  epithelial  cell  from  which  a  fiber  extends 
into  the  central  nervous  system.  Such  an  arrangement  persists  in  the 
olfactory  sense  organs  in  man.  With  the  development  of  longer  nerve 
trunks  in  the  vertebrate  nervous  system  the  cell  body  is  no  longer  found 
at  the  termination  of  the  afferent  fiber,  but  has  taken  up  a  position 
nearer  to  the  central  nervous  system,  in  the  spinal  ganglion.  The  fibers 
of  such  an  afferent  neuron  terminate  peripherally  in  a  number  of  fine 
branches  which  extend  along  the  cells  of  the  epithelium,  forming  a  sense 
organ  known  as  a  free  nerve  termination.  The  sense  of  pain  in  man 
can  be  definitely  associated  with  receptors  of  this  type.  The  highest 
degree  of  sensitivity  cannot  be  attained  by  such  an  arrangement.  For 
this  purpose  special  cells  in  the  skin  become  modified  into  receptors,  and 
about  these  terminate  the  fibers  of  the  sensory  nerves.  Thus  one  cell 
serves  as  a  receptor,  while  the  other  is  concerned  primarily  with  con- 
ducting the  disturbance  set  up  in  the  receptor  to  the  central  nervous 
system.  The  receptors  of  the  ear,  the  eye,  the  sense  of  taste  and  probably 
other  cutaneous  sensations  are  of  this  type.  (Fig.  212.) 

854 


THE   RECEPTORS 


855 


Just  as  a  division  of  labor  has  been  necessary  between  the  receptor 
and  afferent  fiber  in  order  that  the  former  may  become  as  sensitive  as 
possible  to  weak  stimuli,  so  we  find  a  specialization  among  the  receptors, 
each  being  adapted  to  respond  to  some  particular  kind  of  physical  or 
chemical  change  in  its  surroundings.  Thus  we  may  classify  receptors 
with  respect  to  the  stimuli  to  which  they  respond  most  readily.  We 
may  speak  of  chemo-receptors  which  respond  to  chemical  changes 
(taste,  smell),  tango-receptors  which  respond  to  pressure  (touch),  photo- 
receptors  which  respond  to  light  (sight),  phono-receptors  which  respond 
to  sound  (hearing),  and  caloro-receptors  which  respond  to  temperature 
changes  (heat  and  cold).  This  does  not  mean,  however,  that  these  sense 
organs  respond  only  to  the  type  of  stimulus  to  which  they  are  especially 


Fig.  212. — Evolution  of  the  sense  organs.  I.  Receptor  of  coelenterate.  II.  Type  of  receptor 
found  in  many  invertebrates  and  in  gustatory  epithelium  of  vertebrates.  III.  Simple  afferent 
neuron  of  vertebrate  with  free  nerve  terminations  in  skin.  IV.  Specialized  sensory  mechanism  of 
vertebrate,  typified  by  the  organ 'of  the  sense  of  taste.  It  consists  of  specialized  receptor  cells  in 
the  integument,  about  which  terminates  the  axon  of  an  afferent  neuron.  (After  Parker.) 

attuned.  Pressure  upon  the  eyeball  may  stimulate  the  retina,  an  elec- 
tric current  may  give  rise  to  the  sensation  of  taste,  a  temperature  of  45° 
C.  will  excite  the  sense  organs  not  only  of  heat  but  of  cold  and  pain.  But 
in  the  latter  case,  for  example,  the  heat  receptors  alone  are  responsive 
to  temperatures  between  45°  C.  and  the  temperature  of  the  body.  The 
characteristic  of  the  specialized  receptor  is  that  its  threshold  or  lower 
limit  of  stimulation,  is  much  lower  for  one  type  of  stimulus  than  for  any 
other. 

The  Quality  of  Sensation  and  Its  Local  Sign 

Whatever  the  form  of  stimulus  which  excites  a  given  receptor,  the 
quality  of  the  sensation  is  always  the  same.  A  temperature  of  45°  C. 


856  CENTRAL  NERVOUS  SYSTEM 

produces  a  sensation,  not  of  warmth,  but  of  cold  when  applied  to  a  re- 
ceptor for  cold,  and  of  pain  when  applied  to  a  pain  receptor.  Pressure 
applied  to  the  eyeball  gives  similarly  a  sensation  of  light.  This  is  be- 
cause the  quality  of  a  sensation  depends  on  the  part  of  the  brain  to 
which  the  nerve  impulses  set  up  by  the  stimulus  are  conducted.  All 
the  fibers  from  a  given  type  of  receptor  group  themselves  together  in 
the  spinal  cord  or  brain  stem  and  lead  to  a  common  group  of  cells,  or 
sensory  area,  in  the  brain  from  which  the  sensation  arises.  The  im- 
pulses traveling  over  these  fibers  are  apparently  the  same  in  quality 
no  matter  what  form  of  physical  or  chemical  disturbance  has  set  them  up. 
Consequently  on  reaching  the  brain  centers,  no  difference  can  be  recog- 
nized between  them,  and  they  all  give  rise  to  a  common  quality  of  sen- 
sation. The  quality  of  a  sensation  depends  on  two  factors:  (1)  the  low 
threshold  of  a  special  group  of  sense  organs  for  the  particular  stimulus, 
and  (2)  the  anatomical  arrangement  by  which  the  impulses  from  such 
a  group  are  conducted  to  a  common  region  in  the  brain.  From  whatever 
source  impulses  reach  this  region  the  character  of  the  sensation  will 
be  the  same.  These  considerations  give  rise  to  the  law  of  the  specific 
properties  of  nerve,  which  is  to  the  effect  that,  however  excited,  each 
nerve  of  special  sense  gives  rise  to  its  own  peculiar  sensation. 

The  sensations  which  are  set  up  by  the  stimulation  of  receptors  not 
only  have  a  definite  quality,  but  are  recognized  as  coming  from  a  defi- 
nite region  of  space.  They  are  said  to  have  a  local  sign.  Certain  sensa- 
tions are  referred  to  parts  of  our  body,  as  we  recognize  when  we  say 
our  feet  are  cold,  our  tooth  aches,  or  our  skin  itches.  Others  are  referred 
to  objects  recognized  to  be  in  contact  with  the  body,  as  when  we  assert 
that  a  bed  is  hard,  or  a  piece  of  ice  cold.  Still  others  are  referred  to 
distant  objects,  as  when  we  recognize  the  color  of  a  picture,  the  sound 
of  a  bell,  or  the  odor  of  a  flower.  In  all  these  cases  the  process  of  ex- 
citation is  located  actually  in  a  sense  organ  within  or  at  the  surface  of 
the  body,  and  the  phenomenon  of  sensation  is  set  up  somewhere  within 
the  brain.  The  reference  of  sensation  is  a  psychological  phenomenon 
depending  on  the  past  experience  of  the  individual.  We  have  learned, 
for  example,  that  whenever  impulses  arrive  in  certain  regions  of  the 
brain,  giving  rise  to  characteristic  sensations,  that  they  have  come  from 
stimuli  set  up  in  some  particular  group  of  receptors  located  in  some  par- 
ticular part  of  the  body  and  excited  by  a  disturbance  which  we  have 
discovered  can  come  only  from  some  particular  region  in  space.  Thus 
experience  tells  us  that  a  certain  sensation  is  associated  with  an  object 
in  contact  with  the  foot.  Whenever  the  afferent  paths  from  the  foot 
are  brought  into  play,  the  same  sensation  results,  and  we  learn  to  asso- 
ciate the  resulting  sensation  with  the  foot  and  refer  all  such  sensations 
with  accuracy  to  the  foot.  If  the  sensation  is  one  commonly  associated 


THE   RECEPTORS  857 

only  with  the  obvious  contact  of  some  object  with  the  foot,  i.  e.,  if  it 
results  from  a  combination  of  the  sense  of  touch  and  sensations  of  other 
quality,  the  sensation  as  a  whole  is  referred  to  the  external  object,  and 
we  speak  of  the  object  being  cold,  hard,  etc.  When  components  of  such 
a  sensation  occur  without  the  obvious  contact  of  some  object,  the  sensa- 
tion is  referred  to  the  part  of  the  body  in  which  the  stimulation  arises, 
and  we  speak  of  the  foot  being  cold  or  in  pain.  Similarly  we  have  learned 
to  associate  sensations  resulting  from  stimuli  arising  in  certain  sense 
organs  with  objects  at  a  distance  from  the  body.  We  have  learned  for 
example  to  associate  sensations  which  arise  from  stimuli  falling  upon 
particular  parts  of  the  retina  with  the  particular  regions  in  space  from 
which  light  may  come  which  can  stimulate  that  particular  retinal  area. 
Unconscious  of  the  mechanism  of  the  optical  system,  or  of  the  arrange- 
ment of  the  afferent  paths  of  vision,  we  have  simply  learned  that  cer- 
tain visual  sensations  can  always  be  attributed  to  objects  occupying  a 
certain  position  in  space,  and  we  can  consequently  assert  with  assurance 
that  the  upper  part  of  a  picture  is  blue.  The  local  sign  of  sensation  is  con- 
sequently largely  a  matter  of  experience  or  learning. 

Reflex  acts  also  bear  an  accurate  local  sign,  although  they  may  be  carried 
out  by  parts  of  the  nervous  system  apparently  devoid  of  consciousness  or 
of  the  ability  to  learn.  Thus  a  frog,  from  which  the  brain  has  been  re- 
moved will  raise  its  hind  leg  and  attempt  to  sweep  away  an  irritating  ob- 
ject placed  on  any  part  of  the  body,  directing  its  foot  to  the  point  of  stimula- 
tion with  the  utmost  accuracy.  A  spinal  dog  will  carry  out  a  scratch  reflex 
which  differs  considerably  in  its  objective  point,  depending  on  the  part  of 
the  back  to  which  the  stimulus  is  applied.  How  the  mechanism  has  come 
about  which  enables  stimulation  of  receptors  in  one  part  of  the  body  to 
bring  about  these  reflex  movements  of  an  appropriate  sort  is  a  fundamental 
problem  in  evolution  which  we  cannot  take  up. 

The  basis  of  the  recognition  of  quality  and  local  sign  in  sensation  is 
of  the  utmost  importance  in  interpreting  the  sensory  manifestation  of 
disease  in  the  central  nervous  system.  It  rests  on  the  fact  that  sensation 
of  definite  quality  and  local  sign  depends  on  the  arrival  at  a  certain  sta- 
tion in  the  brain  of  impulses  which  are  set  up  ordinarily  in  a  group  of 
sense  organs  specialized  for  the  reception  of  one  particular  type  of 
stimulus  and  located  in  a  definite  region  of  the  body.  Loss  of  sensation 
may  result  from  the  interruption  of  the  path  of  conduction  anywhere 
between,  and  including,  the  receptor  and  the  sensory  center  in  the  brain. 

Sensations  of  definite  quality  may  be  set  up  by  stimulation  of  the 
nerve  fibers  at  any  point  along  this  path,  or  of  the  sensory  center  itself. 
One  must  exercise  great  care  before  accepting  the  location  to  which  the 
patient  attributes  the  source  of  sensation,  for  he  has  only  the  experience 
of  healthy  life  to  guide  him.  Consequently  he  may  be  misguided  into 


858 


CENTRAL    NERVOUS    SYSTEM 


ascribing  sensations  to  definite  parts  of  the  body,  which  in  fact  are 
hallucinations  arising  from  some  functional  disorder  of  the  brain  which 
is  affecting  directly  the  sensory  centers  of  the  cortex. 

Referred  Pain, — The  accuracy  of  sensory  location  seems  to  be  corre- 
lated with  the  abundance  of  sense  organs  in  different  parts  of  the  body 
and  with  the  frequency  of  their  employment.  On  the  hands,  the  lips, 
and  tongue  localization  is  extremely  accurate,  for  these  organs  are  in 
frequent  use  in  examining  the  nature  and  position  of  various  objects. 
Localization  is  good  on  the  soles  of  the  feet,  which  are  used  to  sound 
out  the  ground  in  walking.  On  the  other  parts  of  the  limbs,  the  trunk, 
and  particularly  the  back,  stimuli  can  be  localized  only  in  a  rather  rough 
way.  Particularly  interesting  is  the  phenomena  of  localization  of  sen- 
sations arising  from  the  viscera.  In  healthy  life  these  organs  do  not 
give  rise  to  sensory  manifestations,  but  in  disease  of  the  viscera  acute 
pains  may  be  set  up.  Because  visceral  sensations  arise  from  organs 
within  our  body,  we  have  no  way  of  knowing  just  where  the  trouble 
lies  and  consequently  have  no  basis  for  localizing  the  disturbance  accu- 
rately. In  the  case  of  stationary  organs  such  as  the  heart,  the  pain 
may  be  referred  at  times  to  the  proper  internal  region,  but  in  the  case 
of  movable  organs  such  as  the  intestine,  the  reference  is  most  inexact. 

DISTRIBUTION  OF  REFERRED  PAIN  FROM  VISCERAL  ORGANS  (AFTER  POTTENGER) 

The  eight  cervical  segments  are  indicated  by  Cl,  C2-C8;  the  twelve  dorsal  or  thoracic 
segments  by  Dl,  D2-D12;  the  five  lumbar  segments  by  LI,  L2-L5;  and  the  four  sacral 
segments  by  Sac.  1,  Sac.  2,  Sac.  4.  The  areas  of  the  head  are  indicated  as  follows: 
N — nasal  or  rostral  area;  FN — f ronto-nasal  area ;  MO — medio-orbitalarea;  FT — fronto- 
temporal  area ;  T — temporal  area ;  V — vertical  area ;  P — prietal  area ;  O — occipital  area ; 
NL — naso-labial  area;  Max. — maxillary  area;  Man. — mandibular  area;  M — mental  area; 
L.  S. — Superior  laryiigeal  area;  LI — inferior  laryiigeal  area;  TO— hyoid  area. 


AREA  IN  THE  TRUNK  AND  LIMBS 


AREA  IN  THE  HEAD 


Heart 

Lungs 

Stomach 

Intestine 

Rectum 

Liver 

Gall  bladder 

Kidney  and  urethra 

Bladder  (mucous  membrane 

and  neck) 
Detrusor  vesicac 
Prostate 
Epididymis 
Testicle 
Ovary 

Ovarian  appendix 
Uterus 

Neck  of  uterus 
Mammae 
Spleen 


Ventricles  and  aorta,  N,  FN,  MO,  FT 
03,  C  •     Auricjcs pT    T,  V,  P 

03,  C4— D4— D9 Y.'.NJ  FN,  MO,  FT,'  T,'  V,'  P 

D7— D9 FN,  MO,  T,  V,  P 

D9— D12 V,  P,  O 

Sac.  2— Sac.  4 

C3,  C4— D7— DIG FN,  MO,  T,  V,  P,  0 

D8— D9 T,  V 

Dll— LI 

Sac.  3— Sac.  4 

Dll— L2 

D10— D12— Sac.  1— Sac.  3 

1)11— D12 

DIG 0 

1)10 0 

Dll— LI 
D10— LI 
"9.c.  2— Sac.  4 
D4— D5 
D6 


THE    RECEPTORS  859 

Very  commonly  pain  arising  in  the  internal  organs  is  referred  to  some 
remote  region  on  the  surface  of  the  body.  This  phenomena  is  known  as 
referred  pain,  Such  pains  are  sharp  or  aching  in  character,  whereas  pain 
which  seems  to  come  from  the  internal  organs  is  dull  or  heavy  (Head13). 

The  afferent  nerves  from  the  viscera  apparently  terminate  in  the  cord 
in  close  association  with  afferent  nerves  from  certain  skin  areas.  Just 
how  one  group  of  afferents  affects  the  other  is  not  known,  but  the  fact  is 
that  the  sensation  from  the  viscus  is  referred  to  the  peripheral  distribu- 
tion of  those  fibers  which  terminate  in  the  same  segment  of  the  spinal 
cord.  The  nerves  of  cutaneous  sensation  have  a  definite  segmental  dis- 
tribution (Fig.  214)  and  consequently  the  reference  of  internal  pain 
will  be  to  one  or  another  of  these  segmental  regions.  Not  only  is  the 
visceral  pain  referred  to  these  segmental  areas,  but  these  parts  of  the 
skin  become  hypersensitive,  so  that  the  sensation  of  pain  and  sometimes 
of  heat  and  cold  arising  from  them  is  greatly  exaggerated.  Thus  the 
location  of  the  referred  pain  and  of  hypersensitivity  may  be  taken  as  an 
accurate  indication  of  the  internal  situation  of  the  source  of  irritation. 
The  table  on  page  858  indicates  the  segmental  distribution  of  referred 
pain  from  the  major  viscera. 

The  sensitivity  of  the  viscera  is  of  a  low  order.  When  the  sensitivity 
of  a  region  of  the  skin  is  reduced  to  a  similar  condition  by  disease,  sen- 
sations arising  therefrom  may  be  referred  to  other  parts,  just  as  the  vis- 
ceral pains  ordinarily  are.  This  phenomenon  is  known  as  allocheiria, 
If  the  hyposensitive  area  is  limited  to  one  side  of  the  body,  the  sensation 
arising  from  it  is  referred  to  the  corresponding  part  of  the  other  side 
of  the  body.  If  both  sides  are  hyposensitive,  the  reference  is  to  the 
next  segment  above  or  below.  Like  the  reference  of  visceral  pain,  this 
condition  must  be  attributed  to  the  central  relationship  between  the 
tracts  carrying  afferent  impulses  from  symmetrical  points  on  the  skin 
and  from  neighboring  segments  to  the  sensory  centers.  When  the  mecha- 
nism of  sensation  for  one  part  is  depressed,  the  sensation  is  referred  to 
the  most  closely  associated  normal  region. 

Cutaneous  and  Deep  Sensibility 

The  physiology  of  receptors  may  be  illustrated  by  a  consideration 
of  sense  organs  which  have  a  general  distribution  throughout  the  body. 
These  comprise  the  receptors  of  chief  interest  in  practical  neurology, 
and  will  serve  to  illustrate  principles  which  apply  as  well  to  the  spe- 
cial sense  organs  of  the  head  (of  the  eye,  ear,  gustatory  and  olfactory 
epithelia),  the  consideration  of  which  space  will  not  allow.  They  may 
be  divided  into  organs  of  cutaneous  and  of  deep  sensibility,  depending 
on  whether  the  receptors  lie  in  the  skin  or  in  the  internal  parts  of  the 
body.  We  can  recognize  four  primary  qualities  in  the  sensations  to 


860 


CENTRAL    NERVOUS   SYSTEM 


which  they  give  rise.  These  are  touch,  heat,  cold  and  pain.  When  an 
area  of  skin  is  examined  carefully  it  is  found  that  these  sensations 
are  not  elicited  with  equal  readiness  from  all  parts,  but  that  definite 
spots  exist  which  may  give  rise  to  one  or  another  of  these  sensations. 
Some  give  rise  to  touch  alone,  others  to  the  sensation  of  warmth,  others 
to  that  of  cold,  and  still  others  to  a  feeling  of  pain.  Each  spot  evidently 
marks  the  location  of  one  or  more  receptors  for  the  stimulus  in  ques- 
tion. The  spots  giving  rise  to  the  four  different  qualities  of  sensation 
frequently  do  not  coincide,  nor  do  their  numbers  correspond,  i.e.,  cold 
spots  are  more  numerous  than  heat  spots.  In  many  regions  of  the 
body  one  quality  of  sensation  may  be  lacking  altogether.  Thus  pain  is 
absent  from  the  inner  surface  of  the  cheek  opposite  the  second  molar; 
it  .alone  occurs  on  the  cornea.  These  facts  furnish  proof  that  the  qual- 


A. 

Fig.  213. — Cold  spots  {A)  and  heat  spots  (5)  of  an  area  of  skin  of  the  right  hand.  In  each 
case  the  most  intense  sensations  were  experienced  in  the  black  areas,  less  intense  in  the  lined, 
and  least  in  the  dotted.  The  blank  areas  represent  parts  where  no  special  sensation  of  either 
kind  was  experienced.  (From  Goldseheider.) 

ity  of  the  cutaneous  sensations  depends  on  the  stimulation  of  sense  or- 
gans which  are  specialized  each  for  a  different  type  of  stimulus. 

Touch. — Touch  spots  are  stimulated  by  pressure  which  deforms  the 
tissue.  This  may  be  seen  to  be  so  by  dipping  a  finger  into  mercury 
when  it  will  be  found  that  the  sensation  arises  only  from  a  band  of 
skin  at  the  surface  which  is  bent  by  the  pressure  of  the  mercury.  The 
skin  deeper  down  is  pressed  upon  uniformly  and  consequently  is  not 
deformed  and  no  sensation  is  set  up.  Touch  spots  are  not  uniformly 
distributed  on  all  parts  of  the  body,  as  we  have  already  indicated.  On 
the  hairy  regions  it  is  found  that  they  are  most  numerous  at  the  base 
of  the  hairs,  especially  on  the  "windward"  side.  These  spots  are  stim- 
ulated when  the  hair  is  bent,  and  since  the  hair  acts  as  a  lever,  very 


THE    RECEPTORS  861 

light  pressures  will  excite  them.     Consequently  the  threshold  for  touch 
is  lowered  on  the  hairy  parts  of  the  body. 

The  examination  of  the  sense  of  touch  in  the  skin  is  important  in  the 
study  of  nervous  disease.  The  presence  or  absence  of  the  sensation  is 
tested  by  touching  the  skin  with  a  pledget  of  cotton  or  a  soft  paint 
brush.  If  the  sensation  is  impaired  but.  not  destroyed,  more  exact  in- 
formation can  be  obtained  by  measuring  the  threshold,  i.  e.,  the  smallest 
pressure  which  will  stimulate  the  touch  spots  by  repeating  the  test  with 
a  series  of  hairs  or  brushes  of  graded  stiffness.  The  ability  to  localize 
the  spot  touched  is  known  as  spot  finding1  or  one  dimensional  localiza- 
tion. Two  dimensional  localization  is  the  process  of  recognizing  that 
stimulation  is  being  applied  to  two  spots  at  the  same  time.  If  the  points 
of  a  pair  of  compasses  are  applied  to  the  skin  at  once  they  will  be  recog- 
nized as  distinct  points  only  if  separated  by  a  certain  distance.  This 
distance  becomes  greater  as  the  number  of  touch  spots  becomes  fewer, 
it  apparently  being  necessary  that  a  certain  number  of  unstimulated 
spots  should  separate  them  before  the  points  of  stimulation  are  recog- 
nized as  distinct.  This  process  of  recognizing  the  distinctness  of  two 
spots  is  called  two  dimensional  localization.  The  compass  test  is  use- 
ful in  detecting  deficiencies  in  the  process  which  may  result  from  de- 
struction of  the  afferent  paths  for  the  sense  of  touch. 

Very  closely  associated  with  the  sense  of  touch  are  the  sense  organs, 
which  give  us  knowledge  of  the  position  and  movements  of  the  parts  of 
our  body.  These  are  located  in  the  muscles,  tendons  and  joints,  and  are 
doubtless  stimulated  by  deforming  pressures  arising  from  the  contrac- 
tion of  muscle  and  the  movement  of  the  bones  at  the  joints.  The  senses 
are  tested  by  the  ability  of  a  patient  to  touch  one  part  of  the  body  with 
another,  the  eyes  being  shut  and  the  affected  member  being  moved  into 
various  positions.  Quantitative  measurements  can  also  be  obtained  by 
determining  through  how  many  degrees  a  joint  may  be  bent  before  the 
patient  recognizes  that  the  limb  is  being  moved.  The  ability  to  recog- 
nize the  position  and  movement  of  the  parts  of  the  body  is  called  three 
dimensional  localization. 

Heat  and  Cold. — The  heat  and  cold  spots  are  stimulated  by  abnormal 
temperatures,  heat  spots  being  excited  by  temperatures  above  and  cold 
by  temperatures  below  that  previously  existing  in  the  skin.  Whether 
one  or  the  other  sensation  will  be  felt  depends  not  so  much  on  the  ab- 
solute temperature  to  which  the  heat  and  cold  spots  are  brought  as  to 
the  relation  of  this  temperature  to  that  of  the  skin.  If  the  skin  is 
chilled  luke  warm  water  will  feel  warm  to  it,  whereas  the  same  water 
will  feel  cool  if  the  skin  has  previously  been  brought  to  a  high  tempera- 
ture. Thus  if  one  finger  is  placed  in  cold  water  and  the  other  in  hot 
water  for  a  few  minutes  and  then  both  are  thrust  into  water  at  an 


862  CENTRAL  NERVOUS  SYSTEM 

intermediate  temperature  the  sensation  of  warmth  will  be  felt  in  the 
former  finger  and  of  cold  in  the  latter.  The  sense  organs  thus  become 
adapted  to  the  conditions  to  which  they  are  exposed,  and  become  ex- 
cited again  only  by  a  change  in  these  conditions. 

Adaptation  is  a  quite  general  sensory  phenomenon.  It  occurs  prom- 
inently in  the  retina,  with  the  result  that  an  eye  which  has  become  used 
to  the  dark  is  dazzled  momentarily  by  the  ordinary  daylight.  Adapta- 
tion is  also  a  marked  feature  of  the  touch  sense,  as  is  the  experience  of 
every  one  who  has  worn  flannel  underclothing  or  a  plate  of  false  teeth. 
It  serves  to  protect  the  organism  from  the  fatiguing  effects  of  over- 
stimulation  from  conditions  to  which  it  is  continually  exposed.  Sensory 
adaptation  must  be  borne  in  mind  not  only  when  examining  the  senses 
of  others,  but  in  making  judgments  with  our  own  sense  organs.  Thus  if 
the  hands  are  cold,  the  skin  of  another  may  feel  warm  and  feverish,  even 
though  its  temperature  is  not  above  normal. 

Pain  is  of  particular  importance  to  the  physician,  whose  services  are 
judged  by  the  community  largely  by  his  skill  in  suppressing  this  sen- 
sation. Unlike  the  other  receptors,  the  pain  spots  are  not  specialized  for 
the  detection  of  any  particular  form  of  stimulus,  but  may  become  excited 
by  any  condition  which  threatens  to  harm  the  tissues.  Pain  may  be  pro- 
duced by  excessive  pressure,  the  caustic  action  of  chemicals,  excessive  ex- 
posure to  light  as  in  sunburn,  temperatures  above  45°  C.  and  the  effects 
of  extreme  cold,  as  in  frost  bite.  The  threshold  for  these  stimuli  is  high, 
so  that  in  the  strengths  at  which  they  are  ordinarily  experienced  the 
sensation  of  pain  does  not  arise.  All  stimuli  of  sufficient  intensity  to 
threaten  the  welfare  of  the  tissues  and  give  rise  to  pain  are  called 
noxious  stimuli.  It  was  thought  at  one  time  that  pain  resulted  from 
the  overstimulation  of  any  type  of  receptor.  This  conclusion  was  natural 
when  one  considered  the  great  variety  of  conditions  which  might  give 
rise  to  painful  sensations.  Undoubtedly  the  overstimulation  of  any 
sense  organ  may  produce  sensations  of  unpleasant  character,  but  that 
specific  sense  organs  for  pain  exist  can  no  longer  be  doubted.  This  is 
shown  by  the  presence  of  pain  spots  in  regions  from  which  other  sense 
organs  are  absent,  as  the  cornea,  the  absence  of  pain  in  regions  in  which 
other  sense  organs  occur,  as  the  inside  of  the  cheek  opposite  the  sec- 
ond molar,  by  the  existence  of  special  tracts  in  the  central  nervous  sys- 
tem for  the  conduction  of  the  impulses  which  give  rise  to  pain,  and  by 
the  fact  that  certain  drugs  such  as  cocaine  may  abolish  the  excitability 
of  the  receptors  for  pain  without  disturbing  the  reception  of  other 
sensations. 

Pure  sensations,  arising  from  the  stimulation  of  a  single  type  of  re- 
ceptor, rarely  occur  in  life  except  under  the  artificial  conditions  which 
we  employ  in  the  laboratory.  The  sensations  which  we  experience  are 
the  composite  result  of  the  simultaneous  combination  of  a  variety  of 


THE    RECEPTORS  863 

stimuli,  acting  together  on  sense  organs  which  give  rise  to  sensations  of 
different  quality.  The  nature  of  the  resulting  sensation  is  consequently 
modified.  Water  heated  to  40°  C.  feels  warm  to  the  hand  arid  stimulates 
only  the  heat  spots.  At  45°  C.  the  cold  spots  and  pain  spots  are  also 
excited,  and  the  resulting  sensation  takes  on  a  distinctly  different  qual- 
ity which  we  call  "hot."  Since  pain  is  excited  only  by  extreme  in- 
tensities of  stimuli  which  can  set  up  other  qualities  of  sensation,  it  is 
natural  to  find  painful  sensations  varying  considerably  in  their  quality, 
depending  on  the  sensations  which  occur  in  association  with  them. 
Thus  a  throbbing  pain  is  due  to  the  simultaneous  pressure  produced  by 
dilated  blood  vessels. 

It  is  interesting  to  find  that  certain  qualities  of  sensation  are  incompa- 
tible with  one  another.  When  stimuli  capable  of  setting  up  two  such  incom- 
patible sensations  occur  at  once,  one  sensation  is  suppressed  or  inhibited  by 
the  other.  An  interesting  experiment  is  described  by  Head  which  illustrates 
this.  The  tip  of  the  glans  penis  is  supplied  with  receptors  for  cold  and  pain, 
but  may  be  devoid  of  heat  spots.  If  it  is  dipped  into  water  at  40°  C.  the 
pain  spots  alone  are  stimulated  and  a  disagreeable,  painful  sensation  re- 
sults. If  the  temperature  is  raised  to  45°  C.  the  cold  spots  also  are  stimu- 
lated, the  pain  is  displaced  by  a  vivid  sensation  of  cold.  About  the  corona 
of  the  penis  heat  spots  also  occur.  If  this  region  is  also  immersed,  the 
quality  of  the  sensation  changes  to  one  of  exquisitely  pleasant  warmth.  If 
the  water  employed  in  the  experiment  is  at  a  temperature  higher  than 
45°  C.  the  painful  sensation  persists  and  no  sensation  of  warmth  is  felt. 
The  sensations  of  pain  and  pleasant  warmth  are  incompatible  and  cannot 
occur  simultaneously.  Which  one  will  succeed  in  gaining  control  of 
consciousness  and  in  suppressing  the  other  depends  on  the  relative 
strengths  of  their  stimuli.  An  entirely  analogous  phenomenon  occurs  in 
the  competition  of  incompatible  reflexes  for  the  control  of  a  common 
motor  path  (page  947). 

Noxious  stimuli  give  rise  to  an  exceedingly  impelling  sensation  and 
to  reflexes  which  can  dominate  over  any  others  which  may  be  set  up 
at  the  same  time.  The  response  to  painful  stimulation  is  of  a  protective 
character  and  it  is  imperative  that  such  stimuli  and  their  sensations 
should  control  the  activity  of  the  organism  when  they  arise  with  in- 
tensity. On  the  other  hand,  if  the  noxious  stimuli  are  near  the  thresh- 
old value  of  intensity,  and  little  danger  is  threatened,  it  is  an  advan- 
tage that  its  effects  be  suppressed  so  that  the  organism  may  react  with 
a  discretion  based  on  data  derived  from  other  sensations  as  well. 

The  Distribution  of  Sensitivity  in  the  Body 

Sensations  of  touch,  heat,  cold,  and  pain  are  felt  generally  throughout 
the  surface  of  the  body,  with  the  exception  of  certain  limited  areas  such 
as  we  have  referred  to,  from  which  one  or  another  quality  of  sensation 


864 


CENTRAL    NERVOUS   SYSTEM 


may  be  lacking.  The  presence  of  these  cutaneous  senses  is  obvious  to 
any  one,  and  the  sensations  which  they  arouse  form  the  basis  of  many 
volitional  acts.  The  presence  of  receptors  in  the  deeper  parts  of  the 
body,  on  the  other  hand,  may  be  recognized  only  by  careful  introspec- 
tion, as  when  some  pathological  condition  produces  deep  pain,  or  de- 
ranges the  unconscious  motor  responses  which  depend  on  the  receptors 
of  deep  sensibility.  That  afferent  nerve  impulses  may  arise  from  the 
muscles,  connective  tissue,  tendons  and  joints  is  shown  by  a  number  of 
considerations.  We  are  accurately  aware  of  the  position  of  our  limbs 
and  of  any  change  in  their  position,  whether  made  actively  or  passively. 
This  knowledge  does  not  depend  on  the  cutaneous  sensibility  because  the 
sense  of  position  is  not  impaired  when  the  cutaneous  sensibility  is 
destroyed  by  cutting  the  sensory  nerves  to  the  skin.  When  this  is  done 
sensations  of  pain  and  pressure  may  still  be  felt  if  the  limb  be  pressed 
upon  forcibly.  Painful  sensations  which  are  referred  directly  to  the 
muscles  may  arise  during  a  muscular  cramp  or  in  the  soreness  which  fol- 
lows the  severe  use  of  muscle  groups  which  are  unaccustomed  to  such 
activity.  The  fibers  conducting  afferent  impulses  lie  in  the  trunks  of 
the  motor  nerves,  and  when  these  are  damaged  muscular  sensibility  is 
lost.  On  cutting  the  dorsal  root  of  a  spinal  nerve,  it  is  found  that  a 
number  of  fibers  in  the  motor  nerve  trunks  to  the  muscles  undergo 
degeneration.  The  receptors  in  the  muscles,  connective  tissue,  tendons, 
and  joints  may  give  rise  to  sensations  of  pain  and  touch  and  give  in 
addition  information  which  we  shall  see  is  invaluable  in  coordinating 
the  movements  of  the  body  (page  914). 

The  receptors  of  the  internal  organs  of  the  trunk  may  give  rise  to 
sensations  of  pain,  referred  either  to  the  inside  of  the  body  or  to  some 
region  of  the  skin.  That  the  sensibility  of  these  organs  is  of  a  low  or- 
der is  attested  by  the  fact  that  in  healthy  life  we  are  rarely  aware  of 
their  presence  in  spite  of  the  almost  continuous  activity  of  many  of  these 
organs.  The  study  of  the  distribution  of  the  internal  receptors  for  pain 
has  been  made  by  Lennander14  during  operations  performed  under  local 
anesthesia.  It  has  been  found  that  the  connective  tissue  about  the  ten- 
dons, the  synovial  membranes,  periosteum,  and  perichondrium,  are  all 
very  sensitive  to  pain.  The  parietal  peritoneum  is  very  sensitive  to 
pain,  especially  from  traction.  On  the  anterior  abdominal  wall,  at  least, 
it  is  not  endowed  with  end  organs  of  pressure,  heat,  or  cold.  The  mesen- 
teries are  free  from  pain  when  cut,  but  are  sensitive  to  traction.  When 
free  from  connective  tissue  periosteum  or  perichondrium,  the  bone  sub- 
stance and  marrow,  cartilage,  and  arteries  and  veins  are  insensitive  to 
cutting,  except  those  bony  structures  such  as  the  maxilla  and  teeth  which 
are  traversed  by  sensory  nerves.  The  muscles  are  insensitive  to  cutting, 
although  excruciating  pain  may  arise  in  them  as  the  result  of  a  cramp. 


THE    KKCKPTORS  865 

The  brain  substance  and  pia  arachnoid  are  insensitive  on  the  convexity 
of  the  brain  and  beneath  the  occipital  bone,  but  pain  may  arise  from  it 
beneath  the  frontal  bone  and  toward  the  zygomatic  arch.  In  the  thoracic 
cavity  the  visceral  pleura,  which  is  innervated  by  the  vagus  and  sym- 
pathetic, is  insensitive  to  the  pressure  of  a  stiff  wire.  The  parietal 
pleura,  innervated  by  the  intercostal  nerves,  is  the  seat  of  pain  which  is 
accurately  localized.  The  peripheral  portion  of  the  diaphragmatic  pleura 
is  innervated  by  the  intercostal  nerves  over  a  band  about  two  inches 
wide.  Pain  arising  in  this  region  is  referred  to  the  lower  thorax,  the 
abdomen  and  lumbar  region.  The  central  portion  of  the  diaphragmatic 
pleura,  innervated  by  the  phrenic  nerve,  is  the  seat  of  pain  referred  to 
the  neck.  The  lungs  are  insensitive,  as  is  the  heart,  except  under  trac- 
tion. In  the  abdomen  all  organs  receiving  a  nerve  supply  only  from  the 
sympathetic  nerves  and  from  the  vagus  below  the  branching  of  the  re- 
current nerve  have  no  sensation.  The  substance  of  the  stomach,  intes- 
tines, and  liver  may  be  cut  into  without  causing  discomfort.  The  fibrous 
capsule  and  parenchyma  of  the  kidney  do  not  give  rise  to  sensation  if 
the  fatty  capsule  is  removed.  The  bladder  may  be  cut  or  pinched,  but 
not  pulled,  without  giving  pain. 

It  must  be  remembered  that  these  observations  have  been  made  on 
individuals  undergoing  operation  with  local  anesthetic.  Sensitivity  may 
have  been  modified  by  exposure  of  the  organs  to  the  air,  or  by  spread  of 
the  anesthetic.  They  give  valuable  information  from  a  surgical  point 
of  view,  but  do  not  tell  us  about  the  conditions  which  give  rise  to  sen- 
sation during  the  normal  or  pathological  activity  of  the  viscera.  It 
will  be  noted  that  the  most  adequate  stimulus  for  visceral  pain  is  trac- 
tion, which  may  produce  discomfort  when  cutting  is  ineffective.  It  is 
probable  that  the  pains  of  labor,  menstruation,  colic,  gastric  ulcer,  etc., 
are  set  up  by  tension  within  the  muscles  of  the  uterus,  or  gastrointes- 
tinal tract,  or  to  traction  upon  the  mesenteries  and  their  insertion  into 
the  parietal  peritoneum  by  the  arching  of  these  organs  when  their  walls 
attempt  to  contract  while  in  a  distended  condition. 

The  sensibility  of  the  mucosa  of  the  stomach  has  been  made  the  ob- 
ject of  extensive  study,  particularly  in  men  possessing  gastric  fistulae. 
The  mucosa  is  quite  insensitive  to  pain,  when  pricked  with  a  pin  or 
pinched.  Pain  is  felt  as  the  result  of  such  stimuli  only  when'  they  are 
sufficiently  severe  to  spread  to  underlying  structures.  The  mucosa  is 
also  insensitive  to  touch.  A  stiff  test  tube  brush  may  be  thrust  into 
the  stomach  and  moved  about  vigorously  without  producing  any  sen- 
sation. On  the  other  hand,  the  temperature  senses  are  represented  in 
the  wall  of  the  stomach.  The  introduction  of  water  below  10°  C.  pro- 
duces a  sensation  of  cold,  and  above  50°  one  of  heat.  Intermediate  tem- 
peratures are  without  effect. 


CHAPTER  XCIII 
THE  AFFERENT  PATHS  OF  SENSORY  IMPULSES  - 

The  insulation  of  conduction  in  the  nerve  fiber,  and  the  fact  that  im- 
pulses can  pass  from  neuron  to  neuron  in  one  direction  only,  makes  the 
arrangement  of  neurons  in  the  nervous  system  a  matter  of  great  sig- 
nificance. We  have  already  seen  that  the  recognition  of  the  quality  and 
location  of  a  stimulus  depends  upon  the  connection  of  each  receptor  in 
the  skin  with  a  definitely  corresponding  part  of  the  brain.  The  ana- 
tomical arrangement  of  the  paths  conducting  afferent  impulses  from 
receptors  for  each  quality  of  sensation  and  from  the  different  parts  of 
the  body  is  of  importance  in  elucidating  the  sensory  phenomena  of 
disease. 

The  Segmental  Distribution  of  Afferent  Nerves 

The  vertebrate  embryo  develops  as  a  segmented  organism,  at  least 
so  far  as  its  nervous,  muscular,  and  skeletal  structures  are  concerned. 
The  primitive  segmentation  of  the  vertebrate  embryo  is  preserved  in  the 
arrangement  of  the  spinal  nerves  of  man.  Each  dorsal  root  of  the  spinal 
nerves  contains  afferent  fibers  coming  from  a  definite  segmental  area 
of  the  skin.  This  may  be  shown  by  cutting  all  of  the  dorsal  roots  except 
one  and  then  determining  what  parts  of  the  skin  retain  their  sensitivity. 
The  areas  innervated  by  adjoining  roots  overlap  considerably,  so  that 
most  parts  of  the  skin  receive  a  double  innervation.  Consequently 
damage  to  a  single  dorsal  root  does  not  produce  a  considerable  loss  of 
sensation.  The  areas  supplied  by  each  dorsal  root  agree  closely  with 
the  segmental  areas  to  which  visceral  pain  is  referred,  with  the  exception 
that  the  latter  do  not  overlap  (Fig.  214).  The  areas  of  referred  pain 
appear  to  represent  the  central  portion  of  the  segment  innervated  by  a 
single  dorsal  root  in  which  the  overlapping  is  less  considerable. 

The  position  of  the  skin  areas  do  not  correspond  to  the  level  of  the 
dorsal  roots  which  innervate  them  because  of  the  downward  slope  of  the 
spinal  nerves.  The  skin  areas,  particularly  of  the  lumbar  and  sacral 
roots,  are  somewhat  below  the  corresponding  segments  of  the  spinal 
cord.  In  the  limbs  the  segmental  arrangement  becomes  obscure,  until 
considered  with  respect  to  the  segmental  origin  of  the  limb  buds  in  the 
embryo.  The  areas  innervated  by  the  different  roots  contributing  to  the 
brachial  and  lumbar  plexuses  are  nevertheless  quite  distinct. 

866 


THE    AFFERENT   PATHS    OF   SENSORY    IMPULSES 


867 


The  dorsal  roots  contain  afferent  fibers  not  only  from  the  skin,  but 
from  the  receptors  of  deep  sensibility  located  in  the  muscles  and  viscera. 
We  will  see  that  the  primitive  segmentation  of  the  muscles  is  consider- 
ably disturbed  in  the  course  of  development  (page  890).  The  afferent 
nerves  from  the  muscles  enter  the  cord,  however,  in  the  segment  from 
which  the  muscles  originally  arose.  The  same  is  also  true  of  the  viscera. 
The  heart,  for  example,  which  arises  in  the  cervical  part  of  the  embryo 
has  moved  to  a  lower  position,  retaining,  however,  its  innervation  from 


Fig.    214. — Diagram    showing    the    segmental    arrangement    of    the    sensory    nerves.       (From    Purves 

Stewart.) 

the  cervical  segments.     Pain  from  the  heart  is  referred  consequently  to 
the  neck  and  arm. 

Because  of  this  separation  of  the  muscular  and  cutaneous  distribution 
of  the  fibers  composing  a  single  dorsal  root,  injuries  to  the  peripheral 
nerves  may  destroy  cutaneous  sensibility  without  affecting  deep  sensi- 
bility. This  is  particularly  liable  to  occur  because  of  the  collection  to- 
gether in  nerve  trunks,  especially  in  the  limbs,  of  fibers  from  adjacent 
dorsal  roots  which  have  a  common  (overlapping)  distribution.  When 
this  occurs  the  cutaneous  sensibility  to  light  touch,  two  dimensional 
localization,  heat  and  cold,  and  the  prick  of  a  pin,  may  be  destroyed  over 


868 


CENTRAL  NERVOUS  SYSTEM 


an  area  which  is  still  sensitive  to  deep  pressure  and  the  resulting  pain, 
and  in  which  the  sense  of  position  of  the  part  remains  normal.  Such  a 
lesion  is  said  to  cause  a  dissociation  of  sensation.  Dissociation  between 
cutaneous  and  deep  sensibility  occurs  only  in  the  case  of  peripheral  nerve 
lesions.  Since  the  fibers  of  deep  sensibility  in  muscles  lie  in  the  trunks 
of  motor  nerves,  a  lesion  affecting  it  is  usually  accompanied  by  certain 
disturbances  in  motor  function. 

Ascending  Pathways  in  the  Spinal  Cord 

Our  knowledge  of  the  course  of  afferent  impulses  in  the  cord  is  gained 
by  determining  which  tracts  degenerate  when  the  dorsal  roots  are  cut, 
by  destroying  certain  regions  of  the  cord  in  animals  and  attempting  to 
correlate  the  resulting  degeneration  with  such  disturbances  in  sensation 
as  can  be  made  out,  and  by  studying  the  disturbances  in  sensation  which 
result  from  injuries  or  disease  of  the  cord  in  man.     The  latter  method 
especially  has  been  profitable  because  by  it  alone  can  accurate  informa- 
tion concerning  sensation  be  acquired  (Head  and  Thompson,15  Holmes16). 
Unfortunately,  however,  an  exact  knowledge  of  the  site  of  the  lesion  can- 
not usually  be  had  in  these  cases,  so  that  at  present  the  course  of  the 
afferent  impulses  concerned  with  the  various  qualities  of  sensation  from 
different  parts  cannot  be  stated  with  the  precision  which  will  ultimately 
be  attained.    On  entering  the  spinal  cord  the  course  of  the  dorsal  root  fibers 
branch.     A  few  fibers  pass  posteriorly  in  the  fasciculus  inter fascicularis 
of  the  dorsal  column.     The  majority,  however,  extend  upward  in  the 
ascending  tracts  of  the  dorsal  funiculiis.    As  these  proceed  upward  their 
number  becomes  less  and  less,  because  most  of  the  fibers  pass  into  the 
gray  matter  and  terminate  within  a  few  segments  of  their  point   of 
entrance  into  the  cord.    As  fibers  enter  the  ascending  tracts  of  the  dorsal 
funiculus  from  higher  spinal  nerves,  they  lie  lateral  to  those  which  have 
entered  lower  down,  so  that  the  funiculus  takes  on  a  laminated  structure. 
Upon  entering  the  gray  matter  of  the  cord  the  afferent  fibers  undergo 
synapse  with  association  fibers  which  function   as   secondary  afferent 
neurons  conducting  the  impulses  either  to  the  motor  neurons  within  the 
cord  which  are  involved  in  spinal  reflex  acts,  or  leading  to  higher  cen- 
ters in  the  brain,  some  of  which  give  rise  to  sensation.     The  fibers  of 
the  secondary  afferent  neurons  which  are  concerned  with  sensory  im- 
pulses cross  to  the  opposite  side  of  the  spinal  cord  and  pass  upward  to 
the  brain  in  the  ascending  tracts  (dorsal  and  ventral  spinothalmic)  of  the 
spinal  lemniscus.     Studies  of  the  sensory  disturbances  due  to  lesions  of 
the  spinal  cord  in  man  indicate  that  on  entering  the  cord  the  impulses 
which  give  rise  to  the  various  qualities  of  sensation  undergo  a  charac- 
teristic grouping.    All  fibers  conducting  impulses  which  give  rise  to  pain 
whether  from  the  cutaneous  or  deep  distribution  of  the  sensory  nerves 


THE   AFFERENT   PATHS    OF   SENSORY    IMPULSES 


869 


SENSE  or 

POSITION 

HOVEMENT 


[TOUCH 


PAIN 

HEAT 

COLD 


lrig.  215. — Diagram  of  the  afferent  paths   followed  by   sensory   impulses  within   the   spinal   cord  and 

brain. 


870  CENTRAL  NERVOUS  SYSTEM 

become  grouped  together  in  a  single  tract  which  is  composed  of  second- 
ary afferent  fibers  situated  on  the  side  of  the  cord  opposite  to  that  by 
which  they  have  entered.  The  impulses  giving  rise  to  the  sensation  of 
heat,  and  those  giving  rise  to  the  sensation  of  cold  are  also  each  col- 
lected into  separate  tracts  ascending  through  secondary  afferent  neurons 
on  the  opposite  side  of  the  cord. 

All  impulses  concerned  with  the  tactile  aspect  of  sensation,  including 
the  sensations  involved  in  the  recognition  of  position  and  passive  move- 
ment are  grouped  together  in  the  cord  irrespective  of  their  origin  from 
cutaneous  or  deep  lying  receptors.  These  impulses,  however,  pass  up  the 
cord  in  two  distinct  groups.  Almost  all  impulses  concerned  with  the  recog- 
nition of  touch  and  pressure  and  the  recognition  of  the  location  to  which 
these  stimuli  are  applied  eventually  pass  on  to  secondary  afferent  neurons 
and  cross  to  form  a  definite  tract  ascending  the  opposite  side.  But  whereas 
the  impulses  from  painful  stimuli,  heat  and  cold  cross  within  five  or  six 
segments  from  their  point  of  entrance  into  the  cord,  some  of  the  tactile 
impulses  may  not  have  crossed  until  the  upper  cervical  region  is  reached. 

Impulses  upon  which  depend  the  recognition  of  two  dimensional  local- 
ization, the  sense  of  position,  and  passive  movement  pass  up  the  cord  on 
the  side  on  which  they  have  entered  it,  in  the  fibers  of  the  primary  affer- 
ent neuron  which  lie  in  the  dorsal  f uniculas  and  terminate  in  the  nucleus 
gracilis  and  cuneatus  of  the  medulla. 

As  a  result  of  this  arrangement  of  the  afferent  fibers  in  the  cord,  cer- 
tain characteristics  are  imposed  upon  the  sensory  disturbances  which 
result  from  spinal  cord  lesions.  A  lesion  which  destroys  the  greater  part 
of  one  half  of  the  cord  will  obliterate  the  sensation  of  heat,  cold,  and 
pain  on  the  opposite  side  of  the  body  in  those  parts  whose  nerves  arise 
below  the  level  of  the  lesion.  The  ability  to  recognize  touch  and  pres- 
sure may  be  unimpaired  by  such  a  lesion,  because  the  impulses  on  which 
this  depends  cross  over  gradually  as  they  ascend  the  cord,  and  conse- 
quently there  exists  at  any  one  level  two  paths  over  which  such  impulses 
can  travel.  If  the  lesion  is  located  high  in  the  cervical  region,  a  point 
at  which  the  crossing  over  of  these  tactile  impulses  is  complete,  this  qual- 
ity of  sensation  will  also  be  lost  from  the  opposite  side  of  the  body.  Dis- 
turbances in  the  recognition  of  the  position  of  the  limbs  and  of  passive 
movement  and  the  distinctness  of  two  points  applied  to  the  skin  at  once 
(two  dimensional  localization)  occur,  in  the  case  of  a  considerable  uni- 
lateral lesion,  on  the  the  same  half  of  the  body  as  the  lesion,  because  the 
ascending  tracts  for  the  impulses  involved  in  these  sensations  are 
uncrossed.  On  the  contralateral  half  of  the  body  dissociation  occurs 
between  heat,  cold  and  pain,  which  are  obliterated,  and  the  tactile  sen- 
sations which  persist  in  part.  On  the  homolateral  half  of  the  body  the  disso- 
ciation is  between  the  sensations  of  two  and  three  dimensional  localization, 


THE    AFFERENT    PATHS    OF   SENSORY    IMPULSES  871 

which  are  obliterated,  touch  which  is  greatly  impaired,  and  heat,  cold  and 
pain  which  remain  normal. 

Lesions  of  more  limited  distribution  may  produce  dissociations  of  a 
more  simple  character.  Because  the  fibers  conducting  the  impulses  for 
pain,  heat,  and  cold  are  grouped  together  into  separate  tracts  for  each 
quality  of  sensation  a  limited  lesion  may  destroy  one  of  these  qualities 
without  affecting  the  others.  The  close  association  of  the  three  groups, 
however,  makes  it  probable  that  a  lesion  affecting  one  will  affect  them 
all,  so  that  in  the  majority  of  cases  heat,  cold  and  pain  will  all  be  affected 
together.  When  dissociation  occurs  as  the  result  of  spinal  lesions,  cu- 
taneous and  deep  sensibility  of  any  given  quality  suffers  alike,  and  as  a 
result  these  dissociations  have  a  distinctly  different  character  from  those 
due  to  peripheral  nerve  lesions. 

The  loss  of  sensation  which  results  from  interruption  of  the  afferent 
tracts  in  the  cord  affects  parts  which  may  be  remote  from  the  lesion. 
But  if  the  destruction  involves  only  the  gray  matter  of  the  cord,  it  will 
not  disturb  those  impulses  which  pass  through  either  the  crossed  or 
uncrossed  tracts  of  the  cord  at  the  level  of  the  lesion,  but  only  those 
whose  paths  entered  the  gray  matter  and  cross  the  cord.  As  a  result  the 
sensation  of  heat,  cold,  and  pain  may  be  absent  from  a  segmental  area  on 
the  side  of  the  body  corresponding  to  the  lesion,  or  if  the  destruction  is 
more  extensive,  these  sensations  may  be  absent  from  a  segmental  band 
completely  encircling  both  sides  of  the  body,  without  any  disturbance 
affecting  the  sensation  of  the  lower  segments,  impulses  from  which  have 
crossed  the  cord  at  a  lower  level  and  pass  the  lesion  in  the  tracts  of  the 
lateral  column.  Segmental  disturbances  of  this  type  are  distinguished 
as  the  local  effects  of  an  intramedullary  lesion.  If  the  lesion  is  exten- 
sive so  that  both  white  and  gray  matter  is  destroyed  on  one  side  of  the 
cord,  a  combination  of  the  local  and  remote  effects  occur,  with  the  re- 
sult that  pain  and  the  temperature  senses  are  lost  over  the  entire  half  of 
the  body  opposite  to  and  below  the  lesion  and  also  over  a  local  segment 
at  the  level  of,  and  on  the  same  side  as,  the  lesion. 

Afferent  Paths  in  the  Brain  Stem 

On  reaching  the  medulla  all  impulses  producing  sensations  of  pain, 
heat,  cold,  and  touch  (including  one  dimensional  localization)  have 
crossed  the  cord.  They  continue  without  interruption  through  the  brain 
stem  in  the  tractus  spinothalamicus  lateralis  to  terminate  in  the  nuclei 
of  the  thalamus.  In  their  course  they  are  joined  by  impulses  from 

ie  cranial  nerves,  which  have  also  crossed  to  the  side  of  the  brain  stem 
opposite  to  that  from  which  they  have  entered.  Impulses  which  give  rise 
to  the  recognition  of  posture,  passive  movement,  and  two  dimensional 
localization  reach  the  medulla  on  the  side  from  which  they  have  origi- 


872 


CENTRAL  NERVOUS  SYSTEM 


nated.  They  have  been  conducted  along  fibers  of  primary  afferent  neurons 
which  terminate  in  the  nucleus  gracilis  and  nucleus  cuneatus,  from  which 
arise  the  secondary  afferent  neurons  which  carry  them  to  the  thal- 
amus.  These  fibers  cross  the  medulla  immediately  and  take  up  a  position 
in  the  medial  lemniscus  close  to  those  which  are  conducting  impulses  for 
the  sensations  of  pain,  temperature,  and  touch.  In  their  passage  through 
the  brain  stem  impulses  for  all  qualities  of  sensation  follow  tracts  which 
are  grouped  together  closely  in  the  opposite  side  from  that  in  which  they 
have  originated.  Lesions  in  the  brain  stem  consequently  tend  to  produce 
a  complete,  contralateral  anesthesia.  Impulses  for  any  one  quality  of 
sensation  are  still  grouped  together  in  tracts  which  are  distinct  from 
those  carrying  impulses  for  other  qualities  of  sensation.  Consequently 
lesions  of  limited  extent  may  abolish  sensation  of  any  one  quality  with- 
out disturbing  the  other  qualities  of  sensation.  Observations  on  cases 
of  lesions  of  this  sort  indicate  that  impulses  involved  in  the  recognition 
of  posture  and  movement,  which  have  been  associated  with  those  for  the 
two  dimensional  localization  in  their  passage  up  the  spinal  cord,  become 
separated  in  the  brain  stem,  so  that  the  power  of  recognizing  posture  and 
passive  movement  can  be  effected  independently  of  the  discrimination 
of  two  points  applied  simultaneously  to  the  skin. 

Afferent  Impulses  Which  Fail  to  Produce  Sensation 

Those  impulses  which  are  destined  to  give  rise  to  sensation  will  be 
traced  in  their  course  beyond  the  termination  of  the  secondary  afferent 
neurons  in  the  nuclei  of  the  thalamus,  but  we  shall  first  consider 
the  courses  followed  by  those  afferent  impulses  which  do  not  reach  the 
level  of  consciousness.  These  are  of  three  types:  (1)  the  afferent  im- 
pulses of  spinal  reflexes,  (2)  the  afferent  impulses  of  visceral  reflexes, 
(3)  the  afferent  impulses  of  cerebellar  reflexes. 

The  Afferent  Paths  of  Spinal  Reflexes. — The  connections  within  the 
cord  for  spinal  reflexes  are  undoubtedly  very  primitive.  They  do  not, 
however,  appear  to  have  been  worked  out  in  many  cases  or  in  great  de- 
tail. The  simplest  reflexes  probably  involve  neurons  lying  in  a  single 
segment  and  on  one  side  of  the  cord.  The  flexion  reflexes  which  result 
from  noxious  stimuli  applied  to  the  limbs  are  of  this  type.  In  other  cases 
the  reflex  pathway  may  extend  through  many  segments,  but  lie  totally 
within  one  half  of  the  cord.  An  example  is  seen  in  the  scratch  reflex  of 
the  brainless  dog.  The  method  by  which  its  course  was  worked  out  by 
Sherrington  was  described  on  page  849.  It  was  found  to  consist  of  an 
afferent  neuron  connecting  the  skin  of  the  shoulder  with  the  grey  matter 
of  the  cord  in  the  upper  thoracic  region,  a  propriospinal  neuron  having 
its  cell  body  in  this  part  of  the  cord  and  its  axon  descending  in  the  lateral 
column  of  the  same  side  to  connect  with  the  motor  neurons  of  the  limb 


THE    AFFERENT    PATHS    OF   SENSORY   IMPULSES  873 

muscles  which  are  involved  in  the  scratching  movements.  Other  reflexes 
are  executed  through  paths  which  cross  the  cord.  In  addition  to  pro- 
ducing a  flexion  of  the  foot  to  which  it  is  applied,  a  strong  noxious  stim- 
ulus causes  an  extension  of  the  opposite  limb.  This  is  known  as  the 
crossed-extension  reflex.  Crossed  reflexes  also  involve  paths  which  trav- 
erse considerable  lengths  of  the  cord.  Thus  a  flexion  of  the  hind  limb, 
produced  by  a  noxious  stimulus  applied  directly  to  it,  is  frequently  ac- 
companied by  a  flexion  of  the  fore  limb  on  the  opposite  side  of  the  body. 

The  Afferent  Paths  of  Visceral  Reflexes, — The  visceral  reflexes  are  con- 
cerned chiefly  with  the  regulation  of  the  circulation,  respiration,  and  the 
motor  activities  of  the  internal  organs.  Such  reflexes  are  set  up  by  af- 
ferent neurons  extending  to  the  visceral  organs  themselves  as  well  as 
to  the  skin  and  muscles. 

Visceral  afferent  fibers  are  found  in  the  ninth  and  tenth  cranial  nerves 
and  in  the  spinal  nerves.  Their  cell  bodies  lie  in  the  ganglia  of  the 
medulla  and  in  the  dorsal  root  ganglia  of  the  spinal  nerves.  The  fibers 
reach  the  viscera  by  following  the  course  of  the  pre-  and  postganglionic 
fibers  of  the  autonomic  nervous  system,  passing  through  the  ganglia  and 
plexes  without  interruption.  In  spite  of  this  close  anatomical  associa- 
tion with  the  autonomic  nervous  system,  the  visceral  afferents  are  analo- 
gous in  function  and  homologous  in  origin  and  structure  with  the  affer- 
ent neurons  from  the  skin  and  muscles.  It  is  logical  to  classify  the  vis- 
ceral afferents  with  the  latter,  rather  than  with  the  autonomic  system 
which  is  wholly  motor  in  function.  While  certain  impulses  from  the 
visceral  afferents  reach  the  sensory  centers  of  the  brain  and  give  rise  to 
visceral  pain  and  the  other  sensory  symptoms  of  visceral  disease,  the 
greater  number  never  affect  consciousness.  They  take  part  rather  in  the 
execution  of  visceral  reflexes,  which  modify  the  activity  of  the  muscles 
of  the  internal  organs  and  regulate  the  blood  flow  through  them  in  ac- 
cordance with  the  varying  demands  of  their  functional  activity.  The 
most  important  visceral  afferents  are  those  which  modify  the  action  of 
the  cardiovascular  and  respiratory  centers  of  the  medulla.  The  depres- 
sor nerve  and  the  afferent  fibers  of  the  vagus  which  extend  to  the  lung 
are  examples  with  which  we  are  already  familiar  (pages  243  and  227). 
The  centers  regulating  blood  pressure  and  respiration  are  also  influenced 
by  impulses  which  have  their  normal  origin  in  the  receptors  of  the  skin 
and  which  may  be  initiated  by  stimulating  the  nerve  trunks  in  the  limbs. 
Ranson  and  von  Hess  have  studied  the  location  of  the  afferent  pathways 
in  the  cord  over  which  such  impulses  travel. 

Two  kinds  of  vascular  reflexes  were  studied,  pressor  and  depressor, 
the  former  being  elicited  by  strong  and  the  latter  by  very  feeble  stimu- 
lation of  the  central  end  of  the  sciatic  and  brachial  nerves.  They  found 
that  the  pathways  for  the  pressor  and  depressor  afferent  impulses  were 


874  CENTRAL  NERVOUS  SYSTEM 

quite  different.  Thus,  after  lateral  hemisection  of  the  cord,  the  depres- 
sor reflex  obtained  by  weak  stimulation  of  the  sciatic  on  the  same  side 
as  the  lesion  was  normal,  whereas  it  was  greatly  reduced  when  the  sciatic 
nerve  on  the  opposite  side  from  the  lesion  was  stimulated.  On  the  other 
hand,  the  pressor  reactions  that  were  most  conspicuously  diminished  were 
those  from  the  sciatic  on  the  same  side  as  the  lesion.  The  depressor  fibers 
evidently  cross  in  the  cord,  whereas  the  pressor  do  so  only  to  a  limited 
degree.  Further  it  was  found,  after  cutting  across  the  dorsal  part  of 
the  cord,  that  the  pressor  reflexes  were  interfered  with  but  not  the  de- 
pressor, thus  indicating  that  the  former  are  transmitted  either  by  the 
dorsal  columns  of  white  matter  or  by  the  gray  matter  of  the  posterior 
horns.  To  determine  which,  experiments  were  also  performed  in  which 
the  dorsal  columns  were  alone  destroyed  and  the  results  compared 
with  others  in  which  the  tip  of  the  dorsal  horn  was  included.  Since 
it  was  only  in  the  latter  experiment  that  any  interference  with  pressor  re- 
flexes was  found  to  occur,  it  was  concluded  that  the  dorsal  horn  alone 
was  concerned  in  the  transmission  of  pressor  impulses. 

Regarding  conduction  of  the  afferent  impulses  which  in  consciousness 
produce  pain  and  of  those  concerned  in  the  reflex  changes  in  respiration, 
it  was  found  that  the  dorsal  horn  of  gray  matter  is  not  concerned, 
from  which  it  is  inferred  that  such  impulses  are  conducted  by  the  same 
afferent  path  that  is  involved  in  the  depressor  reflex;  that  is  to  say,  as 
we  have  indicated  above,  the  impulses  cross  in  the  cord  to  the  opposite 
side  and  ascend  in  the  lateral  funiculus. 

The  Afferent  Paths  of  Cerebellar  Reflexes. — The  cerebellum  is  con- 
cerned with  the  coordination  of  muscular  movement,  and  must  be  in  con- 
tinuous receipt  of  information  concerning  the  changes  in  the  position  of 
the  limbs  which  result  from  voluntary  and  reflex  movement.  The  pri- 
mary afferent  neurons  of  cerebellar  reflexes  are  doubtless  those  which 
extend  to  the  muscles,  joints,  and  tendons  along  with  the  afferents  of 
deep  sensibility.  Inasmuch  as  cerebellar  injuries  produce  no  loss  of 
sensation,  impulses  extending  into  the  cerebellum  probably  produce  their 
effects  without  entering  into  consciousness.  Consequently  we  can  learn 
about  the  afferent  paths  of  cerebellar  reflexes  only  by  inference  from 
the  anatomical  arrangements  and  by  observing  the  disturbances  in  co- 
ordinated movement  which  result  from  various  lesions  in  the  nervous 
system. 

The  chief  tracts  in  the  cord  which  degenerate  in  an  anterior  direction 
and  extend  into  the  cerebrum  are  the  tractus  spino  cerebellar  is  dor  sails 
and  the  tractus  spinocerebellaris  ventralis.  The  fibers  of  both  these 
tracts  lie  in  the  lateral  column  of  the  cord,  and  many  of  their  fibers  ex- 
tend directly  into  the  cerebellum,  the  former  by  way  of  the  inferior 


THE    AFFERENT   PATHS    OF   SENSORY    IMPULSES 


875 


peduncle,  the  latter  by  way  of  the  superior  peduncle.  Experiment  shows 
that  after  cutting  the  tractus  spinocerebellaris  dorsalis  a  slight  degree 
of  ataxia  and  loss  of  tone  in  the  muscles  innervated  from  below  the  lesion 
may  result,  thus  confirming  the  inference  from  the  anatomical  arrange- 
ment that  this  tract  is  one  of  the  afferent  paths  of  cerebellar  reflexes. 


CHAPTER  XCIV 

THE  SENSORY  CENTERS  OF  THE  BRAIN 

Sensory  experience  and  the  recognition  of  the  quality  and  location  of 
stimuli  acting  upon  the  receptors  of  the  body  depends  upon  the  arrival 
of  impulses  at  certain  stations  in  the  brain  which  correspond  to  the  re- 
ceptors in  question.  Knowledge  concerning  the  location  of  the  centers 
involved  in  the  perception  of  sensations  arising  from  each  kind  of  recep- 
tor and  from  each  part  of  the  body  has  been  gained  by  inference  from 
the  anatomical  arrangements  of  the  fibers  connecting  the  sense  organs 
with  the  various  parts  of  the  brain  and  from  studies  of  the  reactions  of 
animals  which  have  had  certain  parts  of  the  brain  removed.  But  this 
information  is  of  slight  value,  since  we  can  learn  about  a  sensation  di- 
rectly only  through  the  verbal  report  of  the  person  who  is  experiencing 
it.  Consequently  the  important  contributions  to  the  sensory  physiology 
of  the  brain  have  come  from  the  clinical  study  of  individuals  who  have 
suffered  injury  in  some  part  of  the  cerebrum.  Gushing12  induced  two 
patients  in  whom  part  of  the  brain  was  exposed  to  allow  him  to  stimulate 
it  while  they  were  in  a  conscious  state.  As  the  result  of  the  stimulation 
of  the  postcentral  convolution  definite  sensory  impressions  were  experi- 
enced, consisting  of  a .  sensation  of  numbness,  deadness,  or  tactual  im- 
pressions. No  muscular  groups  underwent  movement  unless  the  precen- 
tral  convolution  was  stimulated,  when  no  sensations  wrere  experienced 
by  the  patient  except  those  which  accompanied  the  change  in  the  posi- 
tion of  the  part  that  was  moved.  The  sensations  which  were  thus  shown 
to  be  represented  on  the  cortex  are  those  of  touch  discrimination  and 
those  relating  to  the  position  and  movements  of  the  muscles.  A  com- 
prehensive analysis  of  sensory  localization  has  been  made  by  Head9  from 
observations  on  soldiers  suffering  from  the  wounds  of  war. 

The  Sensory  Center  of  the  Optic  Thalamus 

It  has  long  been  recognized  that  the  cerebral  cortex  is  the  site  of  cen- 
ters concerned  in  the  perception  of  many  qualities  of  sensation.  Ex- 
periments by  Goltz  on  a  dog  from  which  the  cortex  had  been  removed, 
suggested  that  certain  subcortical  centers  might  also  give  rise  to  sensa- 
tion, since  this  animal  responded  to  various  sensory  stimuli,  and  when 
hungry  gave  evidence,  so  far  as  his  actions  were  concerned,  of  experienc- 
ing sensations  of  hunger.  Head's  clinical  observations  have  led  him  to 

876 


TlIK    SKNSOKY    CKNTKKS    OF    THE    BRATN  877 

assign  a  very  important  part  in  the  origin  of  certain  aspects  of  sensation 
to  a  center  which  he  terms  the  essential  organ  of  the  thalamus. 

According  to  this  view,  afferent  impulses  may  affect  consciousness  in 
two  distinct  ways  on  arriving  in  the  thalamus.  They  may  act  upon 
this  sensory  center  of  the  thalamus,  or  they  may  pass  on  to  the  sensory 
areas  of  the  cerebral  cortex.  The  presence  of  a  sensory  center  in  the 
thalamus,  and  the  nature  of  the  sensations  aroused  as  the  result  of  its 
activity,  are  indicated  by  the  sensations  which  are  experienced  by  in- 
dividuals in  whom  the  sensory  areas  of  the  cortex  have  been  destroyed. 

In  their  path  through  the  cord  and  brain  stem  afferent  impulses  have 
been  grouped  on  a  strictly  physiological  basis,  all  impulses  arising  from 
a  common  type  of  receptor  traveling  together.  On  reaching  the 
thalamus,  a  regrouping  occurs  on  a  psychological  basis,  the  subsequent 
course  of  the  impulse  depending  on  the  kind  of  appeal  which  it  is  to 
make  to  consciousness.  The  thalamic  organ  is  the  center  for  "aware- 
ness," responding  to  all  stimuli  capable  of  producing  sensations  of  a 
change  of  state.  The  cerebral  centers,  on  the  other  hand,  are  recipients 
of  impulses  which  give  rise  to  the  discrimination  of  the  detailed  qualities 
of  a  sensation. 

A  patient  suffering  from  the  destruction  of  the  cerebral  sensory  area 
will  exclaim,  "Something  is  happening  to  me,  I  am  being  hurt,"  instead 
of  "You  are  sticking  a  pin  into  me,"  because  he  fails  to  recognize  the 
distinctive  characters  of  the  stimulus  in  question.  The  cerebral  cen- 
ters, on  the  other  hand,  are  concerned  with  the  recognition  of  fine  detail 
in  sensation,  enabling  us  to  perceive  not  only  the  presence  of  a  stimulus 
and  its  gross  quality,  but  also  to  discriminate  between  stimuli  of  differ- 
ent intensities,  to  recognize  the  shape,  size,  weight,  and  texture  of  the 
stimulating  object  and  to  recognize  the  position  of  the  hand  as  it  explores 
its  surface.  Thus,  to  compare  the  sensations  evoked  by  stimuli  of  each 
of  the  primary  qualities  in  individuals  who  have  lost  the  function  of  the 
cerebral  centers  with  those  of  normal  individuals,  it  is  found  that  contact  is 
recognized,  but  the  distinction  of  differences  in  the  intensity  of  the  stimulus 
cannot  be  made  by  the  unaided  thalamus.  The  special  aspects  of  tactile 
sensation,  including  the  impulses  involved  in  one,  two,  and  three  dimen- 
sional localization  make  no  thalamic  appeal,  so  that  neither  the  location 
of  the  point  stimulated,  nor  the  position  of  the  parts  of  the  body  are 
recognized.  Painful  stimuli* affect  the  thalamic  center  powerfully,  giving 
rise  to  sensations  of  discomfort,  deprived  of  the  distinctive  qualities 
which  we  recognize  in  painful  sensations  when  the  cortex  is  intact.  The 
recognition  of  gradations  of  pain  cannot  be  accomplished  by  the  thala- 
mus alone.  The  thalamus  can  distinguish  between  heat  and  cold,  as 
such,  but  makes  no  distinction  between  various  degrees  of  warmth  or 
coolness.  Thus  if  a  glass  of  hot  water  is  placed  in  the  hand  of  an  in- 


878  CENTRAL  NERVOUS  SYSTEM 

dividual  whose  cortical  area  corresponding  to  the  hand  is  damaged,  he 
will  recognize  the  contact  of  the  object,  and  will  know  that  it  is  unpleas- 
antly hot.  He  will  be  unable,  however,  to  perceive  the  roundness,  size, 
or  weight  of  the  vessel,  to  know  how  hot  it  is,  or  to  recognize  the  posi- 
tion of  the  hand  which  grasps  it. 

The  Sensory  Centers  of  the  Cerebral  Cortex 

The  Area  of  Cutaneous  and  Deep  Sensibility.— Impulses  giving  rise  to 
cutaneous  and  deep  sensibility  which  pass  from  the  termination  of  the 
secondary  afferent  neurons  in  the  thalamus  to  the  cerebral  cortex 
divide  themselves  into  seven  afferent  streams,  which  may  be  affected  by 
cortical  lesions  more  or  less  independently.  These  comprise  impulses 
concerned  with  the  appreciation  of  (1)  touch,  (2)  one  dimensional  local- 
ization, (3)  two  dimensional  localization,  (4)  three  dimensional  local- 
ization, (5)  pain,  (6)  heat,  (7)  cold.  They  pass  to  areas  in  the  cortex 
which  are  more  or  less  distinct  for  sensations  arising  from  different  parts 
of  the  body,  and  for  sensations  of  different  psychical  quality.  The  sen- 
sory area  for  these  sensations  consists  of  the  pre  and  post  central  convo- 
lutions, the  anterior  part  of  the  superior  parietal  lobule  and  the  angular 
gyri.  Afferent  impulses  arising  from  one  half  of  the  body  cross  the 
cord  or  medulla  in  their  ascent  and  affect  this  part  of  the  cortex  of  the 
opposite  side  of  the  brain,  so  that  the  sensory  disturbance  which  arises 
from  a  unilateral  injury  of  the  cortex  expresses  itself  by  a  loss  in  sensory 
discrimination  in  contralateral  parts  of  the  body.  Each  of  these  parts 
is  represented  in  a  definite  part  of  this  sensory  cortex.  The  lower  ex- 
tremity is  represented  in  the  upper  part  of  this  area,  the  upper  extrem- 
ity in  the  middle  portion  and  the  head  in  the  lower  portion.  The  extent 
of  the  cortical  area  corresponding  to  the  different  parts  of  the  body  is 
proportional  to  the  functional  complexity  of  their  acts  and  sensations. 
Consequently  the  hands  are  represented  by  a  very  large  region;  the  feet 
and  face  by  extensive  areas  compared  with  which  the  representation  of 
the  proximal  parts  of  the  limbs  and  trunk  is  insignificant.  The  chances 
are  consequently  greatly  in  favor  of  an  injury  to  the  sensory  cortex  af- 
fecting one  of  these  parts  of  the  body,  and  it  is  very,  rare  that  a  prox- 
imal part  of  a  limb  is  affected  without  the  distal  part  sharing  in  the  dis- 
turbance. In  the  sensory  area  for  the  hand,  distinct  regions  exist  for 
each  finger  and  the  corresponding  proximal  part  of  the  hand.  The  area 
for  the  little  finger  adjoins  the  area  for  the  lower  extremity,  with  the 
result  that  loss  of  sensation  involving  the  little  finger  also  usually  is 
accompanied  by  a  disturbance  of  sensation  in  the  foot.  The  ring,  mid- 
dle, index  fingers  and  thumb  are  represented  one  below  the  other  in  the 
sensory  cortex,  the  thumb  area  adjoining  that  for  the  face,  so  that  sen- 
sory disturbances  in  the  thumb  and  face  are  apt  to  occur  together. 


THE    SENSORY    CENTERS    OF    THE   BRAIN  879 

When  sensory  loss  is  occasioned  on  any  part  of  the  body  as  the  result 
of  a  limited  injury  to  the  cortex,  all  aspects  of  sensation  are  not  affected 
equally,  with  the  result  that  the  ability  to  respond  with  accuracy  is  lost 
more  completely  and  over  a  larger  area  in  the  case  of  certain  tests  than 
in  others.  Such  dissociations  in  the  sensations  which  depend  on  cor- 
tical activity  conform  to  two  general  principles.  First:  The  more  com- 
plex and  difficult  the  psychical  act  required  for  an  accurate  answer  to 
the  test,  and  the  more  completely  the  test  appeals  to  the  cortical  center 
in  contrast  to  the  thalamic  center,  the  greater  is  the  area  of  disturbed 
sensibility,  and  the  more  complete  is  the  sensory  loss  in  any  one  part  of 
this  area.  Thus  the  extent  and  degree  of  disturbance  is  greater  in  the 
case  of  recognition  of  posture  and  movement  than  in  the  case  of  two 
dimensional  localization,  and  is  least  for  one  dimensional  localization, 
which  obviously  involves  a  simpler  psychical  judgment.  Sensibility  to 
touch  is  modified  more  than  to  temperature,  and  temperature  more  than 
to  pain,  because  these  sensations  depend  in  this  order  on  the  cortex  as 
contrasted  to  the  optic  thalamus. 

Second:  The  various  aspects  of  cortical  activity  depend  upon  the  in- 
tegrity of  different  parts  of  the  sensory  area.  These  aspects  are  (1)  spa- 
cial  recognition,  typified  by  the  sense  of  posture  and  movement,  which 
is  dependent  chiefly  on  the  part  of  the  sensory  cortex  which  occupies  the 
precentral  convolution;  (2)  the  recognition  of  similarity  and  difference, 
on  which  depends  the  comparison  of  weights  held  in  the  hand,  etc.,  which 
resides  in  the  postcentral  convolution;  and  (3)  the  recognition  of  the 
intensity  of  the  sensation,  whether  it  be  of  touch,  temperature  or  pain, 
which  is  centered  in  the  foot  of  the  postcentral  convolution,  and  in  those 
parts  of  the  sensory  area  lying  behind  this  convolution.  It  appears  that 
the  sensory  area  of  the  cortex  may  be  divided  into  certain  horizontal 
zones  which  are  each  involved  in  sensation  arising  from  stimuli  acting 
on  various  parts  of  the  body  and  into  three  nearly  vertical  zones  involved 
each  in  the  three  fundamental  aspects  of  discrimination.  The  cortical 
localization  is  based  therefore,  not  on  purely  anatomical  relationships 
by  which  each  part  of  the  body  would  be  represented  in  all  its  sensory 
manifestations  by  a  single  part  of  the  cortex,  but  on  functional  require- 
ments, according  to  which  each  psychical  act  of  sensory  discrimination 
is  centered  in  a  different  group  of  cortical  cells.  Since  these  processes 
are  distinct  for  the  different  parts  of  the  body,  these  parts  have  a  sepa- 
rate representation  in  the  cortex,  but  the  magnitude  of  the  area  devoted 
to  each  part  of  the  body  is  dependent  solely  on  the  degree  in  which  sen- 
sation arises  from  it. 

The  Olfactory,  Gustatory,  and  Auditory  Areas. — The  cerebral  cortex 
contains  in  addition  to  these  centers  for  cutaneous  and  deep  sensibility 
certain  areas  on  which  depend  the  perception  of  olfactory,  gustatory, 


880 


CENTRAL  NERVOUS  SYSTKM 


auditory,  and  visual  sensations.  Very  little  of  importance  can  be  said 
of  the  physiology  of  the  olfactory  and  gustatory  centers,  which  are 
thought  to  lie  in  the  hippocampal  convolution  of  the  median  aspect  of 
the  temporal  lobe,  the  former  occupying  the  more  distal  position.  The 
auditory  center  lies  in  the  lateral  side  of  the  temporal  lobe.  Complete 
destruction  of  both  temporal  lobes  causes  deafness,  but  if  one  lobe  only 
is  destroyed,  hearing  is  not  impaired  in  either  ear.  It  appears  from  this 
that  the  afferent  paths  from  each  ear  lead  to  both  temporal  lobes,  so  that 
if  the  auditory  center  in  one  lobe  only  is  injured,  the  center  in  the  other 
lobe  can  carry  on  auditory  perception  for  both  ears.  Consequently  it  is 
very  unlikely  that  deafness  will  result  from  a  cerebral  injury. 

The  Visual  Areas. — The  visual  centers  are  known  with  much  greater 
precision.  In  order  to  explain  the  disturbances  in  vision  which  result 
from  lesions  in  the  visual  centers,  a  word  must  be  said  about  the 
formation  of  images  upon  the  retina  and  the  course  of  the  afferent  fibers 
which  pass  from  the  retina  to  these  centers.  The  optical  mechanism  of 
the  eye  is  such  that  the  image  of  any  object  at  which  one  looks  is  in- 
verted when  it  falls  upon  the  retina.  Consequently  the  upper  part  of 
the  visual  field  falls  on  the  lower  part  of  the  retina,  the  left  half  of 
the  visual  field  falls  on  the  right  half  of  the  retina,  etc.  The  optic  nerves 
from  the  two  eyes  meet  at  the  optic  chiasm,  and  there  about  half  the 
fibers  in  each  nerve  cross  to  the  opposite  side  of  the  brain  and  follow 
a  course  which  leads  to  the  visual  center,  which  is  contralateral  to  the 
eye  in  which  they  arose.  The  other  half  of  the  fibers  in  each  nerve  do 
not  cross  in  the  chiasm,  but  continue  through  the  brain  by  a  path  which 
leads  to  the  visual  center  on  the  same  side  of  the  body  as  the  eye  in  which 
they  arose.  The  remarkable  thing  about  this  arrangement  is  that  the 
fibers  which  cross  in  the  chiasm  are  those  which  arise  from  the  median 
half  of  both  retinae.  As  a  result,  the  left  visual  center  receives  all  im- 
pulses which  arise  from  the  left  halves  of  the  retinae  of  both  eyes,  and 
since  these  impulses  are  set  up  by  objects  whose  images  are  inverted 
upon  the  retinae,  this  visual  center  is  affected  by  the  right  half  of  the 
visual  field.  Conversely  the  right  visual  center  is  affected  by  the  left 
half  of  the  visual  field.  A  consideration  of  Fig.  216  will  make  this  rather 
complicated  situation  more  clear.  This  arrangement  is  associated  with 
binocular  vision,  that  is,  the  simultaneous  use  of  both  eyes  in  viewing 
a  single  object.  In  the  lower  vertebrates,  in  which  the  eyes  are  on  op- 
posite sides  of  the  head  and  consequently  have  different  visual  fields 
the  crossing  in  the  chiasm  is  complete.  The  arrangement  in  man  is  of 
obvious  importance  in  causing  the  images  formed  by  the  two  eyes  to 
effect  simultaneously  the  same  sensory  centers  in  the  brain. 

Because  of  this  arrangement  certain  characteristics  appear  in  injuries  to 
the  various  parts  of  the  optic  tracts.    A  lesion  located  distal  to  the  chiasm 


THE   SENSORY    CENTERS   OF   THE   BRAIN 

Visual    Field 


881 


Occipital       Lobes 

Fig.  216. — Afferent  paths  connecting  the  retina  with  the  visual  area  of  the  cerebral  cortex. 

will  cause  blindness  in  one  eye  alone.  Lesions,  such  as  those  produced 
by  the  pressure  of  a  pituitary  tumor  upon  the  chiasm,  may  destroy  the 
function  of  those  fibers  which  are  crossing  in  the  chiasm,  and  as  a  re- 
sult a  type  of  blindness  known  as  bitemporal  hemianopsia  results.  This 
is  a  loss  of  sight  in  the  temporal  half  of  both  visual  fields,  occasioned 
by  destruction  of  the  decussating  fibers,  which,  as  we  have  pointed 


882  CENTRAL  NERVOUS  SYSTEM 

out,  arise  in  the  nasal  half  of  each  retina.  Complete  destruction  of 
one  of  the  visual  tracts  between  the  chiasm  and  the  sensory  area  of  the 
cortex  produces  a  condition  called  homonymous  hemianopsia,  or  blindness 
in  the  same  half  of  the  visual  field  of  both  eyes.  Thus  destruction  of 
this  part  of  the  left  optic  tract  which  contains  fibers  from  the  left  half 
of  both  eyes  will  produce  blindness  for  the  right  half  of  their  visual  field. 
The  visual  area  of  the  cortex  is  located  about  the  calcarine  fissure  on 
the  median  and  posterior  surface  of  the  parietal  lobes.  Its  area  is 
sufficiently  great  to  make  it  probable  that  a  lesion  will  involve  only  cer- 
tain parts  of  it,  and  as  a  result  produce  blindness  in  only  part  of  the 
visual  field.  By  correlating  the  position  of  lesions  with  the  resulting 
loss  of  vision  it  has  been  possible  for  Holmes  and  Lister10  to  determine 
what  part  of  the  visual  area  corresponds  with  each  part  of  the  retina. 
They  found  that  the  center  of  each  retina,  or  macula,  is  represented  in 
the  posterior  part  of  the  visual  area.  The  superior  quadrant  of  each 
eye  is  represented  in  the  upper,  and  the  inferior  quadrant  in  the  lower 
half  of  the  visual  area  anterior  to  the  center  for  macular  vision.  It 
has  previously  been  held  that  the  center  of  each  retina  was  represented 
in  the  visual  area  of  both  sides  of  the  brain.  This  was  because  in  the 
lesions  of  civil  life  homonymous  hemianopsia  rarely  affected  the  center 
of  the  visual  field  in  the  blind  half  of  the  eyes.  Holmes  and  Lister 
found,  however,  in  cases  where  the  visual  area  of  one  occipital  lobe 
was  completely  destroyed  that  vision  was  lost  in  the  central  part  of  the 
corresponding  half  of  the  retina  quite  as  completely  as  in  the  more 
peripheral  portions:  They  conclude  consequently  that  the  macula,  like 
the  rest  of  the  retina,  is  not  represented  bilaterally  in  the  cortex.  The 
discrepancy  in  the  condition,  as  they  observed  it,  in  wounded  soldiers, 
and  as  it  occurs  in  civil  life,  depends  upon  the  fact  that  in  the  latter 
case  the  cause  of  the  lesion  is  usually  a  disturbance  of  the  circulation 
of  the  cortex  as  the  result  of  thrombosis,  hemorrhage,  etc.  The  macular 
part  of  the  visual  area  is  supplied  with  capillaries  from  two  sets  of  ar- 
teries, those  of  the  median  and  of  the  lateral  surface  of  the  occipital 
lobe.  An  occlusion  of  the  median  supply  would  destroy  the  visual  area 
for  the  peripheral  half  of  the  retina,  but  would  leave  intact  the  macular 
region  which  would  be  sufficiently  nourished  by  the  blood  from  the 
lateral  arteries. 

Eiddoch11  has  noted  that  in  case  of  injury  to  the  occipital  lobe,  disso- 
ciations in  visual  sensations  occur  which  are  quite  comparable  to  the  dis- 
sociations which  may  occur  in  lesions  of  the  sensory  cortex  for  cutaneous 
and  deep  sensibility.  These  manifest  themselves  in  the  case  of  patients 
who  are  recovering  from  a  functional  disturbance  of  the  visual  areas. 
The  first  visual  perception  to  appear  is  the  recognition  of  the  movement 
of  an  object  in  the  visual  field,  which  occurs  long  before  the  object  as 


THE    SENSORY    CENTERS    OF    THE   BRAIN  883 

such  can  be  recognized.  A  case  is  also  described  in  which  vision  persisted 
in  one  half  of  the  visual  field  on  recovery  from  an  occipital  injury,  and 
yet  things  which  were  seen  quite  well  could  not  be  oriented  in  space, 
and  thickness  and  depth  found  no  place  in  the  visual  perception. 

The  sensory  areas  of  the  cortex  and  thalamus  are  the  end  points  to 
which  we  trace  the  afferent  impulses  which  give  rise  to  sensation.  We 
are  not  justified,  however,  in  concluding  from  this  that  they  are  the 
regions  in  which  the  phenomena  of  sensation  and  consciousness  occur. 
Bather  should  they  be 'thought  of  as  important  junction  points  on  the 
afferent  side  of  the  complex  network  of  neurons  which  links  up  the 
various  centers  of  the  cerebrum  and  in  which  are  carried  out  our  mental 
processes,  which  give  rise  to  consciousness.  In  a  similar  way  the  motor 
centers  which  we  are  to  consider  in  the  next  chapter  are  the  junction 
points  from  which  start  out  the  efferent  impulses  for  voluntary  move- 
ment. 

Sensory  Hallucinations. — It  seems  probable  that  under  pathological 
conditions  disturbances  may  be  set  up  locally  in  the  sensory  centers 
which  resemble  closely  those  naturally  occurring  as  the  result  of  peri- 
pheral stimuli.  Thus  in  Jacksonian  epilepsy  the  irritation  arising  from 
a  splinter  of  bone  pressing  upon  one  of  the  sensory  centers  may  give 
rise  to  vague  sensations  or  aura,  such  as  flashes  of  light,  loud  noises,  or 
tingling  in  the  skin.  If  such  disturbances  resemble  closely  enough  those 
occurring  naturally,  they  may  give  rise  to  those  conscious  phenomena  known 
as  hallucinations  and  the  sensory  disturbance  manifests  itself  as  a  definite 
vision,  the  sound  of  a  bell  or  whistle,  or  a  sensation  of  taste  or  smell. 
Use  has  been  made  of  the  fact  that  hallucinations  may  be  set  up  by 
cortical  stimulation,  in  tracing  out  the  sensory  areas  in  animals.  If  an 
irritant  such  as  strychnine  be  applied  locally  to  the  cortex,  the  sensation 
is  referred  by  the  animal  to  the  corresponding  portion  of  the  body  and 
an  effort  made  which  is  directed  toward  removing  the  irritant  from  this 
region.  Thus  irritation  of  certain  regions  in  the  cortex  will  cause  the 
animal  to  shake  one  paw  and  attempt  to  brush  away  from  it  the  supposed 
source  of  the  sensation. 


CHAPTER  XCV 

THE  MOTOR  AREAS  OF  THE  CEREBRUM  AND  THE  EFFERENT 
PATHWAY  TO  SKELETAL  MUSCLE 

It  is  a  debatable  question  whether  motor  acts  are  ever  initiated  by  the 
nervous  system  except  in  response  to  some  stimulus  which  sends  afferent 
impulses  into  the  brain  or  cord,  or  as  the  result  of  changes  in  the  im- 
mediate environment  of  the  nerve  centers  due  to  abnormal  conditions  in 
the  circulation.  There  are,  however,  a  large  group  of  responses  the  nature 
of  which  is  conditioned  not  only  by  the  immediate  stimulus  which  calls 
them  forth,  but  by  the  previous  experience  of  the  organism.  Situations 
which  have  existed  in  the  past  leave  their  mark  upon  the  nervous  system 
in  the  form  of  memories,  associations  and  the  like,  and  these  determine 
how  the  animal  or  man  will  behave  when  new  groups  of  stimuli,  or  sit- 
uations, arise.  We  shall  see  later,  how  previous  experience  may  alter  the 
nature  of  even  involuntary  responses  to  simple  stimuli,  when  we 
take  up  the  formation  of  conditioned  reflexes  (page  954).  In  the  present 
place  it  will  suffice  to  point  out  that  unless  we  have  considerable  knowl- 
edge of  the  past  experience  of  an  animal  it  is  impossible  to  predict  how 
it  will  respond  to  certain  situations.  Responses  of  this  type  consequently 
are  not  obviously  and  invariably  related  to  any  particular  stimulus,  as 
are  the  simpler  reflex  responses,  and  consequently  appear  to  arise  spon- 
taneously in  the  nervous  system.  They  are  consequently  called  voluntary 
acts,  which  we  shall  take  to  imply  that  their  nature  and  occurrence  is 
related  quite  as  closely  to  preexisting  conditions  in  the  nervous  system 
as  to  the  immediate  situation  which  brings  them  forth. 

In  animals  from  which  the  cerebrum  has  been  removed,  motor  responses 
of  a  very  perfect  nature  may  still  be  carried  out.  A  pigeon  in  this  con- 
dition can  walk,  fly,  coo,  etc.,  quite  normally,  and  if  fed  may  live  indefi- 
nitely. A  dog  from  which  the  cerebral  cortex  is  removed  shows  strik- 
ingly little  difference  in  its  behavior  from  a  normal  animal.  Its  equilib- 
rium is  good,  it  moves  easily,  avoiding  objects  in  its  path,  swims  when 
thrown  into  water,  feeds  himself  if  food  is  brought  into  contact  with 
his  nose  and  rejects  food  of  disagreeable  taste.  The  reactions  of  such 
animals  become  almost  strictly  predictable,  because  they  show  no  signs 
of  being  influenced  by  past  experience.  The  pigeon  is  no  longer  fright- 
ened by  a  loud  noise  or  sudden  movement,  nor  does  it  suddenly  become 
active  for  no  obvious  reason  as  a  normal  bird  would.  The  dog  shows  no 

884 


MOTOR   AREAS    OF    THE    CEREBRUM 


885 


sign  of  affection  or  memory  of  its  master,  it  does  not  recognize  food  as 
good  to  eat  by  its  mere  appearance,  nor  does  it  give  signs  of  dreaming  as 
normal  dogs  do.  The  mechanism  by  which  the  retention  and  association 
of  the  effects  of  past  experience  modifies  behavior  and  produces  acts  of 
an  apparently  spontaneous  and  volitional  nature  evidently  resides  in 
the  complicated  meshwork  of  neurons  which  compose  or  connect  the 
various  parts  of  the  cerebral  cortex. 

The  Motor  Areas  of  the  Cerebral  Cortex 

Just  as  we  saw  in  the  last  chapter  that  there  were  certain  junction 
points,  or  sensory  areas,  by  which  afferent  impulses  are  led  into  the 


Anus  &  Vagina 

Toes// 

Ankle     ' 

Knee 


/5u/c(/5  centralis 


,-Abdomen 
Chest 


Shoulder- 


Fingers 
sthum 


YES 


jaw 
Vocal  cords 


Sulcus  central  is 


Mastication 


Fig.  217. — Outer  aspect  of  the  brain  of  the  chimpanzee,  showing  the  position  of  the  motor  centers. 
Electric  stimulation  at  the  parts  indicated  causes  coordinate  movements  of  the  corresponding  mus- 
cle groups.  (After  Sherrington.) 

cerebral  cortex  so  there  are  certain  foci  from  which  efferent  impulses 
leave  the  cortex  to  initiate  movement  in  the  skeletal  muscles.  These 
are  the  motor  areas  of  the  cortex.  Their  situation  and  the  groups  of 
muscles  related  to  each  part  of  the  motor  area  have  been  made  out  by 
two  methods.  In  animals,  and,  under  exceptional  conditions,  in  man,  the 
cortex  may  be  excited  locally,  preferably  by  some  method  of  unipolar 
electrical  stimulation,  and  the  groups  of  muscles  brought  into  action 
may  then  be  noted.  By  this  method  the  most  precise  data  has  been 
obtained,  especially  in  experiments  upon  the  higher  apes,  the  topography 


886  CENTRAL   NERVOUS   SYSTEM 

of  whose  brains  most  closely  resembles  that  of  man.  Conversely  parts 
of  the  cortex  may  be  removed  and  the  distribution  of  the  muscles  which 
are  then  no  longer  under  voluntary  control  may  be  determined.  By 
these  methods  it  is  learned  that  the  principal  motor  area  lies  in  the 
cortex  immediately  in  front  of  and  extending  into  the  fissure  of  Rolando. 
The  Representation  of  Functional  Activity  in  the  Motor  Area. — When 
this  area  is  explored  with  a  localized  electrical  stimulus  it  is  found  that 
definite  parts  of  the  body  are  excited  by  the  stimulation  of  definite 
parts  of  the  motor  area.  There  is  then,  just  as  in  the  case  of  sensory 
areas,  a  region  corresponding  to  each  anatomical  part  of  the  body. 
Movements  of  the  muscles  of  the  head  are  occasioned  by  excitation  of 
the  lower  portion  of  the  area;  above  it  the  neck,  arms,  trunk,  and  legs 
are  represented  in  turn.  Again,  like  the  sensory  areas,  the  representation 
is  in  respect  to  the  functional  use  of  the  parts,  so  that  each  part  of  the 
cortex  is  the  focus  for  impulses  giving  rise  to  an  orderly  act  rather  than 
to  the  contraction  of  a  single  muscle.  This  is  shown  by  the  fact  that  a 
weak,  sharply  localized  stimulus  gives  rise  to  a  coordinated  movement 
such  as  the  animal  might  make  volitionally,  in  which  certain  groups 
of  muscles  contract  while  their  opponents  relax  by  virtue  of  a  reciprocal 
inhibition.  Thus  stimulation  of  an  appropriate  spot  in  the  motor  area 
of  the  monkey  will  cause  the  fist  to  be  clenched,  an  act  which  involves 
the  setting  of  the  extensors  of  the  wrist,  the  relaxation  of  the  extensors 
of  the  fingers,  and  the  contraction  of  the  flexors  of  the  fingers.  Because 
the  thing  represented  in  the  motor  area  is  a  complete  functional  act, 
the  areas  related  to  each  region  of  the  body  vary  in  size  with  the  num- 
ber and  complexity  of  the  acts  performed  by  these  regions.  Consequently 
the  head  and  arm  occupy  a  large  part  of  the  cortex  because  of  the 
intricacy  of  the  muscular  acts  which  may  be  carried  out  by  the  face, 
tongue,  and  fingers.  The  leg  likewise  has  a  large  representation  when 
compared  with  the  trunk,  the  functional  reactions  of  which  are  obviously 
limited.  In  the  cat  the  sensory  and  motor  areas  of  the  cortex  for  the 
head,  limbs  and  trunk  also  coincide  in  their  position,  but  in  the  higher 
apes  and  man  they  have  become  separated  for  the  most  part.  Only 
those  aspects  of  sensation  which  are  concerned  with  the  recognition  of 
spacial  relationships,  particularly  of  the  muscles  and  joints  are  repre- 
sented in  the  part  of  the  cortex  which  lies  in  front  of  the  fissure  of  Ro- 
lando, and  in  which  the  motor  functions  lie.  This  is  an  obvious  relation- 
ship since  a  very  close  association  is  to  be  expected  between  the  func- 
tions of  coordinated  movement  and  of  recognition  of  the  position  and 
movement  of  the  limbs,  etc. 

The  Visuo-Motor  Areas. — In  addition  to  the  large  motor  area  there  are 
two  smaller  areas,  excitation  of  which  gives  rise  to  movements  of  the 
ocular  muscles.  One  of  them,  the  frontal  visuo-motor  area,  is  located 


MOTOR   AREAS    OF   THE    CEREBRUM  887 

on  the  frontal  lobe.  Its  excitation  causes  conjugate  deviation  of  both 
eyes  to  the  opposite  side.  The  second  area  lies  in  the  occipital  lobe 
coinciding  approximately  with  the  center  for  visual  sensation.  Stimula- 
tion of  it  also  causes  eye  movements,  and  these  are  not  simply  the  result 
of  referred  sensations  which  result  in  movements  initiated  from  the 
frontal  visuo-motor  center,  since  they  persist  after  the  latter  has  been 
destroyed.  Consequently  the  occipital  visual  center  is  both  sensory  and 
motor  in  function. 

Physiological  Bases  of  the  Clinical  Effects  of  Lesions  in  the  Motor 
Area  of  the  Cortex. — Stimulation  of  the  motor  area  of  the  cortex  causes 
usually  a  response  on  the  part  of  the  muscles  on  the  opposite  side  of  the 
body.  From  this  it  appears  that  the  connections  between  the  two  halves  of 
the  cortex  and  the  muscles  they  control  is  a  crossed  one.  In  agreement  with 
this  is  the  fact  which  has  been  known  since  very  ancient  times  that  in- 
jury to  one  side  of  the  brain  frequently  results  in  paralysis  of  certain 
voluntary  movements  on  the  opposite  side  of  the  body. 

But  since  cortical  lesions  are  usually  small  in  comparison  to  the  area 
of  the  motor  regions,  the  derangement  more  commonly  affects  muscular 
acts  represented  in  a  limited  area  of  the  cortex  and  as  a  result  the  move- 
ments of  a  single  arm,  of  one  side  of  the  face,  or  of  one  leg  are  removed 
from  voluntary  control.  Such  a  limited,  unilateral  paralysis  is  called 
monoplegia. 

Jacksonian  Epilepsy, — When  the  strength  of  the  stimulus  applied  lo- 
cally to  the  cortex  is  great,  its  influence  spreads  so  that  adjoining 
motor  cells  are  brought  into  activity  and  larger  and  larger  groups  of 
muscles  take  part  in  the  response.  This  progressive  " march"  of  the 
response  to  cortical  stimulation  is  usually  limited  in  its  spread  to  the 
opposite  half  of  the  body,  in  this  way  differing  markedly  from  the 
spread  of  spinal  reflexes,  which  we  have  seen  to  occur  when  the  stimulus 
is  increased  (page  842). 

The  foregoing  results  obtained  by  experimental  stimulation  in  animals, 
are  very  similar  to  the  symptoms  observed  in  man  when  the  cerebral 
cortex  is  stimulated  by  the  pressure  on  it  of  a  meningeal  tumor  or  a 
spicule  of  bone.  Such  stimulation  causes  contraction  in  the  correspond- 
ing muscular  area;  the  contraction  then  spreads  to  neighboring  groups 
of  muscles,  and  may  ultimately  involve  the  whole  musculature  of  the 
body  in  a  convulsive  fit.  This  is  known  as  Jacksonian  epilepsy,  and 
it  is  to  be  distinguished  from  ordinary  epilepsy  by  its  localized  onset 
and  its  progressive  march.  Like  ordinary  epilepsy,  however,  the  Jack- 
sonian type  is  usually  preceded  by  a  peculiar  sensation  of  numbness  or 
tingling  in  the  area  that  is  to  show  the  first  contraction.  One  of  the  great 
achievements  of  modern  surgery  is  the  cure  of  a  Jacksonian  epilepsy,  by 


888  CENTRAL  NERVOUS  SYSTEM 

opening  the  skull  over  the  affected  center  and  removing  the  menmgeal  tumor 
or  spicule  of  bone  which  is  responsible  for  the  stimulation.  To  enable 
the  surgeon  to  locate  exactly  the  position  of  the  irritating  body,  it  is 
necessary  to  examine  the  patient  very  closely  as  to  the  muscular  group 
which  is  initially  affected  during  the  convulsions,  and  then  to  examine 
an  outline  map  of  the  cerebral  hemisphere  indicating  the  position  of 
the  various  motor  and  sensory  areas  as  deduced  mainly  from  experi- 
ments on  the  higher  monkeys  and  verified  by  the  experience  gained 
by  previous  operations.  Topographic  maps  indicating  the  surface  mark- 
ings corresponding  to  the  various  convolutions  of  the  cerebrum  must 
also  be  used.  In  such  operations  the  surgeon  often  has  the  opportunity 
of  experimentally  verifying  the  position  of  various  centers. 

The  entire  cortical  representation  of  motor  acts  does  not  follow 
this  strictly  crossed  unilateral  arrangement.  Voluntary  movements  which 
involve  muscle  groups  limited  totally  to  one  half  of  the  body  for  their 
completion  are  generally  represented  in  the  cortex  of  the  opposite  side. 
Certain  symmetrical  muscle  groups  which  commonly  operate  in  syn- 
chrony such  as  those  involved  in  mastication  also  are  represented  in 
and  controlled  by  the  contralateral  cortex.  On  the  other  hand  stimula- 
tion of  the  frontal  visuo-motor  area  of  one  side  causes  deviation  of 
both  eyes  towards  the  opposite  side  so  that  the  movement  of  each  eye 
must  be  represented  on  both  halves  of  the  brain.  When  the  motor 
area  of  one  side  of  the  brain  is  destroyed,  the  movements  of  certain 
bilaterally  acting  muscles,  such  as  those  of  inspiration,  of  movements 
in  the  diaphragm,  intercostal  and  abdominal  muscles  and  those  of  the 
larynx  are  not  affected  on  either  side.  This  may  be  due  to  a  bilateral 
representation  of  these  muscles  in  the  cortex,  as  in  the  case  of  the  ocular 
movements  or  to  the  fact  that  certain  of  the  efferent  fibers  connecting  the 
cortex  with  the  lower  motor  neurons  do  not  cross  to  the  opposite  side 
of  the  cord. 

The  Efferent  Pathway  in  the  Brain  and  Cord 

The  crossed  connection  between  the  cerebrum  and  the  functional 
groups  of  muscles  which  it  controls  is  due  to  the  arrangement  of  the 
efferent  neurons  which  link  it  with  the  motor  neurons  of  the  cord  and 
brain  stem.  The  most  important  tract  involved  in  conducting  efferent 
impulses  from  the  motor  areas  arises  from  the  large  pyramidal  cells 
(Betz  cells)  which  are  characteristic  of  the  motor  areas  of  the  cortex 
and  do  not  occur  in  its  other  parts.  This  is  the  pyramidal  tract  (tractus 
cortico-spinalis) .  Its  fibers  converge  from  the  various  parts  of  the  motor 
area  as  they  approach  the  internal  capsule  of  the  cerebrum,  and  pass 
through  the  midbrain  without  crossing.  At  the  level  of  the  pons  fibers 


MOTOR   AREAS    OF    THE    CEREBRUM  889 

are  given  off  which  cross  to  the  nucleus  of  the  facial  nerve  on  the  op- 
posite side  of  the  body.  Similarly  fibers  leave  the  main  tract  in  the 
upper  part  of  the  medulla  to  cross  and  connect  with  the  hypoglossal 
nucleus.  The  main  decussation  of  the  pyramidal  tract  occurs  in. the 
lower  part  of  the  medulla.  A  small  bundle  of  fibers  continue  beyond  this 
point  uncrossed  and  descend  the  cord  in  the  direct  pyramidal  tract, 
(tractus  cortico-spinalis  ventralis)  in  the  ventral  column  of  the  cord.  The 
fibers  which  enter  the  decussation  in  the  medulla  descend  the  cord  in 
the  crossed  or  lateral  pyramidal  tract  (tractus  cortico-spinalis  lateralis) 
in  the  lateral  column  of  the  cord.  In  these  tracts  the  pyramidal  fibers 
descend  to  the  level  of  the  motor  neurons  of  the  peripheral  nerves.  The 
connection  between  cortex  and  muscle  is  consequently  probably  con- 
summated by  no  more  than  two  nerve  cells,  the  pyramidal  and  the  lower 
motor  neuron.  It  is  quite  inconceivable  that  other  descending  tracts  in 
the  cord  are  not  involved  in  voluntary  acts,  but  their  relationships  are  not 
clearly  enough  understood  to  enable  us  to  base  our  explanations  of  the 
motor  symptoms  of  nervous  disease  upon  their  action. 

The  Paralysis  Resulting  from  Injuries  to  the  Pyramidal  Tract.— The 
arrangement  of  the  pyramidal  fibers  in  their  descent  through  the  cord 
imposes  certain  characteristics  on  the  distribution  of  the  paralysis  which 
results  from  lesions  in  different  parts  of  their  course.  We  have  seen 
that  lesions  in  the  cortex  rarely  result  in  a  complete  destruction  of  the 
motor  area,  so  that  the  resulting  paralysis  is  usually  limited  to  a  few 
groups  of  muscles  on  the  opposite  side  of  the  body.  Such  monoplegia 
would  be  accompanied  by  no  loss  of  sensation,  or  by  impairment  in  the 
special  aspects  of  sensation  in  a  limited  region.  In  deeper  parts  of  the 
brain  the  pyramidal  tracts  converge  with  the  result  that  a  lesion  the 
size  of  a  pea  in  the  internal  capsule  will  result  in  a  complete  destruction 
of  the  tract.  Monoplegia  is  consequently  rare  at  this  level,  the  paralysis 
usually  involving  the  entire  opposite  side  of  the  body.  Such  a  condi- 
tion is  known  as  hemiplegia.  If  lesions  in  this  region  affect  sensibility, 
the  discriminative  aspects  of  it  will  be  destroyed,  but  those  sensations 
which  make  a  thalamic  appeal  will  persist.  Lesions  in  the  brain  stem 
as  far  back  as  the  pons  will  similarly  produce  complete  contralateral 
hemiplegia,  accompanied  usually,  if  they  affect  the  afferent  paths  of 
sensation,  by  complete  anesthesia  on  the  paralyzed  half  of  the  body.  At 
the  pons  the  first  group  of  pyramidal  fibers  cross  to  the  opposite  side  to 
connect  with  the  facial  nerve.  Lesions  in  the  lower  part  of  the  pons 
consequently  do  not  involve  these  fibers  and  the  facial  muscles  of  the 
opposite  side  do  not  share  in  the  paralysis.  This  lesion,  however,  will 
interrupt  the  tracts  from  the  opposite  cerebral  hemisphere  which  have 
crossed  to  join  the  facial  nucleus  on  the  side  of  the  lesion.  Consequently 
the  face  becomes  paralyzed  on  the  same  side  as  the  lesion.  The  decussa- 


890  CENTRAL  NERVOUS  SYSTEM 

tion  of  fibers  to  the  hypoglossal  nerve  produces  a  similar  alternating 
paralysis  of  the  muscles  of  the  tongue  and  of  the  limbs  in  case  of  lesions 
in  the  medulla.  The  tongue  is  paralyzed  on  the  same  side  as  the  lesion, 
the  arms  and  legs  on  the  opposite  side,  while  the  facial  muscles  of 
both  sides  escape.  Such  a  condition  is  rare,  however.  Unilateral  lesions 
below  the  decussation  in  the  medulla  which  affect  the  pyramidal  tracts 
cause  paralysis  which  may  affect  those  muscles  whose  motor  neurons  lie 
below  the  level  of  the  lesion  and  on  the  same  side  of  the  body.  If  the  af- 
ferent paths  in  the  cord  are  affected  also,  sensation  will  be  disturbed, 
and,  as  we  have  seen,  heat,  cold  and  pain  may  be  lost  over  the  opposite 
side  of  the  body,  the  sense  of  position,  passive  movement,  and  two  di- 
mensional localization  will  be  impaired  over  the  same  side  of  the  body, 
while  touch  may  be  unimpaired  on  both  halves. 

The  Peripheral  Distribution  of  Efferent  Nerves 

The  motor  neurons  which  conduct  impulses  for  voluntary  movement 
from  the  central  nervous  system  to  the  muscles  have  their  cell  bodies 
in  the  ventral  horn  of  the  grey  matter  of  the  cord.  Like  the  primary 
afferent  neurons  they  have  a  segmental  origin,  and  are  distributed  to  those 
muscles  which  arose  in  the  corresponding  segments  of  the  embryo.  The 
segmental  arrangement  of  the  muscles  has  become  greatly  obscured  dur- 
ing development,  especially  in  the  limbs,  so  that  only  in  the  case  of 
the  intercostal  muscles  does  it  remain  perfectly  evident.  By  the  careful 
study  of  comparative  anatomy  and  by  correlating  lesions,  such  as  may 
occur  in  anterior  poliomyelitis,  which  affect  only  a  single  segment  of 
the  grey  matter,  with  the  resulting  muscular  paralysis,  it  has  been  pos- 
sible to  make  out  the  segmental  origin  and  innervation  of  the  various 
muscles  of  the  body. 

In  man  the  distribution  of  the  ventral  root  fibers  according  to  seg- 
ments for  the  cervical  and  lumbosacral  regions  is  as  follows: 

05  Deltoid,  biceps,  brachialis,  supinators,  rhomboids.     Occasionally 

radial  extensors.    Barely  pronator  radii  teres. 

06  Pronators,  radial  extensors,  pectoralis  major   (clavicular  fibers), 

serratus  anticus. 

07  Triceps,  extensor  carpi  ulnaris,  extensors  of  fingers,  pectoralis 

major. 

08  Flexors  of  wrist  and  fingers. 
Tl       Intrinsic  muscles  of  hand. 

S3,  4  Levator  ani,  sphincter  ani,  perineal  muscles. 

S2  Glutei,  biceps,  semitendinosus  and  semimembranosus. 

SI  Intrinsic  muscles  of  foot,  tibialis  posticus,  and  muscles  of  calf. 

L5  Muscles  of  ventrolateral  leg  (except  tibialis  anticus). 

L4  Extensors  of  leg  and  tibialis  anticus. 


MOTOR   AREAS    OF    THE    CEREBRUM  891 

The  knowledge  of  the  segmental  innervation  of  the  limb  muscles,  as 
furnished  in  the  above  table,  is  of  value  in  the  localization  of  spinal 
lesions.  Paralysis  of  the  extension  movements  of  the  wrist  and  fingers, 
along  with  the  triceps,  for  example,  usually  indicates  a  lesion  of  the 
seventh  cervical.  It  is  more  particularly  in  the  trunk,  however,  that 
the  segmental  innervation  of  the  muscles  is  evident.  The  innervation 
of  the  intercostal  muscles  being  unisegmental,  one  may  diagnose  the 
level  of  a  lesion  of  the  upper  thoracic  region  of  the  cord  by  observing  their 
behavior  during  deep  inspiration.  If  the  fingers  are  placed  in  the  in- 
tercostal spaces,  the  paralyzed  muscles  will  feel  limp  and  the  fingers 
sink  into  the  space  during  the  act. 

Localization  may  also  be  shown  by  studying  the  paralyses  of  the 
abdominal  muscles  when  the  lesion  involves  one  of  the  lower  six  thoracic 
segments.  When  the  patient  with  a  lesion  of  the  eleventh  thoracic  raises 
his  head  from  the  bed  or  coughs,  the  rectus  contracts,  but  the  iliac  re- 
gions bulge  owing  to  paralysis  of  the  lower  portions  of  the  obliques.  Under 
the  same  conditions,  when  the  ninth  segment  is  involved  the  rectus  contracts 
from  about  one  inch  above  the  umbilicus,  whereas  below  this  level  it  remains 
uncontracted,  so  that  the  umbilicus  is  pulled  up. 

The  motor  fibers  leave  the  ventral  horn  and  pass  through  the  ventral 
roots  of  the  spinal  nerves  into  the  nerve  trunks  which  supply  the  muscles. 
In  the  case  of  those  roots  which  contribute  to  the  cervical  and  lumbo- 
sacral  plexus  fibers  from  several  segments  may  be  combined  into  a  sin- 
gle trunk.  These  trunks  moreover  break  up  into  branches  in  which  the 
fibers  are  sorted  out  so  that  motor  fibers  become  separated  from  sensory 
fibers  to  the  skin,  and  so  that  all  fibers  from  several  segments  which 
are  passing  to  neighboring  groups  of  muscles  may  become  combined. 
Consequently  lesions  to  the  nerve  trunks  of  the  limbs  may  show  disso- 
ciation between  the  paralysis  and  the  loss  of  cutaneous  sensation,  and  at 
the  same  time  certain  muscles  originating  from  several  segments  may 
be  affected  while  other  muscles  derived  trom  the  same  segments  remain 
under  normal  control. 

Spinal  Reflexes 

In  addition  to  voluntary  movements,  activated  by  impulses  descend- 
ing through  the  pyramidal  tracts  from  the  brain,  many  reflex  responses 
of  the  skeletal  muscles  may  occur  which  owe  their  initiation  to  afferent 
impulses  which  do  not  affect  consciousness.  These  impulses  are  conducted 
through  the  cord  by  propriospinal  neurons,  and  reach  the  muscles  by 
traveling  over  the  same  peripheral  motor  neurons  which  complete  the 
path  for  voluntary  acts.  Consequently  if  paralysis  is  due  to  an  injury 
to  the  motor  neurons,  either  in  the  ventral  horn  of  the  gray  matter,  or 
along  the  peripheral  course  of  their  fibers,  the  muscles  can  be  excited 


892 


CENTRAL    NERVOUS    SYSTEM 


neither  reflexly  nor  by  volition.  Injuries  to  the  pyramidal  tracts,  how- 
ever may  cause  paralysis  without  affecting  the  reflex  response  of  the 
muscles.  Consequently  an  examination  of  the  reflex  excitability  of  the 
paralyzed  muscles  will  reveal  whether  the  injury  involves  the  motor  neu- 
ron or  not.  Since,  as  we  shall  see  (page  951)  impulses  from  the  cere- 
brum may  have  an  inhibitant  effect  on  certain  reflexes,  disease  which 
cuts  off  this  influence  may  cause  an  exaggeration  of  certain  reflex  re- 
sponses. Moreover  since  these  reflexes  are  carried  out  over  arcs  which 
lie  within  definite  segments  of  the  cord  the  failure  of  a  reflex  may 
indicate  in  what  part  of  the  cord  the  lesion  lies. 

The  segments  involved  in  the  more  important  reflex  tests  are  indicated 
in  the  following  table : 

LOCALIZATION  OF  MUSCULAR  REFLEX  ACTS  IN  THE  SPINAL  CORD 


(After  Starr) 

Pupillary  reflex  through  the  sympathetic:  Dilatation 
of  the  pupil  produced  by  irritation  of  the  neck. 

Scapular  reflex:  Irritation  of  the  skin  over  the  scapula 
produces  contraction  of  the  scapular  mucles. 

Biceps  and  supinator  longus:  Tapping  their  tendons 
produces  flexion  of  the  forearm. 

Triceps  reflex:  Tapping  tendon  produces  extension  of 
forearm. 

Scapulohumeral  reflex:  Tapping  the  inner  lower  edge 
of  the  scapula  causes  adduction  of  the  arm. 

Tapping  extensor  tendons  at  the  wrist  causes  extension 
of  the  hand. 

Tapping  flexor  tendons  at  the  wrist  causes  flexion  of  the 
hand. 

Palmar  reflex:  Stroking  palm  causes  closure  of  fingers; 
finger  clonus. 

Abdominal  reflex:  Stroking  side  of  abdomen  causes 
retraction. 

Genital  reflex:  Squeezing  the  testicle  causes  contraction 
of  the  abdominal  muscles. 

Patella  tendon:  Striking  tendon  at  knee  causes  exten- 
sion of  the  leg;  "knee-jerk." 

Achilles  tendon  reflex:  Tapping  the  Achilles  tendon 
causes  flexion  of  ankle. 

Foot  clonus:  Extension  of  Achilles  tendon  causes  flex- 
ion of  the  ankle. 

Plantar  reflex:  Tickling  sole  of  foot  causes  flexion  of 
toes,  or  extension  of  the  great  toe  and  flexion  of  the 
others. 


Fourth  cervical  to  first  dor- 
sal. 
Fifth  cervical  to  first  dorsal. 

Fifth  and  sixth  cervical. 

Sixth  cervical. 

Seventh  cervical. 

Sixth  to  eighth  cervical. 

Seventh  to  eighth  cervical. 

Eighth  cervical  to  first  dor- 
sal. 
Ninth  to  twelfth  dorsal. 

First  to  third  lumbar. 
Second  and  third  lumbar. 
First  to  third  sacral. 
First  to  third  sacral. 
First  to  third  sacral. 


CHAPTER  XCVI 

THE  AUTONOMIC  NERVOUS  SYSTEM,  OR  THE  EFFERENT  PATH- 
WAY TO  SMOOTH  MUSCLES  AND  GLANDS 

The  development  of  complex  masses  of  association  neurons  in  the  cen- 
tral nervous  system  of  the  higher  animals  is  associated  with  the  acquisi- 
tion of  more  and  more  specialized  motor  mechanisms  and  of  a  diversity  in 
the  responses  which  these  muscular  structures  can  make.  The  organs  con- 
cerned with  nutrition  have  retained  many  of  their  primitive  characters 
such  as  walls  of  smooth  muscle  and  innervation  by  nonmedullated  neu- 
rons, arranged  in  some  cases,  at  least,  as  a  nerve  net.  The  nervous 
mechanism  for  the  control  of  skeletal  muscle  has  developed,  consequently 
as  an  adjunct  to  the  visceral  system,  and  has  reached  such  a  dominating 
position  that  the  latter  has  been  rather  neglected  in  the  hands  of  neu- 
rologists. There  can  be  little  doubt,  however,  as  the  interesting  book 
of  Pottenger18  suggests,  that  the  study  of  visceral  neurology  will  con- 
tribute greatly  to  elucidating  the  symptoms  of  disease.  Because  the 
neurons  of  the  autonomic  nervous  system  are  organized  somewhat  differ- 
ently than  are  the  efferent  paths  to  skeletal  muscle,  and  innervate  organs 
of  a  different  function,  the  mistake  should  not  be  made  of  thinking  that 
it  functions  independently  of  the  central  nervous  system.  There  is  no 
evidence  that  afferent  impulses  play  upon  these  neurons  except  after 
passage  into  the  central  nervous  system.  We  have  seen  that  afferent 
impulses  from  the  viscera  may  give  rise  to  sensory  effects  in  the  central 
nervous  system  (page  873).  Similarly  reflex  change  in  the  viscera  may 
be  set  up  through  impulses  having  an  efferent  path  in  the  autonomic 
nervous  system,  but  originating  from  stimuli  acting  upon  the  surface 
of  the  body.  The  pupillary  reflex  elicited  by  pinching  the  neck  is  a  case 
in  point  as  is  the  psychic  secretion  of  gastric  juice,  the  voluntary 
emptying  of  the  bladder,  and  the  syndrome  of  gastrointestinal  and 
circulatory  changes  which  accompany  great  emotion.  The  autonomic 
nervous  system  comprises  the  group  of  neurons  which  carry  impulses 
to  the  smooth  muscles  and  glands  of  the  body.  It  owes  its  interest  and 
importance  to  the  functions  to  which  these  tissues  contribute  (nutrition 
and  reproduction),  rather  than  to  any  supposed  autonomy  it  may  possess. 

The  Organization  of  Efferent  Nerves  to  the  Viscera 

The  reflexes  in  which  the  autonomic  neurons  take  part  are  conducted 
over  reflex  arcs.  While  the  afferent  side  of  such  arcs  may  arise  from 

893 


894 


CENTRAL    NERVOUS    SYSTEM 


somatic  as  well  as  visceral  sources,  it  is  interesting  that  the  functional 
acts  which  these  reflexes  may  perform  find  no  representation  in  the 
motor  areas  of  the  cerebral  cortex,  and  that  in  only  exceptional  cases 
can  they  be  initiated  voluntarily. 

The  efferent  side  of  the  arc  is  interesting  because  of  its  anatomical 
organization.  The  motor  path  connecting  the  spinal  cord  with  the 
smooth  muscles  and  glands  of  the  viscera  consists  of  two  neurons.  The 
cell  body  of  the  first  lies  in  the  lateral  horn  of  the  gray  matter  of  the 
cord.  It  is  known  as  an  internuncial  neuron  and  its  fiber,  which  is  med- 
ullated,  is  called  a  connector  fiber  or  preganglionic  fiber.  These  fibers 
terminate  in  synapse  with  the  cell  body  of  the  second  neuron  or  effector 


Fig.  218. — Diagram  illustrating  the  different  arrangements  of  the  internuncial  neurons  of  the 
voluntary  and  autonomic  nervous  systems.  In  both  systems  the  afferent  fiber  terminates  (by  col- 
laterals) around  a  cell  of  the  gray  matter  of  the  cord.  In  the  voluntary  system  this  cell  is  sit- 
uated in  the  posterior  horn,  and  its  axon  travels  to  an  anterior  horn  cell.  In  the  autonomic 
system,  on  the  other  hand,  it  is  located  in  the  lateral  horn,  and  its  axon  leaves  the  cord  by  the 
anterior  root  and  travels  by  the  white  ramus  into  a  sympathetic  ganglion,  where  it  connects  with 
a  nerve  cell,  whose  axon  forms  the  postganglionic  fiber.  (From  Gaskell.) 

neuron,  which  lies  in  an  outlying  ganglion.  These  neurons  give  off 
fibers  known  as  postganglionic  fibers  which  extend  to  the  effector  which 
is  innervated.  The  postganglionic  fibers  are  not  medullated  (except  in 
the  case  of  the  path  to  the  sphincter  pupillaB  from  the  third  nerve). 

Connector  fibers  are  given  off  from  three  distinct  regions  of  the  cen- 
tral nervous  system.  The  anatomical  arrangements  and  physiological 
activities  of  these  regions  are  distinctive.  The  bulbar  outflow  consists  of 
connector  fibers  lying  chiefly  in  the  vagus,  but  also  in  the  third,  seventh, 
ninth,  and  eleventh  cranial  nerves.  The  sacral  outflow  consists  of  fibers, 
leaving  the  cord  with  the  second  to  fourth  sacral  nerves,  which  join 
to  form  a  common  nerve  trunk  (the  pelvic  nerve  or  nervus  erigens) 


Fig.  219. — Diagram  of  the  autonomic  nervous  system.  The  preganglionic  fibers  are  in  red,  and 
the  postganglionic  in  black.  S.c.,  superior  cervical  ganglion;  I.e.,  inferior  cervical  ganglion;  T, 
stellate  ganglion;  S.p.,  great  splanchnic  nerve;  (7,  ganglia  of  solar  plexus;  m,  inferior  mesenteric 
ganglia;  h,  hypogastric  nerves;  N.B.,  nervus  erigens.  The  arrows  indicate  the  direction  of  nerve 
conduction.  The  numerals  indicate  the  spinal  nerves.  (From  Howell.) 


THE    AUTONOMIC    NERVOUS    SYSTEM  895 

on  each  side.  Because  they  have  certain  characteristics  in  common  these 
two  outflows  are  classed  together  as  the  bubo-sacral  (sometimes  called 
the  parasympathetic)  division  of  the  autonomic  nervous  system.  The 
thoracico -lumbar  outflow  consists  of  connector  fibers  leaving  the  cord 
between  the  first  thoracic  and  second  or  third  lumbar  segment.  This  out- 
flow is  sometimes  called  the  sympathetic  division  of  the  autonomic 
nervous  system. 

The  terminology  applied  to  these  systems  is  confusing  because  of  the 
different  usage  of  the  same  name  by  different  authors.  The  following 
table  indicates  the  classification  adopted  in  this  book,  together  with  the 
synonymous  terms  in  current  use. 


THIS    BOOK 

SYNONYMS 

(Langley) 

(Meyer) 

(Gaskell) 

Autonomic 
Nervous 
System 

Autonomic 
Nervous 
System 

Vegetative 
Nervous 
System 

Involuntary 
Nervous 
System 

1. 
2. 

Thoracico-lumbar 
Autonomic 
Bulbo-sacral 
Autonomie 

1.  Sympathetic 
2.  Parasympathetic 

1.  Sympathetic 
2.  Autonomic 

1.  Sympathetic 

2.  Enteral 
Oculomotor 

While  the  details  of  the  anatomical  courses  of  the  fibers  to  the  great 
variety  of  structures  innervated  by  the  autonomic  system  is  beyond 
the  scope  of  a  textbook  of  physiology,  it  is  appropriate  to  outline  certain 
generalities  concerning  the  arrangement  of  the  connector  and  effector 
neurons  which  supply  different  organs.  In  addition  to  the  obvious  meth- 
ods for  tracing  the  paths  of  nerve  fibers  by  degeneration  and  by  stimu- 
lating the  roots  of  the  motor  nerves  knowledge  of  the  course  of  the 
connector  neurons  has  been  gained  by  the  use  of  a  special  method  dis- 
covered by  Langley.  This  depends  upon  the  fact  that  nicotine  in  cer- 
tain concentrations  specifically  blocks  the  passage  of  nerve  impulses 
across  the  synapse  between  the  connector  fiber  and  the  effector  neuron 
without  disturbing  conduction  in  the  course  of  nerve  fibers  unin- 
terrupted by  a  synapse.  Consequently  when  nicotine  is  painted  upon  an 
outlying  ganglion  it  is  possible  to  determine,  by  stimulating  the  con- 
nector fibers,  whether  they  pass  through  the  ganglion  without  inter- 
ruption or  not.  In  this  way  it  has  been  learned  that  the  motor  paths  in 
the  autonomic  system  fall  into  three  groups  with  regard  to  the  position 
of  the  synapse  between  the  connector  and  the  outlying  neuron. 

Position  of  the  Effector  Neuron. — The  outlying  neuron  lies  wholly 
in  the  walls  of  the  organs  innervated  by  the  vagus  nerve,  the  sacral 
outflow,  and  that  part  of  the  thoracico-lumbar  outflow  which  supplies  the 
organs  which  have  developed  from  the  Wolfian  and  Mullerian  ducts, 
i.  e.,  the  ureters,  uterus,  and  vas  deferens.  The  cells  of  Auerbach's 
plexus  in  the  gastrointestinal  tract  represent  outlying  neurons  from 


896  CENTRAL  NERVOUS  SYSTEM 

the  vagus,  while  the  sacral  plexus  is  composed  of  the  postganglionie 
fibers  from  the  sacral  outflow.  The  remaining  parts  of  the  thoracico- 
lumbar  outflow  undergo  synapse  in  one  of  two  sets  of  ganglia.  The  seg- 
mental  chain  of  sympathetic  ganglia  contain  the  cells  of  the  outlying  neu- 
rons of  those  thoraeico-lumbar  paths  which  follow  the  course  of  the  spinal 
nerves  to  smooth  muscles  and  glands  located  in  the  skin  and  muscles, 
and  of  those  which  innervate  the  organs  of  the  thoracic  cavity.  The 
typical  arrangement  of  this  group  is  shown  in  Figs.  218  and  221.  The 
connector  fiber  reaches  the  ganglion  through  the  white  ramus  and  the 
postganglionic  fiber  passes  back  to  the  trunk  of  the  spinal  nerve  in 
the  gray  ramus  and  follows  this  trunk  to  the  peripheral  structure  which 
it  innervates.  Many  connectors  do  not  terminate  directly  in  the  ganglion 
of  their  own  segment,  but  send  collaterals  forward  or  backward  through 
the  sympathetic  chain  to  the  other  ganglia,  where  they  connect  with  ef- 
fector neurons.  The  third  group  of  thoracico-lumbar  paths  leads  to  the 
organs  of  the  abdominal  viscera,  including  their  blood  vessels.  The 
connector  fibers  of  these  paths  pass  out  over  the  white  rami  and  through 
the  segmental  sympathetic  ganglia  without  interruption  to  terminate 
in  one  of  the  mesenteric  ganglia  in  connection  with  an  effector  neuron. 

The  Double  Innervation  of  the  Visceral  Organs, — The  innervation  of 
the  smooth  muscles  and  glands  is  peculiar  in  that  each  effector  may  be 
acted  upon  by  two  neurons  which  effect  its  activity  in  opposite  ways. 
Impulses  from  one  neuron  tend  to  increase  the  secretion  of  these  glands, 
or  augment  the  tone  or  degree  of  contraction  of  the  smooth  muscles, 
while  impulses  from  the  other  neuron  set  up  changes  in  the  other  direc- 
tion which  inhibit  or  depress  these  activities.  Because  of  this  double 
innervation  of  structures  supplied  by  the  autonomic  system,  the  activ- 
ity of  any  of  them  will  depend  on  the  balance  which  is  struck  between  the 
effects  of  these  antagonistic  neurons. 

The  details  of  this  arrangement  may  be  learned  in  the  case  of  any 
particular  organ  from  Fig.  221. 

In  general  it  may  be  stated  that  the  bulbar  and  sacral  outflows  do  not 
overlap.  In  the  gastrointestinal  tract  all  parts  cephalad  of  the  ileocolic 
sphincter  are  innervated  by  the  vagus  and  other  cranial  nerves,  and 
are  replaced  below  this  point  by  the  sacral  outflow.  At  the  same  time, 
the  thoracico-lumbar  outflow  supplies  this  entire  tract  below  the  cardiac 
part  of  the  stomach  with  fibers  which  act  upon  it  in  the  opposite  sense. 
The  action  of  the  bulbo-sacral  outflow  on  the  gastrointestinal  tract  is 
excitatory,  except  for  the  ileocolic,  and  internal  anal  sphincters  which 
are  inhibited.  It  consequently  favors  the  movement  of  food  along  the 
digestive  tract  and  the  secretion  of  the  digestive  fluids  of  the  pancreas 
and  salivary  glands,  and  the  emptying  of  the  gall  bladder.  The  thora- 
cico-lumbar outflow,  on  the  other  hand,  tends  to  diminish  the  activities 


Heads  Neck 

(Posting.; 


Medulla    =Key 

PreGangiionic  Sympathetic 
Post  Ganglionic  Sympathetic 
Pre  GanglionicBulbo-Sacral 

(Para5ympathetic) 
Post  Gang!ionicBulbo-5acral 


Splanchnic 

(Posrgang.) 


Coeliac  Plexus  & 
5wp.Mes.Gang. 


minal 
Viscera 
(Preqang.) 


'Pelvic  visceral  nerve 


Fig.  220. — Diagram  showing  the  main  parts  of  the  autonomic  nervous  system.  For  the  sake  of 
clarity  several  of  the  preganglionic  fibers  of  the  sympathetic  autonomies  are  omitted,  but  the  posi- 
tion of  their  egress  from  the  cord  is  indicated  in  the  side  notes.  The  diagram  shows  clearly  the 
distribution  of  the  bulbosacral  autonomic  system  by  way  of  the  vagus  and  the  first,  second  and 
third  sacral  nerves. 


THE   AUTONOMIC   NERVOUS   SYSTEM  897 

of  the  gastrointestinal  muscles  and  of  the  salivary  glands  and  to  close 
the  sphincters  of  the  lower  tract.  These  systems  of  fibers  also  act  in  an 
antagonistic  way  on  the  heart,  bladder,  and  interocular  muscles.  The 
bulbar  outflow  through  the  vagus  inhibits  the  action  of  the  heart,  through 
the  third  nerve  constricts  the  sphincter  pupillae  and  probably  inhibits 
the  radial  fibers  of  the  iris.  The  sacral  outflow  through  the  nervous  eri- 
gens  causes  contraction  of  the  bladder  musculature  and  inhibition  of 
its  sphincters.  In  each  of  these  cases  the  thoracico-lumbar  outflow  acts 
on  these  muscles  in  the  opposite  sense. 

A  large  group  of  smooth  muscles  are  innervated  only  through  the 
thoracico-lumbar  outflow.  Some  of  these,  i.  e.,  the  pilo-motor  muscles 
and  the  muscles  of  the  sweat  glands,  receive  so  far  as  we  know  only  ex- 
citor  fibers  from  this  system.  Others  receive  both  excitor  and  inhibitor 
fibers  from  this  system,  so  that  an  antagonism  exists  in  the  action  of 
different  neurons  from  the  same  outflow.  This  fact  has  been  discovered 
by  the  use  of  a  drug,  ergotoxine,  which  prevents  the  excitor  fibers  from 
acting  upon  the  muscles  but  does  not  impair  the  action  of  the  inhibitor 
fibers.  After  the  application  of  ergotoxine  to  these  organs  the  stimula- 
tion of  their  nerves  results  in  an  inhibition  of  the  muscles  rather  than 
the  normal  excitation.  Inhibitory  fibers  are  found  in  the  thoracico-lum- 
bar supply  to  the  cutaneous  blood  vessels  of  the  bucco-facial  region  and  of 
the  kidney  and  their  activity  results  in  a  vasodilatation  in  these  re- 
gions. The  smooth  muscles  of  the  uterus  also  receive  inhibitory  fibers 
from  the  thoracico-lumbar  system,  and  in  the  virgin  uterus  these  may 
dominate  the  activity  of  the  organ,  so  that  its  muscles  relax  upon  stimu- 
lation of  their  nerves.  In  the  pregnant  uterus,  on  the  other  hand,  the 
constrictor  fibers  in  these  nerves  predominate  and  a  contraction  follows 
their  excitation.  Further  details  of  the  organization  of  the  Autonomic 
system  may  be  obtained  from  the  Monograph  by  Gaskell.17 

The  Function  of  the  Autonomic  Nervous  System 

When  we  examine  the  contribution  which  the  autonomic  nervous 
system  makes  to  the  organization  of  bodily  activity,  we  are  struck  by 
.the  fact  that  these  nerves  regulate  the  activity  of  a  group  of  organs  and 
tissues  which  possess  a  high  degree  of  autonomy,  so  that  their  various 
functions  can  be  carried  out  quite  successfully  when  they  are  completely 
isolated  from  the  central  nervous  system.  The  heart  is  perhaps  the  most 
complex  organ  under  autonomic  control,  yet  not  only  will  isolated  strips 
of  this  organ  contract  in  the  rhythmic  fashion  characteristic  of  the  heart's 
activity  but  the  entire  organ  will  beat  in  a  perfectly  coordinated  way 
when  freed  from  nervous  control.  The  tonic  contraction  of  the  arter- 
ioles,  essential  to  the  maintenance  of  blood  pressure,  is  only  temporarily 
deranged  by  the  destruction  of  their  nerves.  The  musculature  of  the 


898  CENTRAL  NERVOUS  SYSTEM 

gastrointestinal  tract  carries  out  its  rhythmic  movements  and  maintains 
polarity  in  its  action  after  it  is  separated  from  its  extrinsic  nerve  supply. 
Even  the  mechanism  for  operating  the  pyloric  sphincter  does  not  de- 
pend on  nervous  connections  extending  beyond  the  gut  wall.  The  secre- 
tion of  the  gastric,  pancreatic  and  intestinal  juices  is  also  brought  about 
by  hormones  of  the  secretin  type  so  that  nerves  are  unnecessary  for  this 
activity. 

Goltz  and  Ewald  have  succeeded  in  keeping  dogs  alive  and  in  good 
condition  for  long  periods  after  removal  of  the  spinal  cord  below  the 
cervical  region.  After  such  animals  have  recovered  from  the  immediate 
effects  of  the  operation,  the  skeletal  musculature  of  the  posterior  part 
of  the  body  is  paralyzed  and  soon  atrophies.  The  organs  under  auto- 
nomic  control  recover  their  normal  function  to  a  surprising  extent.  The 
tone  of  the  blood  vessels  recovers,  and  they  react  to  temperature  changes 
much  as  a  normal  vessel  would.  The  digestion  becomes  normal,  defeca- 
tion takes  place  regularly,  and  the  bladder  is  emptied  periodically  and 
spontaneously.  A  pregnant  bitch  gave  birth  to  puppies  a  few  hours 
after  9.4  cm.  of  cord  had  been  removed,  and  suckled  one  of  them  suc- 
cessfully. In  these  animals  it  appeared  that  the  organs  innervated  by 
the  autonomic  nervous  system  could  function  successfully  after  the  cord, 
and  with  it  the  connector  neurons,  had  been  destroyed.  The  experiments 
suggest  that  the  autonomic  system  may  contain  reflex  arcs  within  itself, 
which  do  not  pass  into  the  central  nervous  system.  A  difficulty  arises 
here  because  it  has  not  been  possible  to  demonstrate  any  connection  in 
the  outlying  ganglia  between  the  afferent  fibers  passing  through  the 
autonomic  nervous  system  and  the  effector  neurons. 

A  type  of  reflex  which  may  operate  here  is  that  known  as  the  axon 
reflex.  The  only  axon  reflex  which  is  known  to  function,  except  under 
laboratory  conditions  of  stimulation,  affects  the  cutaneous  blood  vessels, 
and  causes  a  local  inflammation  to  be  set  up  in  the  skin  when  mustard  is 
applied  to  it.  This  reaction  was  shown  by  Bruce  to  persist  after  cutting 
the  dorsal  roots  of  the  spinal  nerves  and  consequently  could  not  be  attributed 
to  a  spinal  reflex.  After  the  sensory  fibers  had  degenerated,  however, 
the  effect  could  no  longer  be  elicited.  It  appears  from  this  that  the 
mechanism  depends  on  the  integrity  of  the  peripheral  end  of  the  sensory 
fibers.  It  is  believed  that  these  send  off  collaterals  which  connect  with 
the  cutaneous  blood  vessels.  Impulses  set  up  by  the  mustard  in  the 
sensory  termination  pass  up  the  fiber  to  these  collaterals  and  down  them 
to  the  blood  vessels  where  dilation  is  produced.  This  mechanism  also 
explains  the  observation  of  Bayliss  that  stimulation  of  the  peripheral 
stump  of  the  dorsal  root  of  a  spinal  nerve  causes  a  local  vasodilatation 
in  the  skin.  A  similar  axon  reflex  has  been  found  to  occur  in  certain 
connector  fibers  of  the  thoracico-lumbar  outflow  which  supply  the  smooth 


XP//O  motor  muscle 
Lachrymalrtand 


Submaxillar 

Submaxilldryublingual) 
ganglion 


ll/ocecal 
sphincte 

B/a 
Ves/ca/  sphincter-^ 

Urethra  I  sphincter 

•*'  r  f        \  mi.  aiitji 

Pelvic(Hypoqastricjnteriliac)   <  sphincter 


Cranial  and  Sacral  nerves 
motor = red 
inhibitory = blue 

Thoraclco-lumbar  nerves 


mrPostganglionic  fibers 
aredotted.thus  — 
c. 

N.XI 

Sup.  cervical  ganglion 

Thyroid  gland 


Inf.  cervical  ganglion 
Z-Ansa  subclavia 

-Stellate  (/$? Thoracic) 
ganglion 

Sweat  gland 


Vaso-motor 
fibers 


Pilo  motor  muscle 


Celiac  (Semilunar) 

ganglion(5olarplex) 

Splanchnic  nerves 
Sympathetic  chain 


ll  rtumbar  splanchnics 

-Sup.  Mesenteric 
ganglion 

s. 

Inf.  Mesenteric 
ganglion 

Hypogastric  nerves 


*.  •  r  i  v,  ^  i  f  »  ^  v^  w  w  _/  i  |    r  v-,ii  i  i  N.  i   «ifw  v»y  .  .  y 

p/exu5 .  ( Vestcal  $  reefs/  portions)      Pelvic  nerves  (Nervus  erigens) 


Fig.   221. — Schematic  representation  of  the  autonomic   nervous  system.      (From  Jackson.) 


THE    AUTONOMIC    NERVOUS    SYSTEM 


899 


muscles  of  the  bladder,  the  blood  vessels  of  the  rectum,  and  the  internal 
anal  sphincter.  These  fibers  send  collaterals  to  the  bladder  through 
the  hypogastric  nerves.  When  one  of  these  is  cut  and  stimulated  cen- 
trally, the  muscles  innervated  by  the  collaterals  in  the  other  hypogastric 
nerve  are  seen  to  respond.  There  is  no  evidence,  however,  that  this 
mechanism  is  brought  into  play  in  normal  life. 

The  organs  supplied  by  the  autonomic  nervous  system  appear  to  be 
able  to  carry  out  their  functions  in  an  orderly  way  by  virtue  of  their 
inherent  properties,  of  the  presence  of  the  primitive  nerve  network 
which  makes  up  their  intrinsic  nervous  supply,  and  possibly  by  the  assist- 
ance of  simple  axon  reflexes  through  the  postganglionic  fibers  of  the 
thoracico-lumbar  outflow.  Since  their  reactions  are  simple  and  either 

Post,  root 
gang.- 


Fig.  222. — Diagram  of  an  axon  reflex  in  a  sensory  nerve  fiber  of  the  skin.  A  stimulus  applied  to 
the  skin  is  transmitted  by  the  sensory  fiber  (N),  part  of  it  going  to  the  spinal  cord  (SO,  and 
part  of  it  passing  by  the  collateral  (C)  to  the  arteriole  (A),  which  it  causes  to  dilate. 

strictly  local  or  generally  diffuse,  a  simple  nervous  mechanism  suffices, 
just  as  it  does  for  the  simple  activities  in  the  coelenterates  (page  829). 
Function  of  the  Bulbo-sacral  Division. — The  function  of  the  connector 
fibers  in  the  autonomic  system  would  appear  to  consist  largely  in  adjust- 
ing the  activities  of  these  structures  as  a  whole  to  the  conditions  of 
activity  brought  about  in  the  somatic  musculature  under  the  influence  of 
the  central  nervous  system.  Correlation  takes  place  between  visceral 
activity,  and  somatic  activity,  so  that  the  closest  cooperation  can  ob- 
tain between  the  organs  of  the  body.  This  is  brought  out  by  considering 
the  way  the  three  divisions  of  the  autonomic  system  manifest  themselves. 
The  bulbar  outflow  is  concerned  with  conserving  the  resources  of  the 
organism.  Its  action  on  the  heart  is  to  reduce  its  activity  so  that  there 


900  CENTRAL  NERVOUS  SYSTEM 

may  be  a  reserve  power  for  times  of  need.  The  gastrointestinal  tract 
is  brought  into  activity  by  the  vagus  which  thus  contributes  to  the  nu- 
tritional processes  of  the  body.  When  an  animal  has  acquired  food,  cer- 
tain rather  specific  reflexes  take  place  through  the  bulbar  outflow  which 
result  in  the  psychic  secretion  of  salivary  and  gastric  juice  and  the  re- 
flexes of  swallowing,  and  thus  initiate  the  process  of  digestion.  The 
succeeding  stages  in  the  process  can  no  doubt  be  executed  by  the  intrinsic 
mechanisms  of  the  gastrointestinal  tract,  but  activity  of  the  vagus  fibers 
should  be  expected  to  counterbalance  the  inhibitory  influence  of  the  thorac- 
ico-lumbar  outflow  and  thus  to  reinforce  the  action  of  the  gastrointestinal 
muscles. 

The  bulbosacral  outflow  brings  about  those  reactions  in  the  sphincters 
and  muscular  walls  of  the  bladder  and  cloaca  which  result  in  the  dis- 
charge of  waste  materials  from  these  receptacles.  Although  these  re- 
sponses may  occur  automatically  when  the  spinal  connections  are  de- 
stroyed, under  normal  conditions  these  acts  are  made  volitionally  at 
the  convenience  of  the  individual.  In  them  a  close  cooperation  occurs 
between  the  action  of  voluntary  and  involuntary  muscles  in  which  affer- 
ent impulses  from  these  viscera  play  an  important  part. 

The  mechanism  for  emptying  the  bladder  illustrates  this  correlation 
between  voluntary  and  involuntary  action.  Reflex  micturition  is  set 
up  when,  through  the  accumulation  of  urine,  the  intravesicular  pressure 
reaches  15  to  18  cm.  of  water.  As  the  tension  increases,  rhythmic  con- 
tractions of  the  bladder  musculature  occur  which  increase  in  strength  and 
result  in  afferent  impulses  being  set  up  in  the  pelvic  nerves  which  pass 
to  the  sacral  cord  and  to  the  higher  parts  of  the  central  nervous  system. 
Reflexes  are  thus  set  up  through  centers  in  the  lower  cord,  which  result 
in  excitation  of  the  sacral  autonomic  supply  to  the  bladder,  causing 
a  contraction  of  the  bladder  walls  and  inhibition  of  the  sphincter.  The 
pressure  within  the  bladder  rises  to  20  or  30  cm.  and  forces  the  urine 
through  the  neck  of  the  bladder  and  through  the  urethra.  Normally 
the  emptying  of  the  bladder  is  accompanied  by  a  voluntary  effort  ini- 
tiated by  the  afferent  impulses  which  ascend  to  the  cerebrum,  and  there 
give  rise  to  the  sensations  aroused  by  the  distended  vesicle  as  well  as  to 
efferent  impulses  which  contract  the  respiratory  and  abdominal  muscles, 
so  as  to  increase  the  intraabdominal  pressure,  and  help  squeeze  the  urine 
out  of  the  bladder.  Reflex  emptying  of  the  bladder  depends  then  on  the 
development  of  a  certain  tension  in  the  vesicular  muscle.  It  may  be  in- 
hibited to  a  certain  extent  by  voluntarily  contracting  the  striated  peri- 
neal  muscles  which  help  in  the  closure  of  the  urethra,  either  before  or 
during  the  reflex  act.  Micturition  may  be  initiated  before  the  bladder 
is  full  enough  to  start  the  reflex,  either  volitionally  or  by  virtue  of  im- 
pulses arising  through  sensory  nerves  from  other  parts  of  the  body. 


THE   AUTONOMIC    NERVOUS   SYSTEM  901 

These  types  of  micturition  must  be  set  up  by  impulses  which  affect  the 
spinal  centers  in  much  the  same  way  as  impulses  arising  from  the  blad- 
der itself.  The  bladder  may  consequently  be  emptied  by  three  mecha- 
nisms, (1)  by  its  intrinsic  activity  as  in  Goltz  and  Ewald's  dogs;  (2) 
by  a  purely  spinal  reflex  through  visceral  afferent  and  efferent  impulses, 
and  (3)  through  voluntary  effort  acting  on  the  spinal  centers  and  re- 
inforced by  the  contraction  of  skeletal  muscles.  The  former  mechanism 
is  relatively  inefficient,  as  is  seen  in  the  behavior  of  the  bladder  during 
the  failure  of  the  reflex  mechanisms  which  results  from  the  shock  of 
a  spinal  cord  injury.  The  urine  is  retained  until  the  intravesicular  pres- 
sure becomes  great  enough  to  force  the  sphincter,  and  then  it  dribbles 
out  feebly.  The  bladder  is  not  completely  emptied  and  the  residual 
urine  is  apt  to  putrefy,  giving  rise  to  cystitis  and  other  infections  which 
constitute  the  chief  danger  in  such  injuries.  If  the  local  condition  of 
the  bladder  remains  good,  the  automatic  emptying  of  the  bladder  may 
become  periodic  and  complete  whenever  about  225  c.c.  of  fluid  accumu- 
lates, even  though  the  injury  has  completey  destroyed  the  reflex  con- 
nection between  badder  and  cord.  If  the  injury  to  the  cord  does  not 
interfere  with  the  reflex  centers,  recovery  makes  automatic  reflex  mic- 
turition possible  and  the  bladder  is  emptied  completely  at  periodic  in- 
tervals as  it  becomes  full,  but  is  no  longer  under  voluntary  control 
(Fearnside,19  Head  and  Riddoch20). 

The  Function  of  the  Thoracico-Lumbar  Division. — The  thoracico-lum- 
bar  outflow,  in  contrast  to  the  bulbo-sacral,  inhibits  the  activity  of  the 
digestive  tract  and  brings  about  changes  in  the  organs  of  circulation 
which  are  appropriate  to  increased  activity  of  the  skeletal  musculature 
and  of  the  nervous  system  which  controls  them.  Whereas  the  different 
parts  of  the  cranial  and  sacral  outflow  are  brought  into  activity  sep- 
arately, so  that  the  digestive  secretions  may  be  stimulated  without  the 
heart  or  iris  being  affected  at  the  same  time,  and  micturition  may  occur 
independent  of  defecation,  discharge  over  the  thoracico-lumbar  system 
frequently  has  a  diffuse  nature,  affecting  all  of  the  organs  controlled 
by  it  simultaneously.  A  definite  syndrome  consequently  results  which 
is  brought  about  under  conditions  of  great  emotion,  as  in  fear,  pain, 
and  rage.  It  consist  of  acceleration  of  the  heart  rate,  constriction  of 
the  arterioles  in  the  skin  and  splanchnic  viscera,  inhibition  of  the  mus- 
cular activity  of  the  gastrointestinal  tract,  inhibition  of  the  salivary  se- 
cretion, erection  of  the  hair  and  secretion  of  the  sweat  glands.  These 
changes  occur  under  conditions  when  severe  muscular  effort  is  apt  to 
be  exerted  by  the  animal,  and  are  appropriate  because  they  tend  to  shift 
the  circulating  blood  to  the  muscles  and  nerves  of  the  body  at  the  ex- 
pense of  the  viscera  so  that  the  maximum  energy  may  be  devoted  to 


902  CENTRAL    NERVOUS    SYSTEM 

muscular  acts.  For  this  purpose  the  diffuse  activity  of  this  system  is 
an  obvious  advantage. 

In  this  connection  the  relation  of  the  adrenal  medulla  to  the  thoracico- 
lumbar  outflow  is  of  interest.  Its  cells  are  derived  in  the  embryo  from 
the  same  neuroblasts  which  give  rise  to  the  effector  neurons  of  the  sym- 
pathetic ganglia.  They  are  innervated  directly  by  the  connector  neurons 
of  the  thoracico-lumbar  outflow  so  that  they  are  strictly  homologous 
with  the  effector  neurons  of  this  system.  It  has  been  shown  that  without 
exception  the  effects  produced  on  any  organ  by  epinephrine,  the  secre- 
tion of  these  glands,  is  the  same  as  that  produced  by  the  excitation  of  its 
thoracico-lumbar  innervation.  These  gland  cells  may  be  considered  as 
nerve  cells  which  have  changed  their  mode  of  acting  on  their  effectors,  but 
still  produce  the  same  effect  through  their  secretion.  If  these  glands  are 
brought  into  action,  as  Cannon21  has  shown  them  to  be  during  emotional 
conditions,  they  will  reinforce  the  action  of  the  thoracico-lumbar  nerves 
and  because  their  hormone  is  distributed  through  the  blood,  ensure  the 
general,  diffuse  response  characteristic  of  the  action  of  the  thoracico- 
lumbar  system. 

It  must  not  be  supposed  that  the  reactions  of  the  thoracico-lumbar 
system  always  has  this  diffuse  character.  The  regulation  of  vasomotor 
reactions  is  largely  carried  out  through  its  neurons,  and  it  is  possible 
for  vasoconstriction  to  occur  in  one  part  of  the  vascular  bed  without 
affecting  other  parts.  The  shifting  of  the  mass  of  the  circulating  blood 
from  one  part  of  the  body  to  another  in  response  to  the  varying  needs 
occasioned  by  the  varying  conditions  of  each  organ  must  be  controlled  by 
these  nerves.  The  local  reflex  response  of  the  cutaneous  blood  vessels  to 
temperature  changes  is  a  case  in  point  (page  744). 

The  Effects  of  Impulses  from  the  Viscera  upon  Central  Nervous  Ac- 
tivity.— Just  as  the  visceral  organs  may  be  inhibited  through  the  thora- 
cico-lumbar outflow  in  adaptation  to  the  activity  of  the  skeletal  muscles, 
so  visceral  conditions  may  influence  the  state  of  the  central  nervous 
system  and  the  muscles  which  it  controls.  We  have  considered  the  effects 
of  afferent  impulses  from  the  viscera  in  producing  pain  (page  864).  In 
the  presence  of  visceral  disease  afferent  impulses  tend  to  produce  "de- 
pression" in  the  central  nervous  system,  so  that  muscular  activity  is 
avoided  and  the  sufferer  seeks  retirement  in  which  to  recover.  The  dis- 
agreeable mental  conditions  produced  by  constipation  are  probably  also 
nervous  in  origin,  as  is  indicated  by  their  prompt  relief  following  a  satis- 
factory movement  of  the  bowels.  The  vigorous  contractions  of  the  stom- 
ach musculature  in  hunger  not  only  give  rise  to  this  sensation,  but  make 
the  subject  restless  and  irritable.  Certain  reflex  acts  are  reinforced  by 
impulses  set  up  during  hunger,  as  the  knee  jerk.  The  cough  attending 
diseases  of  the  pulmonary  region  is  believed  by  Pottenger18  to  be  due  to 


THE    AUTONOMIC    NERVOUS    SYSTEM  903 

irritability  set  up  reflexly  in  the  pharynx  in  much  the  same  way  as  is  the 
hypersensitivity  of  the  skin  in  regions  of  referred  pain.  Spasms  in  skele- 
tal muscles  are  also  produced  in  tuberculosis  by  reflexes  arising  from 
the  lung.  These  are  reactions  depending  on  visceral  afferent  fibers. 
Reflex  conditions  arise  from  the  viscera  which  affect  other  viscera 
through  the  autonomic  efferents.  Dmitrenko  accelerated  the  respira- 
tion and  pulse  in  dogs  and  raised  their  blood  pressures  by  stimulating 
the  stomach  in  various  ways,  as  by  distention  with  balloons.  The  vom- 
iting of  pregnancy,  menstruation,  and  the  menopause,  and  of  whooping 
cough,  the  gastrointestinal  disturbances  which  may  follow  injury  to  the 
testis,  etc.,  are  attributed  by  certain  clinicians  to  reflex  effects  carried 
out  through  the  autonomic  nervous  system. 


CHAPTER  XCVII 
MUSCULAR  CONTRACTION 

Voluntary  and  reflex  nervous  activity  expresses  itself  in  the  reactions 
of  the  muscles  of  the  body.  In  order  to  interpret  the  normal  working 
of  the  motor  mechanism,  and  the  abnormal  manifestations  which  dis- 
ease of  the  nervous  system  imposes  on  the  muscles  of  the  body,  the  na- 
ture of  the  contractile  processes  in  skeletal  and  smooth  muscle  must  be 
understood. 

A  muscle  is  an  elastic  body.  That  is  to  say,  for  every  length  to  which 
it  is  stretched  it  will  exert  a  definite  tension  on  its  origin  and  insertion, 
tending  to  pull  them  together  until  it  has  returned  to  its  unstretched 
length.  When  a  muscle  "contracts,"  it  does  not  assume  a  smaller  vol- 
ume; rather  it  tends  to  change  its  shape  so  as  to  become  shorter  and 
thicker.  The  contracted  muscle  has  become  a  body  with  new  elastic 
properties,  i.  e.,  for  each  length  to  which  it  is  stretched,  it  now  exerts 
a  greater  tension  on  its  origin  and  insertion  than  it  did  in  the  "uncon- 
tracted"  condition.  Consequently  if  opposition  is  presented  to  the  short- 
ening of  the  stimulated  muscle  it  will  exert  a  tension  on  the  opposing 
object  equivalent  to  the  tension  necessary  to  stretch  the  contracted  mus- 
cle to  its  resting  length.  The  muscle's  length  does  not  change,  and  hence 
it  is  said  to  contract  isometrically.  If,  however,  the  opposition  is  not 
strong,  i.  e.,  is  due  to  a  light  weight,  the  tension  developed  on  contraction 
will  overcome  the  opposition,  and  the  muscle  will  shorten,  thus  lifting 
the  weight.  Since  the  tension  exerted  by  the  weight  is  the  same  at  all 
times  during  the  contraction  of  the  muscle,  such  a  contraction  is  called 
isotonic.  When  it  shortens  against  a  weight  the  muscle  assumes  a  new 
length  at  which  it  exerts  a  tension  equal  to  the  weight  which  is  lifted. 
A  muscle  is  consequently  a  machine  for  developing  tension,  and  this 
tension  may  or  may  not  do  work  in  lifting  a  weight,  or  moving  a  joint, 
depending  on  whether  or  not  the  tension  developed  is  great  enough  to 
overcome  the  opposition. 

The  elastic  properties  of  skeletal  muscle  may  be  modified  in  two  dis- 
tinct ways  which  differ  in  respect  to  the  energy  required  for  the  processes 
which  cause  the  muscle  to  tend  to  shorten.  A  tonic  contraction  is  one  in 
which  the  processes  which  cause  the  muscle  to  change  its  elastic  con- 
dition so  as  to  take  on  a  shorter  length  when  at  a  given  tension  (or 
to  exert  a  greater  tension  at  a  given  length)  are  maintained  with  great 

904 


MUSCULAR   CONTRACTION  905 

economy.  A  tetanic  contraction,  or  tetanus,  is  one  in  which  the  new  elas- 
tic condition  is  maintained  by  processes  which  require  a  considerable 
expenditure  of  energy.  The  properties  of  these  two  forms  of  contraction 
will  now  be  considered  in  some  detail,  together  with  the  uses  to  which 
they  are  put  by  the  organism. 

The  Tonic  Contraction  of  Skeletal  Muscle 

The  skeletal  muscles  of  the  body  are  normally  maintained  in  a  state 
of  slight  tension  even  when  at  rest.  This  condition,  to  which  the  word 
tone  or  tonus  is  applied,  is  due  to  the  action  upon  the  muscle  of  nerve 
impulses  which  come  to  it  over  reflex  arcs  which  we  will  describe  in  the 
next  chapter.  When  these  reflex  arcs  are  interrupted  the  muscles  loose 
their  tone,  that  is,  their  elastic  properties  change  and  they  can  now 
extend  from  origin  to  insertion  without  developing  any  tension.  Limbs 
in  which  the  muscles  have  lost  their  tone  become  " loose  jointed"  and 
readily  assume  under  the  influence  of  gravity,  a  variety  of  postures 
which  a  normal  limb  would  not  exhibit.  Consequently  it  is  easy  to  dis- 
tinguish between  death  and  sleep  by  the  postures  of  the  limbs,  since  the 
tone  of  the  sleeper's  muscles  is  retained.  Tonic  contraction  is  thus  seen 
to  be  connected  with  the  maintenance  of  posture  in  the  limbs.  The  posi- 
tion of  the  body,  and  particularly  of  the  limbs  is  constantly  changing, 
and  with  each  change  the  muscles  assume  new  lengths,  maintaining 
meanwhile  the  same  tension  which  they  exerted  before.  To  do  this  a 
new  elastic  state  must  be  set  up  in  the  muscle  so  that  the  muscle  can 
exist  at  its  new  length  without  exerting  a  greater  tension  on  its  inser- 
tion. The  tone  of  the  muscles  consequently  may  be  changed  to  fit  the 
new  position  of  the  joint  and  to  maintain  this  new  posture.  It  is  conse- 
quently called  plastic  tonus.  (Sherrington27).  Since  the  greatest  ten- 
sion must  be  exerted  by  those  muscles  which  support  the  weight  of  our 
limbs,  or  the  weight  of  the  body  which  falls  on  the  limb,  these  muscles 
have  developed  the  greatest  powers  of  tonic  contraction.  Consequently 
they  become  affected  most  in  conditions  which  tend  to  increase  the  tone 
of  the  muscles. 

Tonic  contraction,  as  contrasted  with  tetanus,  is  characterized  by  the 
economy  with  which  the  elastic  state  of  the  muscle  is  maintained.  Roaf 
was  unable  to  detect  any  difference  in  the  respiratory  exchange  of  cats 
during  the  highly  developed  tone  of  decerebrate  rigidity  when  com- 
pared with  the  same  animals  in  which  all  muscular  contraction  was  abol- 
ished with  curare.  Evans  has  found  that  the  metabolism  was  less  after 
curare,  but  the  gaseous  exchange  was  clearly  much  less  in  the  state  of  tone 
than  if  the  muscles  had  been  thrown  into  tetanic  activity.  Bayliss  also 
found  a  slight  heat  production  in  muscles  in  decerebrate  rigidity,  which 
varied  with  the  degree  of  tonic  contraction,  but  very  much  less  than 


906  CENTRAL    NERVOUS    SYSTEM 

would  have  been  produced  by  a  tetanic  contraction  of  the  same  height. 
Since  the  metabolic  changes  underlying  tonic  contraction  are  not  great, 
it  is  not  surprising  that  tension  can  be  maintained  by  this  form  of  con- 
traction for  long  periods  without  fatigue. 

It  is  a  peculiar  fact  that  although  tonus  is  maintained  in  skeletal 
muscle  only  by  means  of  a  reflex  arc,  it  is  impossible  to  produce  it  by 
any  known  form  of  artificial  stimulation  applied  to  either  the  efferent 
or  afferent  nerve  trunks.  Under  the  normal  reflex  control  the  tonic  re- 
action may  involve  either  a  shortening  or  a  lengthening  to  a  new  state 
of  tone,  in  which  the  tension  remains  the  same. 

In  the  tonic  contraction  of  skeletal  muscle  only  a  comparatively  low 
degree  of  tension  can  be  maintained.  Consequently  it  does  not  require 
much  force  to  move  a  joint  out  of  the  posture  in  which  it  is  held  by 
the  tone  of  its  muscles.  In  certain  muscles  the  tension  exerted  by  the 
tonic  contraction  is  not  inconsiderable,  however.  In  the  tonic  rigidity 
which  certain  muscles  assume  after  the  cerebrum  is  removed  the  ex- 
tensors of  the  limbs  may  exert  a  tension  well  in  excess  of  that  required 
to  support  the  weight  of  the  animal.  In  order  to  exert  the  maximum 
tension,  however,  muscles  must  resort  to  the  tetanic  mode  of  contraction. 

Tetanic  Contraction  of  Skeletal  Muscle 

When  a  skeletal  muscle  is  stimulated  directly,  or  through  its  nerve 
with  a  single  shock  from  an  induction  coil,  it  gives  a  momentary  con- 
traction or  twitch.  On  page  178  it  was  explained  that  if  a  series  of 
stimuli  are  applied  to  a  muscle  the  resulting  twitches  may  follow  one 
another  so  rapidly  that  the  muscle  does  not  relax  between  them,  and 
a  maintained  or  continuous  contraction  results  to  which  the  name  teta- 
nus is  applied.  That  tetanus  is  really  a  series  of  discrete  contractions 
is  shown  by  the  nature  of  the  electrical  changes,  or  action  currents  set 
up  by  a  muscle  contracting  in  this  way,  for  it  is  found  that  each  part 
of  the  muscle  becomes  alternately  positive  and  negative  as  each  twitch 
is  set  up  in  it  (see  page  188).  It  is  extremely  unlikely  that  the  volun- 
tary and  reflex  contractions  of  our  muscles  ever  consist  of  single  twitches, 
since  a  nervous  discharge  must  usually  consist  of  a  series  of  impulses, 
in  order  that  summation  may  occur  and  the  resistance  of  the  synapses 
be  overcome.  Whenever  our  movements  are  not  due  merely  to  changes 
in  muscular  tone,  they  are  tetanic  in  nature. 

The  action  currents  produced  by  the  voluntary  contraction  of  skel- 
etal muscle  enable  us  to  discover  the  rate  at  which  component  twitches 
of  the  tetanic  contraction  occur,  which  is  about  50  per  second  (Fig.  223). 
This  rate  is  determined  by  the  fact  that  immediately  after  one  contractile 
process  has  occurred  a  second  cannot  take  place  until  a  brief  time,  known  as 
the  refractory  period,  has  elapsed.  In  the  case  of  skeletal  muscle  one  fif- 


MUSCULAR    CONTRACTION 


907 


tieth  of  a  second  is  required  after  one  twitch  has  been  initiated  before 
the  tissue  has  recovered  sufficiently  to  respond  to  a  second  nerve  impulse. 
Forbes  and  Rappleye22  have  shown  that  the  rhythm  is  not  due  to  the 
rate  of  discharge  of  nerve  impulses  from  the  higher  centers,  by  demonstrat- 
ing that  the  rate  of  the  oscillations  of  the  electromyo  graph  is  slowed  by 
chilling  the  muscles  of  the  arm  in  ice  water.  Since  this  procedure  does 


f   I  f  If 


Fig.    223.  —  Electromyogram    of    the    voluntary    contraction    of    the    flexor    muscles    of    the    forearm. 

(From  Forbes  and  Rappleye.) 

not  alter  the  body  temperature  as  a  whole,  it  cannot  be  supposed  that  the 
temperature  of  the  centers  in  the  nervous  system  are  changed,  or  that 
the  diminished  rate  of  the  rhythm  is  due  to  any  change  .in  the  rate  of 
discharge  of  nerve  impulses  from  these  centers.  They  give  evidence 
to  show,  moreover,  that  the  rate  at  which  nerve  impulses  follow  one  an- 


Fig.  224. — The  contraction  of  a  single  fiber  of  the  sartorius  muscle  of  the  frog.  The  appearance 
before  stimulation  is  shown  at  the  left;  during  stimulation  at  the  right.  Note  the  tense  appearance 
of  the  muscle  fiber  (X) ,  the  slight  pull  on  the  deep  blood  vessel  (I7),  and  the  change  in  the  relative 
position  of  the  surface  capillaries  which  are  indicated  by  the  heavy,  wavy  lines.  (From  Fyisenberger.) 

other  down  the  motor  nerves  is  much  faster  than  50  per  second.  Many 
nerve  impulses  must  reach  the  muscle  while  it  is  still  refractory  and  con- 
sequently do  not  take  effect  upon  it. 

Since  tetanic  contractions  are  composed  of  a  series  of  twitches  it  is 
instructive  to  study  the  conditions  which  produce  and  modify  this  form 
of  contraction  in  skeletal  muscle.  These  muscles  are  composed  of  large 
numbers  of  fibers,  each  one  of  which  may  contract  quite  independently 


908  CENTRAL  NERVOUS  SYSTEM 

of  any  of  the  others.  This  may  be  shown  by  applying  an  electric  stimu- 
lus to  a  single  fiber,  by  means  of  the  very  delicate  technic  devised  by 
Pratt,23  when  it  will  be  observed  that  this  fiber  alone  responds  to  the 
excitation  (Fig.  224).  The  fibers  of  the  muscle  are  insulated  from  one 
another  in  such  a  way  that  the  disturbance  set  up  by  the  stimulus  in 
one  of  them  does  not  spread  to  any  other.  In  this  respect  skeletal  mus- 
cle differs  markedly  from  cardiac  muscle  (see  page  177).  The  unit  of 
function  in  skeletal  muscle  is  consequently  the  twitch  of  the  individual 
fiber. 

The  All-or-none  Law. — The  question  obviously  arises  how  the  strength 
of  contraction  of  the  fiber  is  affected  by  the  strength  of  the  stimulus  ap- 
plied to  it.  As  soon  as  it  was  realized  that  a  single  nerve  impulse  did 
not  vary  in  strength,  except  under  conditions  which  affected  the  con- 
ducting power  of  the  nerve  fiber,  it  was  difficult  to  imagine  how  the 
nerve  impulse  could  be  made  to  alter  the  degree  of  contraction  of  the 
muscle  fiber  which  it  excited.  It  was  consequently  suspected  that  the 
all-or-none  law  applied  to  the  activity  of  the  individual  fiber  of  skeletal 
muscle  just  as  it  does  to  heart  muscle  as  a  whole.  The  final  direct  proof 
of  this  view  is  supplied  by  the  experiments  of  Pratt  and  Eisenberger 
who  showed  that  when  a  single  muscle  fiber  is  excited  its  response  is 
maximal  if  it  responds  at  all.  This  fact  is  shown  in  Fig.  225,  in  which 
the  movement  of  a  droplet  of  mercury  placed  on  the  contracting  fiber 
has  been  photographed.  On  increasing  the  strength  of  the  stimulus 
no  change  occurs  in  the  amount  of  contraction  until  the  current  strength 
becomes  strong  enough  to  affect  an  adjoining  fiber.  At  this  point  the 
amount  of  movement  increases  by  a  definite  step,  and  then  continues 
at  the  new  level  until  a  third  fiber  is  brought  into  action  and  another 
step-like  rise  in  the  record  occurs.  As  the  strength  of  stimulus  is  de- 
creased again  the  contractions  fall  off  through  the  same  series  of  steps. 
It  is  consequently  believed  that  if  a  skeletal  muscle  fiber  contracts  at 
all,  it  does  so  to  the  full  extent  to  which  it  is  capable.  Graded  series  of 
muscular  contractions  in  response  to  graded  strengths  of  stimuli,  such 
as  are  shown  in  Fig.  45,  are  due  to  the  fact  that  as  the  stimulus  is  in- 
creased in  strength  more  and  more  fibers,  each  contracting  maximally, 
are  brought  into  play  until  finally  all  are  excited  and  the  contraction 
of  the  muscle  as  a  whole  becomes  maximal  and  cannot  be  further  in- 
creased. The  adjustment  of  the  strength  and  degree  of  muscular  move- 
ment consequently  depends  on  bringing  into  action  the  proper  num- 
ber of  muscle  fibers.  If  the  fibers  were  not  insulated  from  one  another, 
so  that  one  could  contract  without  the  others  joining  in,  graded  muscular 
movements  would  be  impossible  and  our  skeletal  muscles  as  a  whole 
would  act  in  an  all  or  none  way  just  as  the  heart  does. 

Although  the  skeletal  muscle  fiber  contracts  to  the  utmost  if  it  con- 


MUSCULAR    CONTRACTION  909 

tracts  at  all  it  must  not  be  supposed  that  under  all  circumstances  the 
maximal  contraction  is  of  the  same  magnitude.  The  ability  of  the  fiber  to 
develop  tension  varies  from  time  to  time  and  may  be  shown  to  depend 
on  a  variety  of  factors.  The  energy  set  free  in  the  contractile  process 
is  greater,  the  longer  the  muscle  at  the  time  when  it  begins  to  contract. 
This  is  shown  by  the  fact  that  a  muscle  which  is  stretched  at  the  moment 
when  it  begins  to  contract  is  able  to  develop  a  greater  final  tension 
than  an  unstretched  muscle.  The  heat  liberated  in  the  act  of  contraction, 
which  measures  the  total  energy  set  free,  increases  in  a  similar  manner 
with  the  initial  length  of  the  muscle.  This  observation  is  of  importance 


Fig.  225. — The  all  or  none  nature  of  the  contraction  of  a  single  fiber  of  skeletal  muscle.  The 
lower  line  represents  the  strength  of  the  stimulus  applied  to  the  muscle,  which  rises  to  a  maximum, 
and  then  is  reduced  to  its  initial  level.  The  upper  record  is  of  the  movement  of  a  drop  of  mercury 
resting  on  the  contracting  fiber.  The  amount  of  contraction  does  not  change  as  the  stimulus  is  in- 
creased until  the  point  A  is  reached,  when  a  second  fiber  became  excited  causing  a  pronounced, 
step-like  increase  in  the  record.  Later  a  fiber  responded  and  produced  another  step.  The  same  steps 
are  observed  as  the  stimulus  strength  is  gradually  decreased.  (From  Pratt  and  Kisenberger.) 

because  it  shows  that  the  strength  of  the  contraction  is  dependent  upon 
the  surface  area  of  the  contractile  elements  in  the  muscle  fiber,  which 
naturally  becomes  increased  as  the  muscle  is  elongated,  and  not  on  the 
volume  of  muscle  substance,  which  is  unchanged  by  stretching.  We  have 
seen  on  page  217  the  importance  of  this  principle  in  enabling  the  heart 
to  compensate  for  an  increased  load  by  dilating. 

The  previous  history  of  the  muscle  fibers  also  has  a  great  influence 
upon  the  magnitude  of  the  contractions  of  which  each  fiber  is  capable. 
We  have  seen  on  page  178  that  if  a  muscle  is  excited  to  a  maximal 


910  CENTRAL  NERVOUS  SYSTEM 

contraction  several  times  in  rapid  succession  each  twitch  is  somewhat 
higher  than  its  predecessor.  This  phenomenon  is  known  as  treppe  and 
is  explained  by  the  fact  that  chemical  changes  arising  from  one  con- 
traction make  the  muscle  better  able  to  contract  the  next  time.  If 
the  successive  stimuli  are  continued  for  some  time  the  height  of  the 
contractions  soon  reaches  a  maximum  and  then  begins  to  fall  off  as  the 
muscle  becomes  fatigued.  Fatigue  is  due,  in  part  at  least,  to  the  fact 
that  after  prolonged  activity  each  fiber  in  the  muscle  is  able  to  develop 
less  tension  when  it  contracts. 

The  Chemistry  of  Tetanic  Contraction. — In  order  to  understand  the 
nature  of  fatigue,  the  chemical  changes  which  occur  during  the  activity 
of  muscle  must  be  considered.  When  a  muscle  is  excited,  energy  is  lib- 
erated which  sets  up  a  state  of  tension.  The  tension  may  result  in  doing 
external  work,  as  in  lifting  a  weight,  or  it  may  dissipate  its  energy 
as  heat  if  the  muscle  is  not  allowed  to  shorten.  In  either  case  a  supply 
of  potential  energy  stored  in  the  muscle  has  been  drawn  upon.  It  has 
been  shown  by  Roaf  that  the  hydrogen-ion  concentration  of  muscle 
substance  becomes  increased  at  the  moment  of  contraction,  and  chemical 
analysis  shows  that  lactic  acid  appears  in  muscle  as  the  result  of  pro- 
longed excitation.  It  is  consequently  believed  that  the  liberation  of 
lactic  acid  in  the  muscle  substance  is  connected  with  setting  free  the 
energy  for  contraction. 

In  the  process  of  recovery  which  follows  the  activity  of  muscle  when 
it  is  allowed  to  rest,  it  is  found  that  the  lactic  acid  disappears  provided 
a  supply  of  oxygen  is  available.  Since  at  the  same  time  carbon  dioxide 
is  set  free  from  the  muscle,  one  might  suspect  that  the  disappearance 
of  the  lactic  acid  is  due  to  its  being  oxidized  to  carbon  dioxide  and  water. 
This,  however,  cannot  be  the  case,  for  it  is  known  that  after  the  repeated 
fatigue  and  recovery  of  an  isolated  muscle  the  total  quantity  of  lactic 
acid  which  may  be  extracted  from  it  is  undiminished.  In  other  words 
lactic  acid  does  not  disappear  from  the  muscle  during  rest,  but  is  re- 
stored to  the  condition  in  which  it  occurred  before  contraction  took 
place.  Further  evidence  that  lactic  acid  is  not  oxidized  is  afforded  by  the 
fact  that  the  disappearance  of  1  gram  of  lactic  acid  from  fatigued  mus- 
cle is  accompanied  by  the  production  of  450  calories  of  heat,  whereas 
the  oxidation  of  1  gram  of  lactic  acid  would  set  free  3700  calories. 
Apparently  the  oxidation  of  some  other  substance  is  necessary  in  order 
to  restore  lactic  acid  to  the  percursor  condition,  and  to  replace  the  po- 
tential energy  lost  in  the  contractile  process,  and  in  the  course  of  the  oxi- 
dation of  this  substance — carbon  dioxide  is  liberated  and  heat  is  given 
off.  The  nature  of  the  substance  oxidized  is  not  definitely  known,  but 
it  is  presumed  from  the  high  respiratory  quotient  of  muscular  work  that 
it  is  chiefly  carbohydrate.  (Bayliss,24  Fletcher  and  Hopkins.25) 


MUSCULAR    CONTRACTION  911 

Treppe  and  Fatigue. — Applying  these  facts  to  the  phenomenon  of 
treppe  and  fatigue,  we  see  that  the  continued  use  of  a  muscle  will  be 
attended  with  an  increase  in  the  hydrogen-ion  concentration  as  the  re- 
sult of  the  liberation  of  lactic  acid  in  the  muscle  substance.  For  all  tis- 
sues there  is  an  optimal  concentration  of  hydrogen-ions  at  which  their 
activities  are  carried  out  to  the  best  advantage.  The  initial  change  in  the 
hydrogen-ion  concentration  which  accompanies  the  first  few  contractions 
brings  the  muscle  into  a  more  favorable  condition  and  treppe  results. 
On  further  production  of  lactic  acid  the  optimal  condition  is  exceeded 
and  the  muscle  fibers  become  successively  less  and  less  able  to  perform  their 
work.  If  the  muscle  is  supplied  with  an  adequate  circulation  a  point  is 
soon  reached  at  which  the  excess  of  lactic  acid  is  restored  to  the  precursor 
condition  as  fast  as  it  is  formed,  by  virtue  of  the  oxygen  supplied  by  the 
blood,  and  beyond  this  point  fatigue  does  not  proceed  further,  successive 
contractions  following  one  another  for  a  long  time  with  undiminished  force. 
The  muscle  is  then  said  to  have  reached  a  fatigue  level  in  which  the  con- 
structive processes  during  the  rest  between  contractions  just  balance  the 
destructive  processes  during  activity.  If  the  circulation  is  inadequate,  or 
lacking,  as  it  is  in  an  isolated  nerve  muscle  preparation,  the  increase  in 
the  hydrogen-ion  concentration  goes  on  as  the  result  of  the  accumula- 
tion of  lactic  acid  until  the  contraction  of  the  muscle  becomes  impossible. 

The  fatigue  of  muscle  is  consequently  due  to  the  accumulation  of  lac- 
tic acid  and  probably  other  waste  products  in  the  muscle  substance, 
and  in  protracted  exertion  to  the  using  up  of  the  materials  which  upon 
oxidation  restore  the  energy  lost  in  the  act  of  contraction  and  replace 
the  lactic  acid  in  the  condition  in  which  it  existed  in  the  rested  muscle. 

Under  normal  circumstances  skeletal  muscle  is  protected  from  the 
development  of  any  harmful  degree  of  fatigue.  This  is  because  its  ac- 
tivity is  initiated  through  the  nervous  system,  parts  of  which  become 
fatigued  long  before  this  condition  comes  on  in  the  muscles.  We  have 
already  seen  that  the  nerve  fiber  is  unfatigable.  The  synapses,  on 
the  other  hand,  and  the  myoneural  junction  are  easily  fatigued  and 
cease  to  conduct  excitations  to  the  muscles  long  before  the  muscle  it- 
self becomes  too  fatigued  to  respond  to  direct  stimulation.  A  further 
protection  against  fatigue  in  protracted  muscular  activity  is  afforded 
by  the  fact  that  the  threshold  of  excitation  of  the  individual  muscle 
fibers  is  raised  by  repeated  stimulation.  It  is  quite  possible  that  as 
the  result  of  this  tendency  each  fiber  may  fail  to  respond  to  the  nerve 
impulses  reaching  it  as  soon  as  it  becomes  fatigued,  and  consequently 
it  has  an  opportunity  to  rest,  while  other  fibers  in  the  muscle  carry  on 
the  work  in  hand.  The  falling  off  in  the  height  of  the  successive  con- 
tractions of  a  muscle  which  is  being  fatigued  is  probably  due  not  only  to 
the  reduction  of  the  degree  of  contraction  of  which  each  fiber  is  capable, 


912  CENTRAL  NERVOUS  SYSTEM 

but  also  to  the  cessation  of  activity  on  the  part  of  many  fibers  as  their 
thresholds  rise  above  the  level  of  the  exciting  stimulus. 

Smooth  Muscle 

The  smooth  muscles  of  the  mammalian  body  differ  markedly  in  their 
histological  appearance  from  the  skeletal  muscles.  Their  origin  in  de- 
velopment is  also  different  as  they  arise  from  the  mesenchyme,  and  not 
from  the  mesodermic  somites  as  the  skeletal  muscles  do.  It  is  not  sur- 
prising consequently  to  find  that  the  properties  of  smooth  muscle  differ 
markedly  from  those  of  the  skeletal  muscles. 

The  contraction  of  smooth  muscle  is  sluggish  and  never  develops  very 
great  tension.  In  this  respect  it  resembles  closely  the  tonic  contraction 
of  skeletal  muscle,  as  contrasted  with  the  tetanic  contraction.  The  most 
outstanding  feature  is  the  ability  of  this  tissue  to  alter  its  tonic  condi- 
tion so  that  it  may  exist  now  at  one  length,  now  at  another,  under  equal 
degrees  of  tension.  This  is  seen  to  be  a  most  important  property  when 
it  is  considered  that  smooth  muscle  forms  the  walls  of  the  various  hollow 
viscera  and  that  these  organs  must  constantly  alter  their  capacity  to 
fit  the  varying  volume  of  their  contents.  In  the  stomach  and  urinary 
bladder,  especially,  the  muscular  walls  must  be  capable  of  relaxing  as 
the  organ  becomes  filled,  so  that  the  tension  exerted  on  the  contents 
may  not  increase  unduly.  The  pressure  in  the  urinary  bladder  is  much 
the  same  whether  its  contents  be  50  or  150  c.c.  of  urine.  Similarly  after 
injecting  400  c.c.  of  water  into  the  stomach  of  a  dog  the  pressure  within  it 
returns  almost  immediately  to  its  original  level  through  a  change  in  the 
condition  of  the  gastric  musculature.  The  conditions  in  the  blood  vessels 
differ  only  in  degree,  for  here  the  smooth  muscles  adjust  their  tone  to 
the  requirements  of  maintaining  a  uniform  pressure  of  the  blood,  and 
differ  from  the  smooth  muscles  of  the  abdominal  viscera  only  in  the 
relatively  high  degree  of  tension  which  they  can  maintain. 

Like  the  tonic  contraction  of  the  skeletal  muscles,  the  contraction  of 
smooth  muscles  is  maintained  with  very  little  expenditure  of  energy  and 
consequently  without  fatigue.  The  sphincters  of  the  gastrointestinal  tract 
and  bladder  remain  closed  almost  continuously  and  the  muscles  of  the 
arterioles  support  the  relatively  great  pressure  of  the  blood  unremit- 
tingly and  without  becoming  exhausted  in  the  least.  The  smooth  mus- 
cles which  hold  the  shells  of  the  mollusca  closed  can  support  great  weights. 
The  muscle  of  the  fresh  water  clam,  Anadonta,  can  support  a  weight  of  3 
kilos  for  three  hours  without  consuming  any  oxygen  in  excess  of  its  re- 
quirements when  at  rest.  The  economy  of  this  is  seen  when  it  is  considered 
that  the  gastrocnemius  of  the  cat  consumes  when  supporting  a  similar  load 
by  tetanic  contraction  4500  times  as  much  oxygen  as  does  the  Anadonta 
muscle. 


MUSCULAR   CONTRACTION  913 

Like  the  heart,  smooth  muscle  is  capable  of  setting  up  automatic  con- 
tractions of  a  rhythmic  nature  even  when  removed  from  the  body.  This 
automatic  rhythmicity  is  probably  a  fundamental  property  of  the  smooth 
muscle  cells,  just  as  it  is  of  heart  muscle,  for  it  has  been  shown  by  Gunn 
and  Underbill26  in  the  case  of  intestinal  muscle  that  it  continues  after 
the  nerve  plexus  which  lies  between  the  layers  of  muscle  has  been  removed. 
It  is  also  to  be  seen  in  isolated  smooth  muscle  cells  grown  in  tissue  cultures 
in  which  nervous  elements  can  be  observed  to  be  absent. 


CHAPTER  XCVIII 

POSTURAL  COORDINATION 

The  maintenance  of  posture  is  accomplished  by  the  tonic  contraction 
of  the  skeletal  muscles.  Not  only  must  the  muscles  assume  a  new  tonic 
state  in  each  new  position  of  the  body,  but  the  tone  of  the  muscles  must 
alter  rapidly  and  in  harmony  with  voluntary  and  reflex  contractions 
of  a  tetanic  nature.  Each  voluntary  act  must  also  be  made  with  reference 
to  the  preexisting  posture  of  the  parts  involved.  The  smooth  continuity 
of  the  normal  movements  of  the  body  is  dependent  on  the  mechanism 
which  correlates  postural  with  voluntary  and  reflex  tetanic  contraction, 
and  disturbances  in  this  mechanism  give  rise  to  incoordinated  movement, 
ataxia,  and  the  abnormal  states  of  contraction  seen  in  the  muscles  of 
sufferers  from  nervous  disease. 

The  Reflex  Adjustment  of  Tone. — The  tonic  contraction  of  skeletal 
muscle  is  maintained  only  in  the  presence  of  a  reflex  arc.  The  afferent 
neuron  of  this  arc  arises  from  the  muscle  itself.  This  is  shown  by  the  fact 
that  after  cutting  all  the  nerve  trunks  to  neighboring  muscles  and  the 
skin  the  tone  of  the  muscle  persists,  but  it  disappears  at  once  on  sever- 
ing the  dorsal  root  through  which  the  afferent  fibers  from  the  muscle 
pass.  The  receptors  of  the  afferent  neuron  which  lie  in  the  muscle 
substance  are  called  proprioceptors,  and  the  reflexes  which  they  ini- 
tiate proprioceptive  reflexes.  The  efferent  path  of  the  arc  is  completed 
by  the  motor  neurons  of  the  muscle.  In  the  presence  of  this  arc  tone 
is  not  only  maintained,  but  plastic  changes  in  tone  may  be  induced  by 
impulses  traveling  over  it. 

Two  types  of  reaction  are  recognized  which  bring  about  changes  in 
the  postural  tone  of  skeletal  muscle.  If  the  knee  of  a  spinal  or  decere- 
brate  mammal  is  flexed  by  pushing  the  foot  with  the  hand,  the  resistance 
which  the  tone  of  the  extensors  opposes  to  the  movement  may  be  felt  to 
give  way,  almost  suddenly,  as  the  joint  moves  into  its  new  position. 
On  releasing  the  limb,  it  will  now  remain  in  the  flexed  condition  as  the 
result  of  a  reflex  change  in  the  tone  of  its  muscles.  The  explanation 
of  this  is  that  stretching  the  extensor  muscle  has  stimulated  its  proprio- 
ceptors and  set  up  a  reflex  which  causes  a  lengthening  reaction  of  the  mus- 
cle. If  the  knee  is  now  forced  into  an  extended  position  a  similar  phenome- 
non occurs  and  the  tone  of  the  muscles  adjusts  itself  to  the  extended  posi- 
tion. The  proprioceptors  of  the  extensors  have  in  this  case  been  excited  by  a 
decrease  in  the  tension  of  these  muscles  and  have  given  rise  to  a  short- 

914 


POSTURAL    COORDINATION  915 

ening  reaction.  By  this  mechanism  the  tension  which  muscles  exert  on 
their  insertions  is  kept  approximately  constant,  in  spite  of  the  changes 
in  their  length  which  are  occasioned  by  alterations  in  the  position  of 
the  body  (Sherrington27). 

The  plastic  tone  of  a  skeletal  muscle  is  effected  not  only  by  afferent 
impulses  arising  in  its  own  proprioceptors,  but  by  impulses  arising  from 
other  muscles  as  well.  When  the  lengthening  reaction  of  the  extensors  of 
one  limb  is  produced,  a  shortening  reaction  occurs  in  the  extensors  of  the 
opposite  limb.  Conversely  the  stimulus  which  sets  up  a  shortening  re- 
action of  one  limb  causes  a  lengthening  reaction  of  the  opposite  exten- 
sors. The  crossed  lengthening  and  shortening  reactions  may  be  seen 
to  be  appropriate  to  the  normal  mode  of  using  the  two  legs,  for  under 
usual  circumstances  when  one  limb  is  flexed  the  opposite  leg  becomes 
extended  to  support  the  weight  of  the  body.  The  arrangement  is  conse- 
quently one  which  ensures  a  certain  degree  of  harmony  in  the  tonic  ad- 
justments of  muscles  of  parts  which  are  used  synchronously.  A  similar 
adjustment  of  the  tonic  condition  of  the  muscles  must  also  be  made 
when  the  position  of  the  body  is  changed  through  voluntary  or  reflex 
movement.  When  such  movements  are  produced  tone  changes  of  two 
types  occur:  (1)  The  tone  of  the  muscles  which  oppose  the  movement  is 
inhibited;  (2)  the  muscles  which  produce  the  movement  enter  into  a  tonic 
contraction  which  maintains  the  limb  in  the  new  position  after  the  ex- 
citation has  come  to  an  end. 

The  first  phenomenon  is  seen  when  the  leg  of  a  spinal  or  decere- 
brate  mammal  is  thrown  into  flexion  by  stimulating  a  sensory  nerve,  or 
the  pain  receptors  of  the  foot.  The  tone  of  the  extensors,  which  in 
the  decerebrate  cat  is  strong  enough  to  support  the  animals  weight, 
might  be  expected  to  offer  some  resistance  to  the  bending  of  the  joints. 
It  may  be  shown,  however,  that  at  the  moment  the  flexors  contract, 
the  tone  of  the  extensors  vanishes,  so  that  they  do  not  oppose  the  flexion. 
This  is  demonstrated  by  separating  the  flexor  muscles  from  their  insertion 
at  the  knee  and  attaching  them  to  a  weighted  lever,  by  which  changes 
in  their  length  may  be  recorded.  Since  they  are  freed  from  their 
insertion,  any  increase  in  their  length  cannot  be  due  to  stretching  by 
the  flexors,  but  must  be  due  to  a  loss  in  tone.  When  flexion  is  pro- 
duced, it  is  found  that  the  extensor  muscle  lengthens  and  the  lever  falls, 
in  synchrony  with  contraction  of  the  flexor  (Fig.  226).  This  is  an  exam- 
ple of  the  phenomenon  of  reciprocal  inhibition  of  antagonistic  muscles, 
which  ensures  their  cooperative  action. 

The  maintenance  of  the  new  position  of  a  limb  after  the  stimulus  which 
caused  the  change  has  subsided  is  called  the  after-discharge  of  the  re- 
flex. It  is  due  in  certain  cases  at  least  to  a  tonic  shortening  reaction 
which  is  set  up  during  the  response  to  a  stimulus — applied  to  receptors 


916 


CENTRAL  NERVOUS  SYSTEM 


Fig.  226. — Reciprocal  inhibition.  Tracings  made  by  myographs  connected  with  E,  and  ex- 
tensor muscle  (vastus  crureus),  and  F,  a  flexor  muscle  (semitendinosus),  of  a  decerebrate  cat. 
At  signal  /  the  homolateral  peroneal  nerve  was  excited,  causing  contraction  of  the  flexors  and  in- 
hibition of  the  tone  of  the  extensors.  At  signal  //  the  flexors  were  again  thrown  into  contraction  by 
exciting  the  homolateral  peroneal  nerve,  and  (without  removing  this  stimulus)  the  contralateral 
peroneal  nerve  was  excited  (as  shown  in  the  lower  signal),  with  the  result  that  the  contraction 
of  the  flexors  was  inhibited  at  the  same  time  that  the  extensors  contracted.  On  removal  of  the 
latter  stimulus,  the  former  one  reasserted  its  influence.  This  experiment  demonstrates  very  clearly 
the  accurate  coincidence  of  the  reciprocal  action.  (From  Sherrington.) 


POSTURAL    COORDINATION  917 

other  than  the  proprioceptors  of  the  muscles  (called  exteroceptors).  Fig. 
227  shows  how  greatly  the  reflex  contraction  of  the  extensors  of  the 
knee  of  the  cat  may  outlast  the  stimulus.  If  the  afferent  fibers  from 
this  muscle  are  destroyed  by  cutting  the  dorsal  roots  the  reflex  contrac- 
tion scarcely  outlasts  the  stimulus.  It  appears  that  the  reflex  contrac- 
tion is  accompanied  by  a  tonic  shortening  reaction  which  is  maintained 
after  the  exciting  stimulus  has  come  to  an  end.  Its  occurrence  is  de- 
pendent on  the  proprioceptive  reflex  arc  of  the  muscle,  so  that  if  this 
is  interrupted  the  contraction  of  the  muscle  cannot  be  maintained.  The 
reflex  response  fuses  with  the  proprioceptive  reaction  so  that  it  cannot 
be  said  where  one  ends  and  the  other  begins.  It  is  obvious  that  this  is 
a  mechanism  which  greatly  facilitates  the  "smoothness"  of  muscular 


Fig.  227. — Records  of  the  contraction  of  the  isolated  extensor  muscle  (vasto  crureus)  of  the  knee 
of  the  cat  produced  by  stimulating  the  popliteal  nerve  of  the  opposite  leg.  Periods  of  stimulation 
indicated  by  the  signal  below  the  record.  A,  illustrates  the  after-discharge  in  the  normal  muscle; 
B  the  absence  of  after-discharge  following  the  cutting  of  the  afferent  nerves  from  the  muscle. 
(From  bhemngton.) 

acts,  enabling  the  limbs  to  remain  in  the  position  assumed  under  the 
effects  of  certain  stimuli,  until  other  stimuli  cause  new  postures  to  ap- 
pear. 

The  Posture  of  the  Body  as  a  Whole,— When  the  position  of  the  body 
changes  as  the  result  of  voluntary  and  reflex  activity  the  tone  of  its 
entire  musculature  must  be  modified  so  that  each  part  may  make  a  har- 
monious contribution  to  the  act  as  a  whole.  Part  of  the  function  of  the 
central  nervous  system  is  consequently  to  correlate  the  simple  proprio- 
ceptive reflexes  such  as  we  have  described,  not  only  with  one  another,  but 
with  the  voluntary  and  reflex  acts  which  are  initiated  through  the  ex- 
teroceptors. The  afferent  impulses  which  give  rise  to  these  harmonious 
changes  in  the  posture  of  the  body  as  a  whole  arise  in  part  from  the  pro- 


918  CENTRAL  NERVOUS  SYSTEM 

prioceptors  of  the  muscles  and  tendons,  and  in  part  from  the  labyrinth. 
The  former  are  influenced  by  the  position  of  the  parts  of  the  body,  the 
latter  by  the  position  of  the  body  as  a  whole  in  space.  The  attitude  con- 
sequently depends  not  only  on  the  harmonious  adjustment  of  the  posture 
of  its  parts,  but  all  these  are  brought  into  relation  with  the  position 
of  the  body  in  space,  whether  right  side  up,  inverted,  etc.  The  in- 
teraction of  these  two  sets  of  proprioceptors  is  illustrated  by  ex- 
periments on  the  decerebrate  cat.  The  tone  of  the  extensors  of  such 
animals  is  sufficient  to  support  the  body's  weight.  If  the  head  of  the 
standing  animal  is  forcibly  flexed,  the  postural  contraction  of  the  ex- 
tensor muscles  of  the  fore  limbs  is  inhibited,  and  the  forequarters  sink, 
while  at  the  same  time  the  postural  contraction  of  the  extensor  muscles 
of  the  hind  limbs  increases,  raising  the  hind  quarters.  The  animal  as- 
sumes the  appropriate  attitude  for  looking  under  a  shelf.  On  the  other 
hand,  if  the  head  is  passively  tilted  up  and  back,  the  postural  contrac- 
tion of  the  extensor  muscles  of  the  fore  limbs  increases,  raising  the  fore 
quarters,  and  at  the  same  time  the  postural  contraction  of  the  extensors 
of  the  hind  limbs  is  diminished  so  that  the  hind  limbs  sink.  The  at- 
titude is  now  that  of  a  cat  looking  up  at  a  shelf.  These  reactions  per- 
sist after  the  labyrinths  have  been  destroyed  and  consequently  must 
be  due  to  proprioceptors  in  the  muscles  of  the  neck.  The  influence  Oi 
the  labyrinth  was  studied  by  rendering  the  neck  immobile  with  a  plas- 
ter cast,  or  by  cutting  the  afferent  roots  of  the  upper  cervicle  nerv.es. 
On  changing  the  position  of  the  head  the  same  adjustments  occurred 
in  the  position  of  the  limbs,  so  that  the  labyrinth  must  reinforce  the 
proprioceptors  of  the  neck  in  their  action.  In  addition  the  labyrinth 
affected  the  posture  of  the  neck  in  such  a  way  that  it  would,  had  its 
afferents  been  intact,  have  set  up  the  appropriate  change  in  the  limb 
posture.  It  has  long  been  known  that  destruction  of  the  labyrinth  causes 
very  abnormal  postures  to  be  assumed  and  these  can  be  attributed  to 
unusual  positions  set  up  in  the  neck  muscles.  In  case  of  destruction  of 
both  labyrinths  a  great  loss  in  tone  results.  If  the  organ  on  one  side 
only  is  destroyed,  tone  is  diminished  on  the  same  side,  with  the  re- 
sult that  the  trunk  is  curved  and  the  animal  tends  to  roll  over  and  over. 
Compensatory  Movements  of  the  Eyes.— The  position  of  the  eyes  is 
very  markedly  influenced  by  stimulation  set  up  in  the  labyrinth.  This  is 
of  obvious  importance,  since  as  our  bodies  move,  compensation  must  be 
made  by  the  eye  muscles  in  order  that  the  gaze  may  remain  fixed  on  any 
object.  This  relationship  is  nicely  demonstrated  in  the  dogfish  where 
the  labyrinth  is  large  and  easily  experimented  upon.  As  the  head  of  the  fish 
is  turned  from  side  to  side,  as  it  is  in  swimming,  the  eyes  move  so  as 
to  compensate  for  the  change  in  position.  When  the  head  turns  to  the 
left  the  left  eye  is  turned  forward,  the  right  eye  backward  so  as  to  re- 


POSTURAL    COORDINATION 


919 


tain  the  original  point  of  fixation.  On  rotating  the  head  to  one  side, 
the  eye  of  that  side  is  turned-  upward,  that  of  the  other  side  downward 
in  compensation.  Similar  movements  can  be  induced  by  stimulating  the 
sense  organs  in  the  semicircular  canals  directly.  Stimulation  of  the  hori- 


Fig.  228. — Compensatory  movements  of  the  eyes  and  fins  of  the  dogfish.  A  and  C  illustrate  the 
position  of  the  fish  when  at  rest.  B  shows  the  compensatory  movements  of  the  eye.5  which  occur 
during  swimming,  or  on  bending  the  tail  into  the  position  indicated.  D  illustrates  the  compensatory 
movements  which  occur  on  rotating  the  fish  about  its  horizontal  axis. 


Fig.    229. — The   semicircular   canals   of   the   ear,   showing  their   arrangement   in   the    three   planes    of 
space.      (From    Howell's   Physiology.) 

zontal  canal,  which  is  normally  excited  by  a  movement  in  its  plane,  i.  e., 
by  turning  the  head  to  one  side,  causes  the  eye  of  the  same  side  to  turn 
forward;  similarly  the  anterior  vertical  canal  causes  a  rotation  of  the 
eye  upward  and  forward,  the  posterior  vertical  canal  a  rotation  upward 
and  backward  (Lee28).  Appropriate  movements  of  the  fins  accompany 


920  CENTRAL  NERVOUS  SYSTEM 

these  reactions.  In  the  dogfish  the  positions  of  the  eyes  is  also  con- 
trolled by  the  proprioceptors  of  the  tail  muscles,  for  if  the  tail  is  bent 
from  side  to  side  compensating  movements  of  the  eye  are  produced  of 
the  same  nature  as  those  which  accompany  the  movements  of  the  tail 
in  swimming  (Lyon29).  Eye  movements  of  a  compensatory  character  are 
also  seen  in  man  during  rotation  of  the  body.  As  the  body  turns  the 
eyes  swing  slowly  in  the  opposite  direction  so  as  to  maintain  their  fixa- 
tion. Having  turned  as  far  as  possible,  they  swing  quickly  back  in  the 
opposite  direction  to  fix  a  new  object  which  in  turn  they  follow  by  a  slow 
deviation.  This  slow  deviation  alternating  with  a  rapid  movement  in 
the  opposite  direction  is  called  nystagmus.  It  also  occurs  during  the  sen- 
sation of  turning  which  persists  for  some  seconds  after  the  rotation  of  the 
body  has  come  to  an  end,  and  in  certain  pathological  conditions. 

Clinical  Tests  of  the  Labyrinthine  Mechanism. — The  influence  of  the 
labyrinth  on  the  postural  coordination  of  the  eye  and  limb  muscles,  forms 
the  basis  for  certain  useful  clinical  tests  by  which  the  condition  of  the 
labyrinth  and  of  its  central  connections  can  be  determined.  These  have 
been  developed  chiefly  by  Barany.  In  normal  individuals  when  the  semi- 
circular canals  are  stimulated  in  addition  to  the  turning  sensation  and 
nystagmus,  a  phenomenon  known  as  past  pointing  occurs.  If  the  sub- 
ject is  directed  to  close  his  eyes,  extend  his  arm,  raise  and  then  lower 
it  in  a  vertical  plane  he  will  have  no  difficulty  in  bringing  it  back  to  its 
original  point.  If  he  attempts  to  do  this  while  the  labyrinth  is  being 
stimulated  he  will,  if  normal,  return  the  arm  to  a  position  which  de- 
viates from  the  original  point  in  the  direction  from  which  he  thinks  he 
is  turning,  i.  e.,  in  the  rotation  test  in  the  direction  toward  which  he  has 
been  spun. 

The  methods  used  to  excite  the  canals  are  called  the  rotation  test  and 
the  caloric  test.  The  rotation  test  is  performed  by  spinning  the  subject 
about  two  or  three  times  in  a  pivoted  chair,  with  the  head  held  so  that 
the  pair  of  canals  to  be  tested  lie  in  the  plane  of  rotation.  The  caloric 
test  depends  on  the  fact  that  if  warm  (112°  F.)  or  cold  (68°  F.)  water 
is  poured  into  the  external  auditory  canal  it  will  set  up  convection  cur- 
rents in  that  semicircular  canal  which  lies  in  a  vertical  position,  and 
there  give  rise  to  excitation.  By  holding  the  head  in  various  positions 
any  one  of  the  three  canals  can  be  stimulated.  The  caloric  test  has 
the  obvious  advantage  that  it  excites  the  canals  of  one  labyrinth  only. 
If  labyrinthine  stimulation  by  these  methods  does  not  produce  after 
turning  sensations,  nystagmus,  or  past-pointing  it  is  concluded  that  a 
lesion  occurs  in  the  sense  organ  or  some  part  of  the  nervous  system  in- 
volved in  the  reaction.  The  past-pointing  test  is  particularly  useful, 
since  it  can  be  applied  to  any  joint  and  in  any  plane,  and  consequently 
it  has  been  possible  to  study  the  localization  of  the  centers  in  the  cere- 


POSTURAI;    COORDINATION  921 

bellum  which  are  concerned  with  the  postural  tone  of  each  of  these  parts. 
(Black.30) 

Other  Clinical  Tests  of  the  Proprioceptive  Reflex  Mechanism. — Certain 
phenomena  may  be  considered  at  this  point  which  form  the  basis  for 
practical  tests  of  the  integrity  of  the  mechanism  by  which  posture  and 
tone  is  maintained.  The  posture  of  the  body  is  adapted  to  the  position 
which  it  occupies  in  space,  i.  e.,  equilibrium  is  maintained,  not  only  by 
virtue  of  afferent  impulses  arising  from  the  semicircular  canals,  but 
as  the  result  of  visual  sensations  and  of  information  supplied  to  the 
central  nervous  system  by  the  receptors  of  deep  sensibility  in  the  limbs. 
Loss  of  function  in  any  of  these  three  groups  of  sense  organs  may  be  com- 
pensated by  the  other  two.  As  a  result  sufferers  from  a  destruction  of 
the  deep  sensibility  of  the  legs  have  little  difficulty  in  maintaining,  an 
upright  position,  so  long  as  they  are  aided  by  the  use  of  their  eyes. 
In  the  dark,  however,  their  balance  is  kept  with  great  difficulty.  It  is 
consequently  possible  to  test  the  integrity  of  the  afferent  paths  from 
the  limbs  involved  in  the  maintenance  of  equilibrium  by  noting  the 
ability  of  the  subject  to  stand  with  the  feet  close  together  and  the 
eyes  shut.  Under  these  circumstances  a  normal  person  will  stand  quite 
steadily,  but  a  sufferer  from  locomotor  ataxia,  in  whom  the  afferent 
neurons  from  the  limbs  are  diseased,  will  sway  violently  and  tend  to 
fall.  This  test  is  known  as  Romberg's  sign. 

The  tendon  jerks  are  a  group  of  reactions  which  result  from  tapping 
the  tendons  of  the  muscles  of  the  knee,  ankle,  elbow  and  wrist.  The 
contraction  of  the  muscle  which  results  is  not  solely  one  of  postural  tone, 
but  it  depends  for  its  elicitation  on  the  integrity  of  the  reflex  arc  between 
the  proprioceptors  of  the  tendon  and  the  muscle.  It  may  consequently 
be  used  as  a  test  for  the  condition  of  the  afferent  neurons  from  the  deep 
structures  in  the  limbs  and  for  the  condition  of  the  lower  motor  neurons 
to  the  muscles,  i.  e.,  for  the  integrity  of  reflex  arcs  quite  similar  to 
those  involved  in  the  maintenance  and  adjustment  of  tone.  When  a 
lesion  affects  either  the  afferent  neuron,  as  in  locomotor  ataxia,  or  the 
lower  motor  neuron,  as  in  anterior  poliomyelitis,  the  tendon  jerks  and 
tone  alike  are  wanting.  The  character  of  the  tendon  jerks  is  also  pro- 
foundly modified  by  conditions  in  the  central  nervous  system  which  affect 
the  tone  of  the  muscles.  In  the  normal  individual  when  the  patellar  ten- 
don is  tapped,  the  response  of  the  extensor  muscles  is  prolonged  by  a 
tonic  contraction  which  gives  way  slowly  as  the  flexors  draw  the  leg  back 
into  its  original  position.  The  tone  of  the  antagonistic  muscles  checks 
the  limb  on  its  return  to  this  position,  with  the  result  that  there  is  little 
tendency  for  the  leg  to  bounce  up  and  down  after  the  response  is  over. 
When,  however,  the  tone  of  the  muscles  is  reduced  as  the  result  of  in- 
jury to  remote  parts  of  the  central  nervous  system,  as  in  cerebellar  le- 


922  CENTRAL  NERVOUS  SYSTEM 

sions,  or  the  later  stages  of  spinal  shock,  the  knee  jerk  is  much  more 
brisk  in  character  because  the  contraction  of  the  muscles  is  unimpeded  by 
the  tone  of  their  antagonists.  The  return  of  the  leg  to  its  original  posi- 
tion is  very  rapid  since  there  is  no  tonic  prolongation  of  the  contraction 
of  the  extensors,  and  the  shank  tends  to  bounce  up  and  down  in  the 
absence  of  any  constraining  tonic  action  on  the  part  of  the  muscles 


Fig.  230. — A,  tracing  of  the  knee-jerks  of  a  normal  man.  B,  tracings  of  the  knee-jerks  of  the 
hypotonic  leg  of  a  man  with  a  cerebellar  injury  of  eight  years'  duration.  The  records  should  be 
read  from  right  to  left.  (From  Holmes.) 

(Fig.  230).  Under  these  conditions  the  return  is  a  passive  act  produced 
by  the  weight  of  the  leg,  and  not  by  a  compensating  flexor  contraction, 
for  if  the  limb  is  supported  on  a  bed  when  the  knee  jerk  is  elicited,  it 
shows  no  tendency  to  flex  again  after  the  extension  has  been  produced. 
Impulses  from  other  parts  of  the  nervous  system  may  prevent  the 
occurrence  of  the  tendon  jerks  by  preventing  the  afferent  impulses  set 


POSTURAL    COORDINATION  923 

up  by  tapping  the  tendons  from  controlling  the  activity  of  the  motor 
part  of  the  reflex  arc  (see  the  Final  Common  Path,  page  945).  If  the 
leg  of  an  animal  be  thrown  into  flexion,  the  extensor  muscles  are  in- 
hibited from  contraction  and  the  knee  jerk  can  no  longer  be  elicited, 
even  though  the  extensor  muscles  are  separated  from  their  insertion 
and  consequently  do  not  have  to  pull  against  the  contraction.  In  a 
similar  way  the  knee  jerk  may  be  inhibited  by  influences  arising  in 
the  cerebrum,  and  consequently  it  is  frequently  necessary  to  distract 
the  subject's  attention  before  the  response  can  be  brought  out. 


CHAPTER  XCIX 

THE  CENTRAL  CONTROL  OF  POSTURAL  REACTIONS;  THE 

CEREBELLUM 

The  prime  essential  for  muscular  tone  and  its  plastic  reactions  is  the 
integrity  of  its  own  proprioceptive  reflex  arc.  Certain  centers  in  the 
brain  exert  a  modifying  influence  upon  the  degree  of  tone  which  this 
arc  maintains,  but  if  the  afferent  fibers  from  the  muscles  are  damaged, 
these  centers  cannot  replace  them  in  their  effect  on  the  motor  neuron 
of  the  proprioceptive  reflex  arc.  Thus  the  exaggerated  tone  of  the  ex- 
tensor muscles  which  is  produced  by  the  action  of  the  centers  in  the 
brain  of  animals  from  which  the  cerebrum  is  removed  disappears  at  once 
if  the  afferent  roots  are  cut. 

Since  the  proprioceptive  reflex  arc  is  necessary  for  the  production 
of  tone  in  muscles,  conditions  of  diminished  tone  or  flaccidity  appear 
in  disease  affecting  either  the  afferent  fibers  from  the  muscle  or  its 
motor  neurons.  If  the  former  alone  is  damaged  tone  will  be  dimin- 
ished or  lost  without  paralysis  of  the  muscle.  This  is  an  unusual  con- 
dition since  the  afferent  and  efferent  paths  are  only  separated  during 
their  passage  into  the  cord  through  the  spinal  nerve  roots.  It  occurs, 
however,  in  locomotor  ataxia,  in  which  the  primary  lesion  lies  in  the 
dorsal  spinal  roots,  and  in  the  ganglia  of  the  cranial  nerves.  If  the 
motor  neuron  alone  is  affected  the  loss  of  tone  will  be  accompanied  by 
paralysis  of  the  muscles,  that  is  a  flaccid  paralysis  will  result.  This  is 
an  important  principle  in  determining  where  the  lesion  which  gives  rise 
to  paralysis  is  situated,  since  paralysis  produced  by  lesions  of  the  higher 
motor  centers  and  tracts  is  not  accompanied  by  permanent  flaccidity. 
A  typical  flaccid  paralysis  occurs  in  anterior  poliomyelitis  in  which 
the  lesion  is  situated  in  the  ventral  horn  of  the  gray  matter  of  the  cord, 
involving  the  cell  bodies  of  the  motor  neurons. 

The  Influence  of  the  Brain  on  the  Local  Tonic  Reflex 

When  the  proprioceptive  reflex  arc  is  isolated  from  the  brain  by  com- 
plete section  of  the  spinal  cord,  a  condition  called  spinal  shock  inter- 
venes for  a  period  during  which  reflexes  may  not  be  elicitable  and  the 
muscles  become  atonic.  After  a  period  of  time,  which  is  longer  the 
higher  the  animal  in  the  evolutionary  scale,  the  reflexes  return  and  tone 
is  regained,  but  not  quite  in  normal  degree.  This  condition  holds  true 

924 


CENTRAL    CONTROL    OF   POSTURAL   REACTIONS  925 

for  complete  transections  of  the  cord  at  levels  up  to  the  medulla.  It 
appears  that  the  higher  centers  exert  a  reinforcing  effect  on  the  local 
tonic  reflex,  which  may  be  compensated  for  when  these  influences  are 
removed,  but  never  with  complete  success.  The  reinforcement  of  the 
tone  of  skeletal  muscles  by  the  higher  centers  of  the  nervous  system 
represents  the  resultant  of  two  opposing  tendencies,  one  augmenting  the 
tonic  contraction,  the  other  inhibiting  it. 

The  augmentation  of  tone  is  seen  in  the  condition  known  as  decere- 
brate  rigidity,  to  which  we  have  already  referred,  in  which  the  tone  of 
the  extensor  muscles  is  greatly  exaggerated.  Experiments  on  animals 
show  that  the  rigidity  is  not  the  result  of  separating  the  cerebrum  from 
the  central  nervous  system,  as  the  name  would  imply,  for  if  successive 
slices  of  the  brain  be  removed  from  above  downward  the  condition  does 
not  develop  until  the  section  separates  the  optic  thalamus  from  the  mid- 
brain.  The  researches  of  Sherrington,31  Thiele,33  and  particularly  of 
Weed,32  indicate  that  the  mechanism  supporting  the  rigidity  is  probably 
somewhat  as  follows.  The  afferent  impulses  on  which  the  "  reflex  stand- 
ing" depends  arise  in  the  muscles  themselves,  since  cutting  the  posterior 
roots  of  the  spinal  nerves  supplying  the  muscles  in  question  abolishes  the 
rigidity.  They  pass  up  the  cord  in  the  ventrolateral  column  of  the  same 
side  and  probably  enter  the  cerebellum  through  the  superior  cerebellar 
peduncles  and  pass  to  the  cerebellar  cortex.  From  thence  the  path  leads 
back  through  the  same  peduncles  to  the  midbrain  in  which  lies  the  main 
center  for  maintaining  this  condition,  probably  the  nucleus  ruber.  From 
there  the  paths  descend  through  the  cord  in  extrapyramidal  tracts,  prob- 
ably the  rubrospinal.  Afferent  paths  also  probably  lead  directly  to  the 
midbrain  center  without  passing  through  the  cerebellum,  for  in  some 
animals  removal  of  the  cerebellum  is  not  followed  by  loss  of  rigidity  or 
its  loss  is  not  immediate. 

The  Inhibition  of  Tone. — The  rigidity  may  also  be  inhibited,  once  it 
has  developed,  by  stimuli  applied  to  various  parts  of  the  nervous  system. 
If  the  "decerebration"  is  limited  to  one  side  of  the  body  rigidity  may 
develop  on  that  side  only  and  it  becomes  possible  to  study  the  effect  of 
stimulating  the  cortex  of  the  other  half  of  the  cerebrum.  Stimulation  of 
the  sensory-motor  area  inhibits  the  existing  tone  in  the  extensor  mus- 
cles. Excitation  of  the  cerebral  peduncles  also  inhibits  the  rigidity. 
Weed32  considers  that  the  cerebellum  forms  an  essential  link  in  the  path 
over  which  these  inhibitory  impulses  pass  from  the  cerebrum  to  the 
centers  which  maintain  the  rigidity,  because  severence  of  the  middle 
cerebellar  peduncles  eliminates  the  inhibition  which  is  produced  by 
stimulation  of  the  cerebral  peduncles.  In  support  of  this  observation  is 
the  fact  that  excitation  of  the  anterior  part  of  the  superior  vermis  or  of 


926  CENTRAL  NERVOUS  SYSTEM 

the  stump  of  the  superior  or  middle  cerebellar  peduncle  inhibits  the 
rigidity  of  the  limbs. 

The  maintenance  of  the  excessive  extensor  tonus  known  as  decere- 
brate  rigidity  consequently  depends  upon  the  reflex  connection  of  a  cen- 
ter in  the  midbrain  with  the  muscles.  Normally  the  activity  of  this 
reflex  mechanism  is  held  in  abeyance  by  the  inhibitory  influence  of  the 
fore  brain.  The  fact  that  both  the  afferent  impulses  from  the  muscles 
and  the  inhibitory  impulses  from  the  cerebrum  pass  through  the  cere- 
bellum suggests  strongly  that  this  organ  must  have  a  very  important 
relation  to  the  regulation  of  postural  tone,  and  that  this  is  the  case  is 
indicated  conclusively  by  what  is  known  of  the  physiology  of  this 
structure. 

The  Function  of  the  Cerebellum,— The  function  of  the  cerebellum  has 
been  the  subject  of  exhaustive  study,  particularly  on  the  part  of  Luci- 
ani.3G  Stimulation  of  the  cortex  of  the  cerebellum  with  an  electrical 
current  does  not  give  rise  to  any  detectable  reactions  unless  the  current 
is  so  strong  as  to  spread  to  the  deeper  ganglia  of  the  brain.  Conse- 
quently it  has  been  necessary  to  study  the  effects  of  removing  all  or 
part  of  the  cerebellum  and  to  attempt  to  deduct  from  the  resulting  dis- 
turbances the  function  which  the  ablated  parts  perform.  When  this  is 
done  it  is  found  that  three  stages  can  be  distinguished  in  the  condition 
of  the  animal,  following  the  operation.  In  the  initial  stage  a  definite 
group  of  symptoms  are  presented  which  are  presumably  due  to  certain 
immediate  effects  of  the  operation.  These  effects  change  quite  com- 
pletely after  several  days  and  a  set  of  conditions  present  themselves 
which  appear  to  be  the  permanent  result  of  the  loss  of  the  cerebellar 
tissue.  Finally,  however,  a  certain  improvement  in  the  behavior  of  the 
animal  occurs  which  may  be  attributed  to  the  compensatory  action  of 
other  parts  of  the  nervous  system  which  modify  their  activities  so  as 
to  correct  for  the  loss  of  cerebellar  influences.  The  second  stage  is  ob- 
viously of  chief  interest  in  the  interpretation  of  the  normal  function  of 
the  cerebellum.  The  conditions  existing  in  this  stage  in  man,  following 
gunshot  injuries,  have  been  exhaustively  described  by  Holmes,35  and  as 
they  agree  closely  with  the  results  obtained  on  animals  and  are  of  greater 
interest  to  human  physiology,  we  may  draw  our  conclusions  from  them. 

The  destruction  of  tissue  in  one  half  of  the  cerebellum  manifests  it- 
self in  the  condition  and  behavior  of  the  muscles  on  the  same  side  of  the 
body.  When  compared  to  the  muscles  of  the  uninjured  side,  these  ex- 
hibit several  forms  of  abnormality  which  may  be  designated  as  atonia, 
asthenia,  astasia,  and  ataxia.  To  atonia  are  attributed  those  symptoms 
which  manifest  themselves  as  the  result  of  a  diminution  in  the  tone  of 
the  muscles.  As  the  result  of  this  condition  the  muscles  feel  soft  and 
flabby  and  the  limbs  tend  to  assume  unnatural  positions.  When  the  arm 


CENTRAL    CONTROL    OF    POSTURAL    REACTIONS  927 

is  held  upright,  for  example,  the  wrist  is  flexed  under  the  weight  of  the 
hand.  If  the  joints  are  passively  bent,  their  movement  is  not  checked 
by  the  action  of  the  muscles,  but  continues  until  the  articulations  cause 
them  to  lock.  The  characters  which  the  disturbance  in  tone  imposes  on 
the  knee  jerk  have  been  described  on  page  921. 

Asthenia  expresses  the  fact  that  the  muscles  of  the  injured  side  are 
weaker  than  on  the  normal  side.  Not  only  are  the  patients  conscious 
that  these  muscles  feel  weaker,  but  measurement  with  a  dynamometer 
shows  that  they  can  exert  in  some  cases  only  50  per  cent  of  the  force 
of  which  the  normal  muscles  are  capable.  The  limbs  in  which  the  mus- 
cles are  asthenic  are  also  unusually  subject  to  fatigue.  It  should  be 
emphasized  that  the  muscles  which  have  been  deprived  of  a  cerebellar 
influence  are  never  paralysed:  the  asthenia  is  not  a  failure  of  function, 
but  rather  an  expression  of  inefficiency  in  the  act  of  voluntary  contraction. 
Closely  associated  with  the  asthenia  is  the  discontinuity  or  irregu- 
larity of  a  maintained  muscular  contraction  known  as  astasia.  The  af- 
fected muscles  frequently  tend  to  give  way  under  the  load  they  bear,  so 
that  objects  held  in  the  hand  are  liable  to  be  dropped,  or  the  leg  on  the 
injured  side  may  suddenly  collapse  under  the  body's  weight  and  thus 
cause  the  patient  to  fall  as  he  attempts  to  walk.  A  tremor  may  occur 
in  maintaining  an  attitude,  if  it  requires  the  exertion  of  some  force,  par- 
ticularly as  the  muscles  begin  to  tire.  It  is  a  less  prominent  symptom  in 
man,  however,  than  in  animals.  The  destruction  of  the  cerebellum  seems 
to  disturb  the  mechanism  by  which  the  individual  twitches  of  the  con- 
tracting muscle  become  fused  so  as  to  maintain  a  constant  tension.  We 
have  pointed  out  on  page  917  that  the  continuity  of  muscular  movement 
is  facilitated  by  the  reinforcement  of  the  primary  response  by  an  adjust- 
ment in  the  postural  tone  of  the  muscle,  and  it  would  seem  that  this  is 
the  mechanism  whose  disturbance  gives  rise  to  the  astasia  of  cerebellar 
injuries. 

Under  asynergia  may  be  grouped  those  symptoms  which  are  due  to  ir- 
regularities in  the  voluntary  movements  of  the  body.  The  limbs  of  the 
affected  side  are  ill  directed  when  an  attempt  is  made  to  perform  some 
precise  movement.  The  finger  may  strike  the  eye,  when  its  true  objec- 
tive is  the  mouth  and  consequently  the  patient  fears  to  hold  his  cigarette 
in  the  affected  hand  while  smoking.  It  is  impossible  to  stop  the  move- 
ment at  the  right  point,  with  the  result  that  in  trying  to  reach  some  ob- 
ject, the  hand  strikes  it  forcibly  or  else  falls  short  of  its  objective.  When 
voluntary  movements  are  made  they  are  interrupted  in  their  progress 
by  a  tremor,  particularly  as  they  approach  their  objective,  and  greater 
need  for  accuracy  becomes  necessary.  This  jerky  character  of  the  mo- 
tion is  obviously  closely  associated  with  the  static  tremor  described  as 
astasia.  Certain  abnormalities  in  movement  indicate  that  difficulty  ex- 


928  CENTRAL   NERVOUS   SYSTEM 

ists  in  the  synchronous  adjustment  of  the  activities  of  various  muscle 
groups  which  should  cooperate  for  a  common  end.  When  the  fingers  are 
flexed  the  extensors  of  the  wrist  normally  contract  synergically  in  order 
to  prevent  simultaneous  flexion  of  the  wrist.  If  a  patient  with  a  cere- 
bellar  lesion  grasps  a  small  object  quickly,  the  wrist  may  be  extended 
excessively  so  that  the  hand  is  bent  backwards  before  the  fingers  are 
half  flexed.  Movements  which  involve  the  activities  of  several  joints 
are  frequently  decomposed  into  their  component  parts  which  are  exe- 
cuted one  at  a  time  instead  of  all  at  once.  In  bringing  the  finger  to  the 
nose  the  patient  will  first  depress  the  arm  by  a  movement  of  the  shoulder, 
and  then  flex  the  elbow  after  the  first  act  is  complete.  Difficulty  is  also 
experienced  in  making  rapid  alternate  movements  such  as  flexion  and 
extension  of  the  fingers.  The  actual  movement  may  be  made  nearly  as 
rapidly  as  with  the  normal  hand,  but  a  considerable  delay  intervenes  be- 
tween the  successive  acts,  indicating  a  difficulty  in  adjusting  the  neuro- 
muscular  mechanism  for  the  new  act.  In  making  such  rapid  alternating 
movements  groups  of  muscles  not  concerned  in  the  desired  action  may 
come  into  play.  When,  for  example,  the  ankle  is  voluntarily  flexed  and 
extended  in  rapid  succession  the  knee  and  hip  may  flex  and  extend  also. 
The  asynergia  produced  by  the  destruction  of  cerebellar  tissue  consists  then 
in  a  disturbance  of  the  normal  harmony  and  correct  cooperation  in  time 
and  degree  of  the  various  muscular  contractions  concerned  in  movements 
and  in  the  maintenance  of  posture. 

We  may  conclude  that  the  cerebellum  is  actively  concerned  with 
the  maintenance  of  tone  and  in  the  adjustment  of  voluntary  contraction 
and  plastic  tone  to  the  posture  of  the  body,  not  only  as  it  is  maintained 
in  rest,  but  as  it  changes  when  in  action.  Injuries  to  it  result  in  a  mis- 
coordination,  rather  than  an  incoordination  of  muscular  activity.  Sher- 
rington37  has  called  the  cerebellum  the  main  ganglion  of  the  proprioceptive 
system.  The  passage  of  impulses  from  the  proprioceptors  and  from  the 
cerebrum  through  the  cerebellum  in  their  course  to  the  centers  of  the 
midbrain  which  are  involved  in  the  maintenance  of  decerebrate  rigidity 
consequently  assumes  an  important  functional  significance. 

No  Sensory  Disturbances  Follow  Injury  to  the  Cerebellar  Cortex.— 
In  considering  the  function  of  the  cerebellum  it  should  be  pointed  out 
that  although  it  receives  afferent  impulses  from  the  proprioceptors  of 
the  body  there  is  no  evidence  that  it  is  concerned  in  any  way  with  sen- 
sation. The  only  sensory  tests  to  which  those  afflicted  with  cerebellar 
injuries  fail  to  respond  with  normal  accuracy  are  those  involving  the 
comparison  of  weights  placed  in  the  normal  and  the  affected  hand.  In 
this  test  the  weight  in  the  latter  is  judged  heavier  than  it  should  be  be- 
cause of  the  greater  effort  required  to  support  it  with  the  asthenic  mus- 
cles. Although  the  ability  to  maintain  the  equilibrium  of  the  body  may 


CENTRAL    CONTROL    OF    POSTURAL    REACTIONS 


929 


be  disturbed  as  the  result  of  cerebellar  injury,  this  is  because  the  mus- 
cles do  not  respond  properly  in  the  attempt  to  prevent  falling,  and  not 
because  the  sense  of  equilibrium  is  in  any  way  impaired. 

Localization  of  Function  in  the  Cerebellum. — The  observations  on  cere- 
bellar injuries  in  man  which  we  have  described  indicate  that  the  two 
halves  of  the  cerebellar  cortex  are  each  concerned  with  the  regulation  of 
tone  and  movement  in  the  corresponding  half  of  the  body.  Beyond  that 
they  do  not  afford  any  evidence  of  localization  of  function  in  the  cere- 
bellum. By  studying  the  correlation  between  the  functional  importance 
of  different  muscle  groups  and  the  development  of  the  different  parts  of 
the  cerebellum  in  different  animals  Bolk  has  assigned  the  control  of  each 
muscle  group  to  a  definite  part  of  the  cerebellar  cortex,  as  is  indicated 
in  Figure  231. 

Basing  his  work  on  these  anatomic  conclusions,  Van  Rijnberk  has  studied 
the  effect  of  circumscribed  extirpation  of  certain  lobules  of  the  cerebellum 


Fig.  231. — Schema  of  the  parts  of  the  mammalian  cerebellum  spread  out  in  one  plane.  (After  Bolk 
by  Van  Rijnberk  from  Luiciani.  Op.  cit.)  On  the  right  side  of  the  figure  the  relation  .  of  tne 
different  lobules  to  the  functional  development  of  the  musculature  is  indicated  according  to  the 
theory  of  Bolk  noted  in  the  text.  (From  Davidson  Black.) 

on  the  muscular  control  of  the  different  parts  of  the  body,  with  the  following 
results.  Total  or  partial  extirpation  of  the  lobulus  simplex  produces  side  to 
side  oscillations  of  the  head,  indicating  the  removal  of  the  influences  of  the 
cerebellum  that  control  the  movements  of  the  muscles  of  the  neck.  Complete 
extirpation  of  the  crus  primum  of  the  lobuli  ansiformes  causes  as  an  imme- 
diate— irritative — effect  dynamic  disturbances  of  the  fore  limb  of  the  same 
side,  replaced  later  by  a  condition  of  atonia,  which  makes  the  limb  hang 
limp,  and  of  asthenia,  which  makes  it  feeble  in  its  movement  when  it 
is  excited  to  contract.  Extirpation  of  the  crus  secundum  has  a  similar 
influence  on  the  muscles  of  the  hind  limb  of  the  corresponding  side.  Extir- 
pation of  both  crura  of  the  lobulus  ansiformis  causes  marked  asthenia  and 
atonia  in  both  fore  and  hind  limb  on  the  same  side  as  the  lesion.  A  char- 


930 


CENTRAL   NERVOUS   SYSTEM 


acteristic  disturbance  in  walking  develops  as  a  late  effect  of  this  extirpation. 
It  has  been  termed  the  "hen's  gait."  Extirpation  of  the  lobulus  para- 
medianus  causes  rotation  on  the  longitudinal  axis  of  the  body,  with  pleuro- 
thotonus  to  the  operated  side.  (Fig.  232.) 

Just  as  in  the  case  of  cerebral  localization,  so  in  cerebellar  we  find  that 
within  each  of  the  largest  centers  a  more  particular  localization  can  be  made 
out;  thus,  in  each  of  the  centers  for  the  upper  and  lower  extremities, 
there  is  a  definite  arrangement  of  subsidiary  centers  for  the  direction  of 
the  activities  of  antagonistic  muscle  groups  concerned  in  the  movements  of 
particular  joints. 

Localization  of  function  in  the  cerebellum  of  man  has  been  worked  out 
by  Barany  by  correlating  the  position  of  cerebellar  lesions  with  disturb- 


Fig.  232. — Diagrams  to  represent  respectively  a  ventral  view  of  the  left  half  and  a  dorsal 
view  of  the  right  half  of  the  human  cerebellum  illustrating  the  scheme  of  subdivision  according 
to  Bolk.  (From  photographs  of  specimens  from  the  Anatomical  Museum,  Western  Reserve  Medical 
School.)  (From  Davidson  Black.) 

ance  in  the  past-pointing  tests  (described  on  page  920)  which  appear 
when  the  action  of  each  joint  is  examined  in  turn.  Barany 's  conclusions 
so  far  may  be  summarized  as  follows: 

(1)  The  centers  for  the  extremities  are  located  on  the  cortex  of  the 
hemispheres  in  the  semilunar  (superior  and  inferior)  and  digastric  lobules 
(see  Fig.  233).    The  representation  is  uncrossed  or  homolateral,  thus  con- 
trasting with  cerebral  localization,  in  which  it  is  crossed  or  heterolateral. 

(2)  Within  each  of  these  chief  centers  there  is  a  further  localization, 
which  however  does  not  refer  to  anatomical  groups  of  muscles  but  rather  to 
the  functional  performances  of  the  different  segments  of  the  limb.    Thus, 
within  the  arm  centers  there  are  subsidiary  centers  concerned  in  the 
movements  of  the  limb  in  the  various  planes  in  rotation,  in  pronation 


CENTRAL    CONTROL    OF   POSTURAL    REACTIONS 


931 


and  in  supination.    It  is  a  functional  rather  than  an  anatomical  localization. 

(3)  When  a  center  concerned  in  the  movements  of  the  limb  in  a  certain 
direction,  e.  g.,  to  the  right,  is  suddenly  destroyed,  a  spontaneous  devia- 
tion is  produced  in  the  opposite  direction  (to  the  left). 

For  further  details  see  the  paper  by  Black.30 

Compensation    for    Cerebellar    Injuries. — The    final    stage    following 


Fig.  233. 


Fig.  234. 

Figs.  233  and  234  represent  respectively  the  inferolateral  and  the  posterior  aspect  of  the  human 
cerebellum  indicating  certain  cerebellar  localizations  according  to  Barany.  (After  Barany,  from 
Andre-Thomas  et  Durupt.  Op.  cit.)  N.  VII,  Nervus  facialis;  N.  IX,  Nervus  Glossopharyngeus; 
N.  XII,  Nervus  hypoglossus. 

The  signs  in  the  above  diagram  indicate  the  exact  localization  of  the  centers  for  the  tonus  of 
the  musculature  concerned  in  some  of  the  movements  of  the  right  arm  and  leg,  ®  marks  the 
center  for  downward  movements  of  the  arm;  X,  for  abduction  of  the  arm;  O,  adduction  of  the 
hand;  +  adduction  of  the  arm;  ±,  adduction  of  the  hip.  N.  V.  indicates  Nervus  trigeminus; 
N.  VI,  Nervus  abducens;  N.  VII,  Nervus  facialis;  N.  IX,  Nervus  glossopharyngeus;  N.  XII, 
Nervus  hypoglossus.  (From  Davidson  Black.) 

the  removal  of  cerebellar  tissue  is  one  in  which  compensation  is  made 
for  this  loss  by  other  parts  of  the  nervous  system,  so  that  in  time  the 
symptoms  gradually  tend  to  disappear.  The  initial  disturbances  in  lo- 
comotion and  the  improvement  which  comes  with  time  are  illustrated  in 
Fig  235,  which  represents  the  footprints  of  a  dog  from  which  the  cere- 
bellum has  been  removed. 


932  CENTRAL  NERVOUS  SYSTEM 

It  will  be  of  interest  to  consider  for  a  moment  the  possible  causes  for  the 
ultimate  disappearance  of  the  symptoms  of  cerebellar  extirpation.  These 
are  either:  (1)  an  organic  compensation  by  the  uninjured  parts  of  the  cere- 
bellum, or  (2)  a  functional  compensation  by  the  voluntary  centers  of  the 
cerebrum.  Although  the  former  of  these  methods  of  compensation  may 
sometimes  develop  after  partial  destruction  of  the  cerebellar  cortex,  it  can 
not  of  course  explain  the  recovery  which  we  have  seen  to  occur  after  the 


e  d  c  b  a 

Fig.    235. — Footprints    after    destruction    of    the    cerebellum    in    a    dog:      a,    before    the    operation; 
b,  four  days  after;   c,  five  days  after;  d,  a  month  after;  e,  two  months  after.      (From  Luciani.) 

entire  cerebellum  has  been  removed.  The  most  important  compensation  no 
doubt  is  effected  by  the  cerebrum,  as  the  following  observation  clearly  in- 
dicates. If  half  of  the  cerebellum  of  a  dog  is  destroyed,  and  the  animal 
kept  alive  until  the  symptoms  of  cerebellar  extirpation  have  entirely  dis- 
appeared, it  will  then  be  found,  if  the  cerebral  center  on  the  opposite  side 
is  removed,  that  the  symptoms  return  in  their  original  severity.  After  this 
second  operation  the  powers  of  standing  in  the  erect  position  and  of 
walking  are  permanently  lost. 


CHAPTER  C 
THE  INTEGRATION  OF  ACTION  WITHIN  THE  REFLEX  ARC 

In  considering  the  anatomical  arrangements  which  give  rise  to  sensa- 
tion and  motor  activity,  we  have  taken  the  risk  of  creating  a  false  im- 
pression that  the  action  of  the  nervous  system  is  carried  out  in  a  rigid 
and  immutable  manner,  and  that  nerve  impulses  travel  over  the  conduct- 
ing paths  with  the  invariability  with  which  an  electric  current  flows  over 
a  fixed  system  of  wires.  While  the  constancy  of  the  anatomical  paths 
by  means  of  which  certain  nervous  functions  are  carried  out  is  of  ines- 
timable value  in  clinical  neurology  it  must  be  emphasized  that  in  the 
nervous  system  continuous  adjustment  is  made  to  the  end  that  the  activ- 
ity of  one  part  may  adapt  itself  to  the  activities  of  other  parts,  and  con- 
sequently the  results  of  a  given  stimulation  are  not  always  strictly  pre- 
dictable. In  other  words  the  activity  of  the  various  reflex  paths  is  closely 
coordinated.  Before  we  can  consider  how  this  coordination  between 
reflexes  is  accomplished,  we  must  first  examine  into  how  the  activity  of 
the  various  parts  of  a  reflex  arc  are  related  so  that  the  reflex  may  bring 
about  an  act  of  functional  significance;  i.  e.,  a  response  in  which  a  local- 
ized group  of  muscles  act  in  a  coordinated  way  so  as  to  accomplish  some 
purpose  which  is  related  to  the  exciting  stimulus. 

The  Receptors. — Reflex  acts  are  initiated  by  the  stimulation  of  recep- 
tors. Because  each  receptor  is  specialized  to  respond  more  readily  to 
one  quality  of  stimulus  than  to  any  other  (page  856),  each  reflex  arc  is 
brought  into  action  only  by  stimuli  of  an  appropriate  sort.  The  selective 
excitability  of  the  receptors  of  the  different  reflex  arcs  consequently 
enables  the  organism  to  respond  in  different  ways  to  stimuli  of  different 
kinds  when  they  are  applied  to  the  same  receptive  skin  area.  As  an 
example  we  may  consider  the  reactions  which  may  result  from  stimulat- 
ing the  foot  of  a  spinal  or  decerebrate  cat.  By  pressing  against  the  under 
surface  of  the  paw  a  reflex  may  be  elicited  known  as  the  extensor  thrust, 
consisting  of  a  vigorous  extension  of  hip,  knee,  and  ankle  of  the  corre- 
sponding leg.  This  response  cannot  be  called  out  by  any  other  form  of 
stimulus.  In  life  it  would  be  expected  to  occur  when  in  running  the 
cat's  foot  comes  in  contact  with  the  ground,  thus  throwing  the  animal's 
weight  on  the  leg.  If  a  harmful  stimulus  is  applied  to  the  same  part  of 
the  foot  the  response  is  of  a  totally  different  character,  consisting  of  a 
flexion  of  the  joints  of  the  limb.  The  foot  is  pulled  away  from  the  stim- 

933 


934  CENTRAL    NERVOUS   SYSTEM 

ulating  object.  This  would  serve  to  relieve  the  cat  of  pain,  such  as  might 
be  occasioned  if  it  stepped  on  a  thorn.  The  receptors  for  these  two 
reflexes  have  their  thresholds  lowered  each  to  a  particular  form  of  stimu- 
lus, and  the  nature  of  the  response  is  such  that  the  leg  moves  in  a  way 
which  is  appropriate  to  the  conditions  under  which  stimulation  occurs  in 
nature. 

When  nerve  impulses  are  set  up  in  the  afferent  neuron  of  a  reflex 
arc,  the  path  over  which  they  may  travel  is  limited  by  the  insulation  of 
the  fibers  of  the  nerve  trunk  to  those  neurons  with  which  the  afferent 
fiber  makes  connection  through  synapses  located  in  the  grey  matter  of 
the  spinal  cord.  The  characteristics  of  the  synapse,  which  we  have  de- 
scribed in  Chapter  XC  determine  the  destiny  of  the  nerve  impulse  and  the 
characteristics  of  the  reflex  response  which  results. 

Summation. — It  was  pointed  out  that  a  single  nerve  impulse  frequently 
fails  to  pass  across  a  synapse,  over  which  a  series  of  impulses  may  travel 
if  they  follow  one  another  in  rapid  succession,  so  that  their  effects  are 
summated.  This  characteristic  of  synaptic  conduction  is  of  importance  in 
regulating  reflex  activity,  as  may  be  realized  when  it  is  considered  that 
the  organism  is  constantly  in  receipt  of  many  unimportant  stimuli.  Be- 
cause of  the  necessity  for  summation  only  those  stimuli  call  forth  a  re- 
sponse which  are  of  some  intensity  and  duration.  Consequently  mo- 
mentary and  hence  insignificant  stimuli  do  not  affect  its  behavior. 

6.  The  Refractory  Period. — This  has  been  well  defined  by  Sherrington 
as  being  "a  state  during  which  apart  from  fatigue  the  mechanism  shows 
less  than  its  full  excitability."  We  are  already  familiar  with  the  re- 
fractory period  in  the  cases  of  the  heart  muscle  and  the  musculature  of 
the  esophagus  and  intestine.  For  example,  the  application  of  a  stimu- 
lus to  the  quiescent  frog  heart  while  it  is  contracting  in  response  to  an  im- 
mediately preceding  stimulus  fails  to  produce  any  further  effect.  The  re- 
fractory period  is  extremely  brief  (one  thousandth  of  a  second)  in  a 
nerve  trunk,  but  is  much  longer  in  a  reflex  arc,  being  probably  longest 
in  the  case  of  the  scratch  reflex,  in  which  it  is  demonstrated  by  the 
fact  that,  however  frequently  we  apply  suitable  stimuli  to  the  sensory 
surface,  the  rhythm  of  response  of  the  contracting  limb  is  always  the 
same.  After  each  stimulus,  therefore,  a  refractory  period  must  become 
developed  during  which  a  repetition  of  the  stimulus  has  no  effect.  It 
is  evident  that  the  existence  of  the  refractory  period  is  the  factor 
responsible  for  the  rhythm  of  the  movements. 

It  is  interesting  to  consider  what  part  of  the  reflex  arc  is  responsible 
for  the  existence  of  the  refractory  phase.  It  obviously  can  not  be  a 
function  of  the  motor  neuron,  for  through  the  same  motor  neuron  may 
be  discharged,  at  one  time,  impulses  which  bring  about  the  scratching 
movement  and,  at  another,  those  causing  a  tonic  flexion  of  the 


INTEGRATION   OF   ACTION   WITHIN   THE   REFLEX  ARC  935 

same  muscles.  Nor  can  the  seat  of  the  refractory  period  be  in  the 
sensory  area  of  the  skin  or  the  afferent  neuron,  for  if  a  scratch  move- 
ment is  elicited  by  stimulation  at  a  point  A  in  the  proper  skin  area, 
the  rhythm  of  response  which  it  calls  forth  will  not  in  any 
way  be  altered  by  the  application  of  a  second  stimulus  applied  at  B 
at  some  distance  from  A  and  having  a  different  frequency  (Fig.  236). 
There  is  evidently,  therefore,  some  part  of  the  reflex  arc  that  is  common  to 


Fig.  236. — Tracing  from  the  hind  limb  of  a  spinal  dog  during  the  scratching  movements  pro- 
duced by  applying  stimuli  at  two  skin  points  (A  and  B),  the  application  of  the  stimuli  being  in- 
dicated by  the  signals.  Not  only  were  the  stimuli  applied  at  different  points,  but  at  B  they 
were  of  much  greater  frequency  than  at  A.  Although  there  is  a  slight  change  in  "local  sign,"  it 
will  be  observed  that  there  is  no  alteration  in  rhythm,  indicating  that  this  property  can  not  be  a 
function  of  the  final  common  path.  (From  Sherrington.) 

impulses  starting  both  at  A  and  at  B,  for  if  in  each  of  these  spots  a  refrac- 
tory phase  occurred,  then  there  would  be  interference  before  the  two  im- 
pulses had  reached  the  centers  of  the  spinal  cord.  By  exclusion,  there- 
fore, "the  seat  of  the  refractory  phase  seems  to  lie  somewhere  central 
to  the  receptive  neuron  in  the  afferent  arc" — (Sherrington18). 

Many  other  types  of  reflex  activity  illustrate  rhythm  due  to  the  re- 
fractory phase.  Two  laboratory  examples  may  be  given:  (1)  When 


936 


CENTRAL  NERVOUS  SYSTEM 


the  central  end  of  an  afferent  root  is  stimulated  in  the  lumbar  region  of  the 
spinal  cord,  the  movement  produced  is  distinctly  rhythmic  in  character. 
(2)  Upon  stimulating  the  central  end  of  the  sciatic  nerve  in  a  frog  whose 
spinal  cord  has  been  cut  some  days  previously,  a  clonic  action  of  the 
contralateral  foot  occurs,  and  the  rate  of  the  rhythm  is  not  affected  by 
variation  in  the  frequency  of  the  stimulus. 


Fig.  237. — Diagram  showing  the  reflex  arcs  involved  in  the  scratch  reflex.  Ra  and  R0  represent 
ihe  afferent  neurons  connected  with  hairs  on  the  skin  of  the  back  and  flank.  The  afferent  im- 
pulses are  transmitted  by  these  fibers,  and  on  entering  the  corresponding  segments  of  the  spinal 
cord  terminate  by  synapses  on  cells  of  the  internuncial  neurons,  whose  arrows  Pa  and  PQ  travel 
down  in  the  lateral  columns  to  terminate  similarly  around  the  cells  of  the  motor  neurons  that 
innervate  the  muscles  of  the  hind  limb.  Since  afferent  impulses  coming  from  elsewhere,  par- 
ticularly from  the  skin  of  the  leg  (R  and  L),  also  terminate  on  these  neurons  and  may  excite 
them  to  a  different  type  of  action,  the  motor  neuron  is  called  the  final  common  path  (F.C.). 
(From  Sherrington.) 


Fig.   238. — The  region  of  body  of  dog  from  which  the  scratch  reflex  can  be  elicited.      (From 

Sherrington.) 

In  all  the  above  cases  the  refractory  period  may  be  held  responsible 
for  the  rhythmic  nature  of  the  contraction.  In  other  reflexes  it  exists 
for  another  purpose.  In  the  case  of  the  extensor  thrust,  which  it  will 
be  remembered  is  elicited  by  pressure  applied  to  the  pads  of  the  plantar 
aspect  of  the  foot,  the  momentary  extension  of  the  leg  lasts  only  for  a 
little  less  than  two-tenths  of  a  second,  but  is  followed  by  a  refractory 


INTEGRATION    OF    ACTION    WITHIN    THE    REFLEX   ARC  937 

period  lasting  nearly  a  whole  second,  during  which  a  second  stimulus 
elicits  no  response.  The  object  of  this  long  refractory  period  is  no  doubt 
that  opportunity  may  be  given  for  the  flexor  muscles  to  perform  the 
contraction  that  would  naturally  ensue  during  the  normal  occurrence 
of  the  extensor  thrust,  as  in  the  act  of  walking.  When  the  animal 
places  his  foot  on  the  ground,  the  sudden  pressure  exerted  on  the  pad 
of  the  foot  immediately  calls  forth  the  extensor  thrust,  by  means  of 
which  the  weight  of  the  body  is  temporarily  removed  from  the  ground, 
and  the  muscles  perform  the  contractions  necessary  to  produce  flexion 
of  the  limb.  Although  the  refractory  period  is  unaffected  by  the  strength 
of  the  stimulus  it  is  very  dependent  upon  the  internal  condition  of  the 
reflex  arc,  such  as  that  caused  by  changes  in  blood  supply  or  by  narcosis. 

Reciprocal  Inhibition 

It  might  appear  that  to  bend  a  joint  or  to  move  the  eyeball  the  only 
muscular  action  required  would  be  contraction  of  the  muscles  which 
flex  the  joint  or  rotate  the  eyeball,  and  that  the  antagonistic  muscles 
would  merely  become  passively  elongated.  When  we  remember,  how- 
ever, that  all  the  muscles  of  the  body  are  ordinarily  in  a  condition 
of  slight  tonic  contraction,  and  that  this  tends  to  become  increased 
when  the  muscles  are  passively  stretched,  then  we  see  that  for  effi- 
cient movement  there  must  be  inhibition  of  the  tone  of  the  muscles 
which  oppose  those  that  are  contracting.  This  reciprocal  inhibition, 
as  it  is  called,  is  a  very  widespread  function  throughout  the  animal 
body.  Sometimes  it  is  purely  peripheral  in  origin,  as  in  the  claw 
of  the  crayfish,  where  stimulation  of  the  nerve  causes  an  opening  of  the 
claw  due  to  the  contraction  of  one  set  of  muscles  and  the  simultaneous 
inhibition  of  their  antagonists.  Instances  of  peripheral  reciprocal  in- 
hibition in  the  higher  animals  are  not  so  common,  but  are  illustrated  in 
the  case  of  the  myenteric  reflex,  where  it  will  be  remembered  a  contraction 
of  the  intestine  over  a  bolus  of  food  is  accompanied  by  inhibition  in  front  of 
the  bolus.  The  reciprocal  action  in  this  case  is  probably  dependent  on 
the  myenteric  plexus. 

On  the  other  hand,  reciprocal  inhibition  of  central  origin  is  very  com- 
mon in  the  higher  mammalia.  Thus,  in  the  case  of  the  lateral  movement 
of  the  eyes,  if  we  cut  the  third  and  fourth  nerves  to  one  eye,  say,  the 
left,  the  external  rectus  of  that  eye  will  alone  be  under  the  control 
of  the  nervous  system,  through  the  sixth  nerve;  nevertheless,  if  we  after- 
ward cause  the  animal  to  look  toward  the  right,  as  by  holding  some  ob- 
ject in  that  direction,  it  will  be  found  that  the  left  eye  as  well  as  the 
right  follows  the  object.  Obviously  there  must  be  an  inhibition  of  the 


938  CENTRAL    NERVOUS    SYSTEM 

external  rectus  muscle  of  the  left  eye,  an  inhibition  which  is  pronounced 
enough  to  bring  about  a  movement  of  the  eyeball,  and  which  exactly  cor- 
responds in  point  of  time  with  the  contraction  of  the  external  rectus  of 
the  right  eye.  This  movement,  due  to  the  atonicity  of  the  external  rec- 
tus, does  not  however  succeed  in  causing  the  eye  to  rotate  beyond  the 
midline  of  the  field  of  vision.  This  is  an  instance  of  a  willed  reciprocal 
inhibition ;  i.  e.,  a  reciprocal  inhibition  brought  about  by  stimuli  coming 
from  the  motor  centers  in  the  cerebrum.  The  same  result  may  be 
obtained  by  electric  stimulation  of  the  center  for  eye  movements  on  the 
cerebral  cortex. 

The  most  important  details  concerning  the  mechanism  of  reciprocal 
inhibition  have  been  obtained  by  studying  the  flexion  reflex  in  a  spinal 
animal  which  has  completely  recovered  from  shock.  In  such  an  animal 
the  tonus  of  the  extensor  muscles  of  the  knees  is  well  marked.  If  we  pre- 
vent the  flexors  from  acting  on  the  knee  joint  and  the  leg  is  held  in  an  ex- 
tended position,  irritation  of  the  skin  of  the  leg  will  cause  the  flexion  of  the 
disconnected  hamstring  muscles  simultaneously  with  a  visible  relaxation 
of  the  extensors.  If  the  leg  is  held  properly,  this  relaxation  may  be 
marked  enough  to  cause  a  slight  flexion  at  the  joint  under  the  influence 
of  gravity.  This  experiment  is  very  striking  when  performed  on  a  de- 
cerebrate  animal,  in  which,  as  we  have  seen,  the  extensor  muscles  of  the 
limb  are  in  a  permanent  state  of  hypertonicity. 

Reciprocal  inhibition  can  also  be  demonstrated  by  stimulating  the 
central  end  of  suitable  afferent  nerves — that  is,  certain  afferent  nerves 
acting  on  the  same  groups  of  neurons  will  produce  a  flexion  reflex,  others 
an  extension  reflex;  thus,  stimulation  of  the  homolateral  peroneal  nerve 
produces  a  flexion  reflex  of  the  hind  limb  (excitatory  for  flexors,  in- 
hibitory for  extensors),  whereas  stimulation  of  the  contralateral  peroneal 
nerve  produces  an  extension  (inhibitory  for  flexors,  excitatory  for  ex- 
tensors). (Fig.  239.) 

Before  we  can  conclude  that  the  two  elements  in  reciprocal  inhibition 
are  part  and  parcel  of  the  same  reflex  it  must  be  shown  that  under  what- 
ever conditions  the  contraction  of  one  group  of  muscles  is  brought  about, 
inhibition  of  their  antagonists  must  also  occur  and  that  the  responses 
take  place  at  exactly  the  same  time.  If  records  are  made  of  the  move- 
ments of  the  flexors  and  extensors  of  the  knee  in  an  experiment  such 
as  we  have  just  described,  it  is  found  that  the  latent  period  for  the  re- 
sponse of  agonist  and  antagonist,  whether  it  be  contraction  or  inhibition 
exactly  coincides  (Fig.  226).  If  the  strength  of  the  stimulus  is  gradually 
increased  the  latent  period  becomes  shorter  for  the  inhibitory  and  active 
reaction  alike  and  the  synchrony  of  the  reciprocal  responses  is  still  pre- 
served. Moreover  the  receptive  field  on  the  skin  from  which  contraction 


INTEGRATION    OF    ACTION    WITHIN    THE    REFLEX   ARC  939 

may  be  elicited  coincides  exactly  with  that  for  the  inhibition  of  the  antag- 
onistic muscles,  as  do  also  the  kinds  and  strengths  of  stimuli  which  are  effec- 
tive in  each  case.  The  inhibition  of  antagonists  may  consequently  be 
considered  a  part  of  the  same  reflex  which  excites  the  agonists  to  contrac- 
tion. 

It  is  impossible  to  demonstrate  any  trace  of  inhibition  of  the  skeletal 
muscles  by  stimulation  of  their  motor  nerves,  thus  indicating  that  in- 
hibition is  dependent  upon  the  nerve  center.  Furthermore,  since  inhibition 
occurs  along  with  contraction  of  the  antagonistic  muscle,  we  must  assume 


Fig.  239. — Record  from  myograph  connected  with  the  extensor  muscle  of  the  knee.  During 
the  time  marked  by  the  lower  signal,  the  skin  of  the  opposite  foot  was  stimulated,  thus  causing 
the  crossed  extension  reflex.  While  still  maintaining  this  stimulation,  faradic  shocks  were  ap- 
plied to  the  skin  of  the  foot  of  the  same  side  (as  indicated  by  the  upper  signal),  with  the  result 
that  immediate  inhibition  of  the  contracted  extensor  occurred.  (From  Sherrington.) 

that  the  afferent  impulse  on  entering  the  spinal  cord  divides  into 
two  branches,  one  going  to  one  motor  neuron  so  as  to  excite  it,  the  other 
to  another  neuron  so  as  to  inhibit  the  tonic  stimuli  which  it  is  con- 
stantly sending  to  the  muscles  (Fig.  240).  According  to  this  assumption 
the  effect  of  impulses  carried  over  each  branch  depends  on  the  nature  of 
the  synapse  which  these  make  with  the  motor  neurons  of  the  antagonistic 
groups  of  muscles. 

Since  the  seat  of  the  inhibition  is  in  the  nerve  center,  it  is  to  be  ex- 
pected that  impulses  transmitted  from  other  parts  of  the  nervous  system 


940 


CENTRAL  NERVOUS  SYSTEM 


than  the  particular  level  of  that  reflex,  will  also  be  able  to  induce  the 
inhibition.  In  the  case  of  the  decerebrate  cat  this  can  be  demonstrated 
by  stimulation  of  the  lateral  columns  of  the  spinal  cord;  inhibition  of 
the  extensor  muscles  of  the  elbow  joint  occurs,  which  is  all  the  more 
marked  because  in  such  a  preparation  these  muscles  are  in  a  state  of 
hypertonicity.  Through  the  pyramidal  tract  impulses  may  descend  from 
the  cerebrum  which  exercise  a  marked  inhibitory  influence  over  the  reflex 
activities  of  the  cord. 

Finally,  it  must  be  pointed  out  that  this  mechanism  of  reciprocal  in- 
hibition is  by  no  means  confined  to  the  voluntary  muscles.     We  have 


Fig.  240. — Sherrington's  diagram  illustrating  the  mechanism  of  reciprocal  inhibition.  The 
afferent  fibers  (d)  from  the  skin  of  the  leg  and  (d)  from  the  flexor  muscles  of  the  knee  (in 
hamstring  nerve)  pass  to  the  spinal  cord,  where  each  gives  off  a  branch  which  divides  into  two 
others,  of  which  one  in  each  case  goes  to  a  motor  neuron  of  the  extensor  muscles  (H)  and  the 
other  to  a  motor  neuron  (5)  of  the  flexor  muscles  (F).  Branches  also  pass  across  the  median 
line  to  similar  motor  neurons  on  the  opposite  side  of  the  cord.  As  indicated  by  the  plus  and 
minus  signs,  the  afferent  stimuli  either  stimulate  or  inhibit  the  activities  cf  the  motor  neurons, 
the  determination  of  the  exact  effect  being  a  function  of  the  synapsis.  (From  Sherrington.) 

already  seen  that  it  occurs  in  the  case  of  the  myenteric  reflex.  It  is  also 
a  most  important  function  in  the  innervation  of  the  blood  vessels,  dilata- 
tion in  one  vascular  area  being  accompanied  by  constriction  in  another. 
These  facts  have  been  already  sufficiently  dwelt  upon  elsewhere  (page 
247).  Sometimes  also  we  may  have  reciprocal  action  between  differently 
acting  nervous  mechanisms,  as  for  example  in  the  case  of  the  submaxil- 
lary  glands,  which  respond  to  stimulation  of  the  chorda  tympani  nerve 
by  dilatation  of  the  blood  vessels,  an  inhibition  of  their  tone  occurring 
along  with  stimulation  of  the  activity  of  the  gland  cells. 


INTEGRATION    OF    ACTION    WITHIN    THE    REFLEX   ARC  941 

The  Action  of  Strychnine  and  Tetanus  Toxin  on  Reciprocal  Inhibition 

Under  certain  conditions  reciprocal  action  may  fail  to  occur,  as,  for 
example,  at  certain  stages  of  strychnine  poisoning  and  during  the  action 
of  tetanus  toxin.  In  order  to  demonstrate  this  failure  of  reciprocal  ac- 
tion, it  is  necessary  to  examine  muscles  which  act  on  one  joint  only,  and 
to  observe  their  behavior  when  an  afferent  nerve  is  stimulated  which  un- 
der ordinary  conditions  would  throw  them  into  inhibition.  Such  a 
preparation  can  be  obtained  in  the  hind  limb  of  a  dog  by  cutting  all  the 
muscles  that  act  on  the  knee  joint  except  the  vasto-crureus,  which  in  a 
normal  animal  invariably  undergoes  inhibition  when  the  central  end  of 
the  internal  saphenous  nerve  is  stimulated.  If  a  suitable  dose  of  strych- 
nine is  injected,  it  will  be  found  that  stimulation  of  the  internal  saphenous 
nerve,  in  place  of  inhibition,  causes  contraction  of  the  vasto-crureus 
muscle.  The  same  result  is  obtained  by  injection  of  tetanus  toxin. 

The  failure  of  the  reflex  inhibition  explains  the  symptoms  produced 
by  these  substances.  It  explains,  for  example,  the  well-known  rigidly 
extended  condition  of  the  limbs  in  strychnine  poisoning,  and  the  dis- 
tressing symptom  of  lockjaw  in  tetanus  infection.  In  this  latter  con- 
dition the  sufferer  is  subjected  to  extreme  torture  with  every  endeavor 
that  he  makes  to  open  the  jaw  for  the  purpose  of  taking  food  or  drink. 
Firmer  closure  is  the  result  because  the  normal  inhibition  of  the  temporal 
and  masseter  muscles  does  not  occur,  but  instead  they  become  excited 
and  the  jaw  all  the  more  firmly  closed.  Not  only  does,  the  inhibition  fail 
to  occur,  but  the  above  muscles  are  usually  in  a  state  of  constant  hy- 
perexcitability,  which  it  is  impossible  for  the  patient  to  restrain ;  indeed, 
whenever  he  attempts  to  do  so  the  opposite  occurs  and  the  excitation 
becomes  heightened.  Chloroform  acts  on  reciprocal  innervation  in  an 
opposite  way  from  strychnine  and  tetanus;  namely,  it  paralyzes  the  ex- 
citation of  the  contracting  muscles. 

The  Reflex  Figure 

We  have  seen  in  the  preceding  paragraphs  that  the  afferent  fibers  of 
a  single  reflex  arc  make  connection  with  the  motor  neurons  of  a  con- 
siderable group  of  muscles,  exciting  some  and  having  an  inhibitory  in- 
fluence on  others  to  the  end  that  all  may  cooperate  in  producing  an  or- 
derly movement  of  some  functional  significance.  The  effects  of  stimulating 
a  single  afferent  path  may  not  be  limited  to  the  antagonistic  muscles  ar- 
ranged about  a  single  joint,  but  may  extend  to  the  flexors  and  extensors  of 
all  the  joints  in  a  single  limb  and,  further,  to  each  of  the  other  limbs  and  to 
muscles  of  the  head,  trunk,  and  tail  as  well.  The  response  which  follows 
the  application  of  a  strong  stimulus  to  the  receptors  of  a  reflex  arc  may 
consequently  involve  nearly  the  whole  musculature  of  the  animal.  The  par- 


942 


CENTRAL   NERVOUS   SYSTEM 


ticular  attitude  which  is  assumed  is  called  a  reflex  figure,  and  is  the  expres- 
sion of  the  complete  central  connections  of  the  reflex  in  question.  Fig.  241 
illustrates  three  characteristic  reflex  figures  obtained  by  applying  a  harm- 
ful stimulus  to  various  parts  of  the  skin  of  a  decerebrate  cat. 

The  reflex  figure  which  results  from  such  a  stimulus  when  applied 
to  the  foot  of  the  hind  leg  consists  in  a  flexion  of  this  leg,  an  extension 
of  crossed  hind  leg  (the  crossed  extension  reflex),  extension  of  the 
homolateral  fore  leg,  and  flexion  of  the  crossed  fore  leg.  This  group 
of  responses  may  be  considered  to  be  a  compensatory  reaction,  inas- 
much as  the  movement  of  certain  parts  is  adapted  to  restore  a  balance 
which  is  disturbed  by  the  movement  of  other  parts,  and  the  result 
is  an  orderly  change  in  the  position  of  the  body  as  a  whole  which  is 


Fig.  241. — Reflex  figures.  A,  the  position  of  the  cat  in  decerebra 
:ctiyely,  are  the  reflex  figures  resulting  from  stimulating  the  left  pinna, 
:  hind  foot.  (After  Sherrington.) 


. 

spectively 
left    hind 


1) 


decerebrate    rigidity.    B,    C,    D,    re- 
the  left  forefoot,  and  the 


significant  in  meeting  the  exigency  which  has  given  rise  to  the  reflex 
response.  The  reflex  figure  which  we  have  just  described  might  be 
brought  into  play,  for  example,  when  a  cat  steps  on  some  object  which 
hurts  its  hind  foot.  The  hind  foot  is  lifted  from  the  ground  by 
virtue  of  the  contraction  of  the  flexors  and  the  compensatory  inhibi- 
tion of  their  antagonists.  The  weight  of  the  hind  quarters  is  thus 
thrown  on  the  contralateral  hind  leg,  which  extends  to  support  this 
weight,  preventing  the  animal  from  sitting  on  the  source  of  discom- 
fort. At  the  same  time  the  cat  must  prepare  to  move  away  so  that 
the  stimulus  may  not  be  encountered  again,  and  for  this  act  the  exten- 
sion of  the  crossed  hind  leg  and  of  the  homolateral  fore-foot,  with  their 
backward  thrust,  tend  to  throw  the  body  forward  and  support  it  while 
the  flexion  of  the  stimulated  hind  leg  and  the  crossed  fore  leg  move 


INTEGRATION    OF   ACTION    WITHIN    THE    REFLEX   ARC  943 

these  limbs  forward  preparatory  to  supporting  the  body  at  the  next 
step.  The  reflex  figure  is  seen  from  this  to  be  an  integral  mechanism 
out  of  which  is  built  the  functional  act  of  stepping  away  from  a  stim- 
ulus which  endangers  the  hind  foot. 

The  entire  reflex  figure  may  be  considered  to  be  an  unified  reflex 
act  depending  on  the  central  connections  of  a  single  afferent  path,  for 
much  the  same  reasons  which  lead  us  to  conclude  that  excitation  and 
inhibition  of  the  antagonistic  muscles  at  a  single  joint  are  parts  of  a 
single  reflex.  In  all  parts  of  the  reflex  figure  reciprocal  inhibition 
may  be  seen  to  occur,  as  may  be  proved  by  studying  that  component 
known  as  the  crossed-extension  reflex.  As  we  have  pointed  out  above, 
stimulation  of  an  afferent  nerve  from  one  foot  produces  a  contraction 
of  the  contralateral  extensors  and  an  inhibition  of  any  contraction 
which  may  exist  in  the  flexor  muscles  (Pig.  226).  Certain  collaterals 
of  the  afferent  paths  of  the  reflex  must  be  assumed  to  cross  the  cord 
and  exert  an  inhibitory  effect  upon  motor  neurons  of  the  flexors  of 
the  crossed  hind  limb  somewhat  in  the  manner  which  Fig.  240  indicates. 
In  a  similar  way  the  paths  which  lead  to  the  fore  limbs  must  give 
off  collaterals  which  inhibit  the  contraction  of  those  muscles  which 
would  oppose  the  assumption  of  the  reflex  figure.  A  single  afferent 
path  may  in  this  way,  not  only  produce  contraction  in  a  large  group 
of  muscles,  but  by  the  inhibition  of  the  activity  of  their  antagonists 
it  can  preoccupy  a  large  part '  of  the  reflex  mechanism  of  the  spinal 
cord  to  the  exclusion  of  other  reflexes.  Because  of  the  compensatory 
nature  of  the  component  parts  of  the  reflex  figure,  (including  the  occur- 
rence of  reciprocal  inhibition  in  each  part),  which  is  brought  about  by 
the  connections  of  the  various  collaterals  of  the  afferent  path,  the  spinal 
cord  is  enabled,  quite  independently  of  the  higher  centers  in  the  brain, 
to  effect  a  high  degree  of  coordination  in  reflex  response. 

The  various  parts  of  the  reflex  figure  do  not  respond  to  the  same 
threshold  value  of  stimulation.  Weak  stimulation  brings  into  activity 
only  those  muscles  which  affect  the  part  to  which  excitation  is  applied. 
If  the  strength  of  stimulation  is  gradually  increased,  more  and  more 
parts  of  the  total  reflex  figure  appear.  In  stimulating  the  hind  foot 
with  increasing  intensity,  first  the  ankle  alone  is  flexed,  then  the  knee, 
and  finally  the  hip.  The  response  then  spreads  to  include  the  extension 
of  the  crossed  hind  leg  and  finally  involves  the  fore  legs  also.  The 
mechanism  which  determined  the  course  of  this  march  of  the  reflex 
figure  is  the  graded  resistance  of  the  synapses  described  on  page  842. 
It  may  be  reemphasized,  however,  that  as  the  reflex  spreads  to  each 
new  joint  the  inhibition  of  the  antagonists  occurs  coincidently  with  the 


944  CENTRAL  NERVOUS  SYSTEM 

contraction  of  the  active  muscles,  and  the  resistance  of  the  synapses  lying 
in  the  path  to  the  antagonistic  muscle  groups  must  be  equal. 

Rules  for  the  Spread  of  Spinal  Reflexes 

Sherrington37  has  laid  down  the  following  rules  for  the  spread  of 
short  spinal  reflexes,  as  the  components  of  a  reflex  figure  which  in- 
volve only  a  few  spinal  segments  may  be  designated: 

1.  The  degree  of  reflex  spinal  intimacy  between  afferent  and  efferent 
spinal  roots  varies  directly  as  their  segmental  proximity. 

2.  For  each  afferent  root  there  exists  in  immediate  proximity  to  its 
own  place  of  entrance  in  the  cord,  e.  g.,  in  its  own  segment  a  reflex 
motor  path  of  as  low  a  threshold  and  of  as  high  potency  as  any  open 
to  it  anywhere. 

3.  Motor  mechanisms  lying  in  the  same  region  of  the  cord  are  un- 
equally accessible  to  the  local  afferent  channels,  if  judged  by  pressor  ef- 
fects, i.  e.,  the  production  of  contraction.     This  rule  breaks  down,  how- 
ever, when  it  is  considered  that  an  afferent  path  may  produce  inhibition 
in  many  of  the  motor  mechanisms  to  which  it  has  access. 

4.  The  groups  of  motor  nerve  cells  contemporaneously  discharged  by 
spinal  reflex  action  innervate  synergic   and  not  anergic   muscles.     As 
a  consequence  the  muscular  contractions  are  harmonious  with  one  another 
(Reciprocal  Inhibition). 

5.  The  spinal  reflex  movement  elicitable  in  and  from  any  one  spinal 
region  will   exhibit  much   uniformity   despite    considerable    variety    of 
the  locus  of  incidence  of  the  exciting  stimulus. 

The  spread  of  long  spinal  reflexes,  which  are  parts  of  a  reflex  figure 
involving  many  segments  of  the  cord,  is  too  inconstant  in  a  single  re- 
flex figure  and  varies  too  greatly  in  different  figures  to  permit  any  defi- 
nite rules  to  be  laid  down. 


CHAPTER  CI 

THE  INTEGRATION  OF  SIMULTANEOUS  AND  SUCCESSIVE  RE- 
FLEXES 

The  Principle  of  the  Final  Common  Path 

A  single  reflex  acting  independently  of  the  rest  of  the  central  nervous 
system  does  not  really  occur.  An  afferent  impulse  on  entering  the  cord 
spreads  so  as  to  involve  a  large  variety  of  motor  neurons,  each  of  which 
may,  however,  be  excited  through  other  afferent  fibers  arriving  either 
from  other  receptors  or  from  higher  nerve  centers.  The  motor  neuron 
itself  may  therefore  be  a  pathway  occupied  at  different  times  by  very 
different  types  of  nerve  impulse.  Hence  it  is  appropriately  called  the 
final  common  path,  and  its  activity  at  any  moment  must  depend  on  the 
nature  of  the  various  afferent  impulses  that  are  transmitted  to  it  through 
the  synapses.  That  each  motor  neuron  must  be  at  the  service  of  several 
afferent  neurons  becomes  evident  when  it  is  remembered  that  in  the 
spinal  nerve  roots  there  are  three  times  as  many  afferent  fibers  as  there 
are  efferent  fibers,  and  if  the  afferent  fibers  of  the  cranial  nerves  are 
taken  into  account  the  proportion  of  afferent  to  efferent  fibers  becomes 
five  to  one.  Reflex  connections  involve  usually  one  or  more  internun- 
cial  neurons,  and  these  may  act  as  a  common  path  connecting  several 
receptors  with  a  common  motor  mechanism.  The  propriospinal  neurons 
of  the  reflex  arc  for  the  scratch  reflex  described  on  page  935  act  as  a 
common  path  for  impulses  arising  from  distinctly  different  parts  of  the 
skin. 

The  various  reflexes  which  share  the  final  common  path  leading  to  a 
single  group  of  muscles  may  cause  these  muscles  to  respond  (1)  in  some 
definite  way — as  in  the  maintained  contraction  of  the  flexion  reflex; 
(2)  in  some  different  way,  as  in  the  rhythmic  response  of  the  scratch 
reflex;  or  (3)  inhibition  may  be  produced  so  that  no  contraction  can  be 
brought  about.  Reflexes  belonging  to  any  one  of  these  groups  are  allied 
reflexes,  because  they  have  a  common  effect  on  the  motor  mechanism. 
Reflexes  belonging  to  different  groups,  which  consequently  affect  the 
final  common  .path  to  different  purposes  are  antagonistic  reflexes.  Inte- 
gration in  reflex  activity  depends  on  the  consequences  which  follow  when 
allied  or  antagonistic  reflexes  act  upon  the  final  common  path,  either 
simultaneously  or  in  rapid  succession. 

945 


946  CENTRAL  NERVOUS  SYSTEM 

The  Integration  of  Allied  Reflexes 

Simultaneous  Combination. — The  scratch  reflex  is  well  adapted  for 
the  study  of  this  subject  since  the  skin  area  from  which  this  reflex  can  be 
elicited  is  very  widespread  (see  Fig.  238).  The  type  of  reflex  produced 
from  any  given  area  is  in  general  the  same,  although  "the  local  sign" 
—that  is,  the  point  at  which  the  animal  scratches — will  vary  according 
to  the  point  stimulated.  If  we  take  point  A  in  the  reflex  scratch  area 
and  apply  to  it  a  stimulus  which  is  just  inadequate  to  produce  any  reflex 
at  all,  and  then,  while  this  stimulus  is  still  in  progress,  apply  a  similar 
subliminal  stimulus  to  point  B  a  little  removed  from  it,  the  two  sub- 
liminal stimuli  will  become  effective  and  produce  a  typical  scratching 
movement.  In  other  words,  the  subliminal  stimulus  of  point  A  be- 
comes added  on  the  final  common  path  with  the  subliminal  stimulus  of 
point  B;  the  one  has  reinforced  the  other. 

In  a  similar  way  two  stimuli  each  of  which  are  adequate  to  excite 
a  weak  reflex  response  from  a  common  motor  mechanism,  will  reinforce 
one  another  and  produce  a  strong  response  if  they  are  applied  at  the 
same  time. 

The  receptors  from  which  these  mutually  reinforcing  impulses  are  re- 
ceived need  not,  as  in  the  above  example,  be  of  the  same  kind,  similar 
results  being  obtained  by  stimulation  of  receptors  of  widely  different 
kinds,  such  as  exteroceptors  and  proprioceptors.  For  example,  if  a  stimu- 
lus inadequate  to  elicit  a  flexion  reflex  is  applied  to  the  skin  of  the  leg, 
and  another  stimulus,  itself  also  inadequate,  is  applied  to  the  central  end 
of  some  deep  afferent  nerve  in  the  same  leg,  then  the  two  subliminal 
stimuli  will  become  effective  in  producing  a  flexion  movement. 

We  have  seen  that  in  the  development  and  maintenance  of  posture 
the  closest  alliance  takes  place  between  the  exteroceptive  reflexes  which 
initiate  movement  and  the  proprioceptive  reflexes  which  adapt  the  tone 
of  the  muscles  to  the  new  positions  of  the  limbs  (page  917).  Allied  re- 
flexes may  reinforce  one  another  even  though  the  exciting  stimuli  are 
applied  far  apart.  The  flexion  of  the  fore  limb  which  results  from 
stimulation  of  the  fore  paw  is  reinforced,  for  example,  by  a  simultaneous 
excitation  of  the  contralateral  hind  foot — a  stimulation  that  gives  rise 
to  a  reflex  figure  involving  flexion  of  the  fore  limb  as  we  have  seen  in  the 
last  chapter.  Reflexes  which  give  rise  to  inhibition  may  also  reinforce 
one  another  in  their  action  on  the  final  common  path. 

Successive  Combination. — The  reinforcement  which  one  reflex  lends  to 
a  second  allied  reflex  lasts  for  a  short  time  after  the  stimulus  for  the 
first  response  has  been  removed.  Consequently  successive  allied  reflexes 
may  reinforce  one  another.  This  reinforcement  also  can  be  illustrated 
in  the  case  of  the  scratch  reflex.  If  a  stimulus,  inadequate  to  excite  when 


INTEGRATION    OF    SIMULTANEOUS    AND    SUCCESSIVE    REFLEXES  947 

acting  alone,  is  applied  to  a  point  A  on  the  skin,  and  immediately  after  a 
second  stimulus  also  inadequate  to  excite,  is  applied  to  a  point  B,  the 
combined  effect  of  the  two  successive  subliminal  stimuli  may  give  rise 
to  a  reflex  response.  The  threshold  of  some  common  part  of  the  reflex 
arc  has  been  lowered  by  the  effect  of  the  preceding  inadequate  stimulus, 
even  though  it  was  applied  to  a  somewhat  remote  part  of  the  skin.  For 
this  reason  a  moving  stimulus  applied  to  the  scratch  area  is  far  more 
effective  than  a  stationary  stimulus  applied  over  the  same  extent  of  area. 
This  phenomenon  is  called  immediate  induction,  and  it  is  by  no  means 
confined  to  the  spinal  cord.  It  is  well  illustrated,  for  example,  in  the 
case  of  vision.  If  a  thin  line  drawn  on  a  white  card  be  looked  at  so  that 
it  falls  on  the  edge  of  the  receptive  field  of  the  retina,  it  will  not  be  seen 
so  well  as  a  dot  of  similar  width  which  is  moved  through  the  same 
distance  as  the  line. 

The  Integration  of  Antagonistic  Reflexes 

Simultaneous  Combination. — Two  antagonistic  reflexes,  which  use  the 
final  common  path  to  cross  purposes,  naturally  cannot  both  succeed  in 
occupying  it  at  the  same  time.  We  must  examine  what  results  when  two 
such  reflexes  come  into  competition  for  the  control  of  a  common  motor 
mechanism.  The  crossed  extension  reflex  and  the  flexion  reflex  are 
two  responses  utilizing  a  common  group  of  muscles  in  opposite  ways. 
If  we  apply  a  stimulus  to  the  skin  of  the  leg  of  a  decerebrate  animal 
while  the  limb  is  extended  as  the  result  of  a  stimulus  applied  to  the 
contralateral  leg,  the  extension  gives  way  completely  to  the  flexion 
reflex  (Fig.  239).  By  choosing  the  relative  strengths  of  the  stimuli 
properly  a  preexisting  flexion  reflex  may  also  be  interrupted  by  a  crossed 
extension  reflex  (Fig.  226).  In  a  similar  way  the  scratch  reflex  gives  way 
before  a  flexion  reflex.  The  significant  fact  is  that  when  antagonistic 
reflexes  are  in  simultaneous  competition  for  the  final  common  path,  one  of 
them  occupies  the  path  to  the  exclusion  of  all  others.  Accordingly  there 
is  no  tendency  for  a  fusion  of  their  effects,  and  this  is  most  fortunate,  for 
fusion  would  only  result  in  confusion,  since  the  response  would  be  ap- 
propriate for  neither  of  the  simultaneous  stimuli.  This  is  perhaps  the 
most  important  principle  in  the  integration  of  spinal  reflexes  by  the 
final  common  path. 

In  the  competition  of  antagonistic  reflexes  for  the  control  of  the  final 
common  path  several  principles  determine  the  outcome.  These  depend  on 
(1)  the  nature  of  the  reflexes,  (2)  the  relative  intensity  of  the  stimulus, 
and  (3)  fatigue. 

The  nature  of  the  reflex  is  dependent  on  the  quality  of  the  stim- 
ulus and  the  purpose  to  which  it  is  employed.  The  most  prepotent  re- 
flexes are  the  flexions  which  result  from  the  application  of  harmful 


948  CENTRAL    NERVOUS    SYSTEM 

stimuli.  Their  purpose  is  to  protect  the  body  from  immediate  danger 
and  consequently  they  tend  to  displace  other  kinds  of  reflexes  from  occu- 
pancy of  the  final  common  path.  The  reflex  responses  to  all  stimuli  which 
are  capable  in  the  conscious  animal  of  giving  rise  to  strongly  affective 
sensations  tend  to  prevail  over  all  others  and  consequently  the  sexual 
reflexes  share  with  the  responses  to  painful  stimuli  a  position  of  domi- 
nance in  the  competition  of  reflex  activity.  At  the  opposite  extreme  are 
the  postural  reflexes  which  arise  from  proprioceptive  stimuli  and  con- 
cern chiefly  the  extensor  muscles  which  must  support  the  weight  of  the 
body.  These  give  way  before  competing  reflexes  of  other  types  with 
facility.  It  is  important  that  they  should  do  so,  since  postural  tone 
must  always  adapt  itself  to  the  position  into  which  the  body  has  been 
forced  in  response  to  the  stimuli  of  the  environment. 

In  the  case  of  antagonistic  reflexes  of  equal  potency  the  result  of 
competition  for  the  common  path  depends  on  the  relative  strength  of 
the  exciting  stimuli.  Thus  a  flexion  reflex  of  the  hind  leg  will  usually 
displace  a  simultaneous  scratch  reflex,  but  if  the  stimulus  eliciting  the 
scratch  is  strong,  and  that  tending  to  produce  flexion  is  weak,  the 
scratch  reflex  may  persist  and  the  flexion  fail  to  assert  itself. 

When  a  reflex  has  occupied  the  final  common  path  for  some  time 
it  will  become  fatigued,  and  may  then  be  displaced  by  an  antagonistic 
reflex  which  could  not  previously  compete  against  it  successfully.  Thus, 
ordinarily  the  scratch  reflex  is  much  less  readily  elicited  than  the  flexion 
reflex,  and  if  both  are  excited  at  the  same  time  the  latter  will  prevail; 
but  if  the  flexion  reflex  is  kept  up  until  it  shows  signs  of  fatigue,  then 
by  simultaneous  excitation  of  both  reflexes  the  scratch  reflex  will  obtain 
the  mastery.  The  development  of  successive  induction,  which  is  de- 
scribed below,  also  assists  the  competing  reflex  in  gaining  control  as  its 
antagonist  becomes  fatigued. 

The  susceptibility  of  reflex  arcs  to  fatigue  is  probably  of  importance 
in  assuring  the  development  of  variety  in  reflex  responses,  since  it 
prevents  prepotent  responses  from  occupying  the  final  common  path  for 
too  long.  Many  characteristics  differentiate  reflex  fatigue  from  the 
fatigue  of  an  isolated  nerve-muscle  preparation.  The  most  impor- 
tant of  these  distinguishing  features  are  as  follows:  (1)  The  fatigue 
comes  on  intermittently;  thus,  when  the  flexion  reflex  is  persistently 
elicited,  the  first  sign  of  fatigue  is  an  irregular  decline  in  the  flexion 
movement  followed  by  its  entire  disappearance  for  a  short  time.  These 
lapses  become  more  and  more  frequent,  until  at  last  complete  fatigue 
sets  in  and  no  flexion  occurs.  (2)  Reflex  fatigue  soon  passes  off.  (3) 
It  appears  earlier  for  weak  than  for  strong  stimuli.  (4)  The  movement 
produced  by  the  reflex  action  may  also  change  in  character  during  re- 
flex fatigue ;  thus,  the  beat  of  the  scratch  reflex  may  become  slower 


INTEGRATION    OF    SIMULTANEOUS    AND    SUCCESSIVE    REFLEXES  949 

and  less  steady  and  the  foot  be  less  accurately  directed  to  the  spot 
stimulated.  The  locus  of  the  fatigue  in  the  reflex  arc  can  not  be  the 
motor  neuron  itself,  for,  after  this  has  been  completely  fatigued  by 
stimulation  of  the  scratch  area,  the  same  muscles  may  quite  readily 
execute  the  flexion  reflex  if  a  painful  stimulus  is  applied  to  the 
skin  of  the  hind  leg.  It  must  consequently  lie  in  some  part  of  the  afferent 
side  of  the  reflex  arc.  Since  we  know  that  the  nerve  trunk  is  infatigable, 
the  natural  assumption  is  that  reflex  fatigue  is  due  to  a  change  in  con- 
duction across  the  synapses  of  the  neurons. 

Successive  Combination. — If  antagonistic  reflexes  occupy  a  final  com- 
mon path  in  succession   it  is  found   that  the  use   of  it   by   one   reflex 


Fig.  242. — Successive  induction  illustrated  by  the  crossed-extension  reflex.  The  reflex,  elicited 
periodically  with  a  stimulus  of  low  intensity,  is  recorded  in  A  and  B.  Between  B  and  C  a  strong 
flexion  reflex  was  provoked  and  maintained  for  45  seconds.  C  illustrates  the  immediately  succeeding 
extension  reflex,  which  is  greatly  augmented  by  successive  induction.  The  next  extension  (Z?)  is 
also  slightly  augmented,  but  in  the  third  extension  (E)  the  augmentation  has  passed  off.  The 
signal  recording  the  stimulation  is  above;  time  is  indicated  in  seconds  below.  (From  Sherrington.) 

facilitates  its  subsequent  use  in  a  movement  antagonistic  to  that  which 
first  occupied  the  motor  mechanism.  This  phenomenon  is  known  as 
successive  induction. 

In  the  spinal  animal  successive  induction  is  demonstrated  by  us- 
ing two  reflexes  that  are  of  a  more  or  less  antagonistic  character — 
for  example,  the  flexion  reflex  and  the  knee-jerk,  or  better  still  the 
crossed  extension  reflex  and  the  flexion  reflex.  If  we  elicit  the  knee- 
jerk  in  a  spinal  dog  at  regular  intervals,  with  stimuli  of  equal  intensity, 
the  extension  movements  (the  kicks)  will  be  approximately  equal.  If 
now  we  apply  a  nocuous  stimulus  to  the  skin  of  the  foot  and  so  throw 
the  leg  into  flexion,  it  will  be  found,  after  the  flexion  movement  has  dis- 


950  CENTRAL  NERVOUS  SYSTEM 

appeared,  that  the  knee-jerk  is  much  more  pronounced  than  previously. 
Similarly,  if  we  elicit  the  crossed  extension  reflex  by  nocuous  stimuli 
of  equal  intensity  applied  to  the  opposite  limb,  the  extension  movements 
will  be  approximately  equal.  By  now  throwing  the  limb  exhibiting  them 
into  the  flexion  reflex,  the  extensor  movements  will  of  course  disappear, 
but  after  the  flexion  has  been  discontinued,  they  will  reappear  with 
increased  intensity  (Fig.  242). 

These  facts  show  us,  then,  that  after  the  final  common  path  has  been 
occupied  by  a  reflex  of  one  type,  it  becomes  more  available  to  a  reflex 
of  an  opposite  type.  Successive  induction  gives  rise  to  a  series  of  re- 
sponses which  afford  a  further  example  of  the  compensatory  movements 
produced  by  the  integrative  action  of  the  spinal  cord.  By  facilitating 
the  occupancy  of  the  final  common  path  by  reflexes  opposite  in  nature 
to  those  which  have  just  occupied  it,  movements  are  brought  about  which 
restore  the  position  which  was  disturbed  by  the  primary  response. 
In  other  words,  it  is  evident  that  if  the  two  opposite  reflexes  are 
constantly  competing  with  each  other  for  possession  of  the  final  com- 
mon path,  they  will  tend  alternately  to  occupy  it,  thus  bringing  about 
a  rhythmic  movement.  Such  is  the  mechanism  involved  in  walking; 
the  leg  is  lifted  from  the  ground  (flexion  reflex)  ;  it  is  then  brought 
on  the  ground,  and  the  mechanical  push  given  to  the  plantar  surface 
of  the  foot  brings  out  the  extensor  thrust,  the  appearance  of  which 
is  greatly  facilitated  by  the  fact  that  immediately  before  the  flexion 
reflex  occupied  the  final  common  path. 


CHAPTER  Oil 

THE  INTEGRATIVE  ACTION  OF  THE  CEREBRUM 

The  motor  areas  of  the  cerebral  cortex  are  connected  through  the 
pyramidal  tracts  with  the  various  lower  motor  neurons  of  the  body. 
We  have  seen  that  the  excitation  of  a  localized  area  in  the  motor  cor- 
tex may  bring  about  a  response  of  some  localized  group  of  muscles 
which  is  coordinated,  involves  recriprocal  inhibition,  and  develops 
through  an  orderly  march  in  much  the  same  way  as  does  the  reflex 
figure  which  arises  from  a  cutaneous  stimulation.  These  responses 
utilize  the  same  motor  mechanisms  as  the  spinal  reflexes  do,  and  con- 
sequently come  in  competition  with  them  for  use  of  the  final  common 
paths.  Consequently  cerebral  influences  may  modify  profoundly  re- 
flex responses,  reinforcing  them  when  both  affect  the  motor  mechanism 
in  the  same  way,  inhibiting  them  when  their  actions  are  antagonistic. 
The  inhibitory  aspects  of  the  cerebral  influence  are  particularly  prom- 
inent, and  consequently  many  reflexes  are  elicited  with  greater  cer- 
tainty in  animals  from  which  the  cerebrum  has  been  removed.  In  this 
competition  probably  much  the  same  factors  determine  which  influence 
shall  control  the  common  path  as  govern  which  of  two  antagonistic 
spinal  reflexes  shall  prevail.  Cerebral  influences  are  apparently  prepo- 
tent over  all  but  the  most  intense  reflex  responses  to  harmful  stim- 
uli and  those  which  result  from  strongly  affective  sensations.  We  can, 
for  example,  inhibit  the  reflex  withdrawal  of  the  hand  from  hot  water 
unless  the  pain  is  particularly  intense.  On  the  other  hand  it  is  diffi- 
cult to  refrain  from  winking  when  the  cornea  becomes  irritated.  Within 
limits  the  respiratory  reflex  may  be  controlled  by  the  will,  but  when 
the  stimulus  to  the  respiratory  center  becomes  intense,  the  breath 
can  no  longer  be  held.  A  large  group  of  reflex  arcs  concerned  with 
the  regulation  of  the  visceral  organs  are  not  connected  with  the  paths 
from  the  cerebrum  and  consequently  cannot  be  brought  under  vol- 
untary control. 

In  describing  the  motor  areas  in  the  cortex  it  was  pointed  out  that 
these  were  points  at  which  many  neurons  from  widely  separated  parts 
of  the  brain  converge  upon  paths  which  lead  to  the  lower  motor  neu- 
rons and  their  muscles.  The  pyramidal  fibers  consequently  are  com- 
mon paths  used  in  many  diverse  volitional  responses.  For  their  con- 
trol many  different  influences  come  into  competition  and  the  unpre- 
dictable nature  of  volitional  response  is  no  doubt  due  to  the  impos- 

951 


952  CENTRAL    NERVOUS    SYSTEM 

sibility  of  determining  which  of  the  antagonistic  elements  in  this  com- 
petition will  prevail.  Deviation  from  the  " straight  and  narrow  path" 
may  well  be  due  to  the  failure  of  the  proper  influences  to  gain  control 
of  the  internuncial  mechanism  of  voluntary  action  to  the  exclusion  of 
all  others.  The  paralyses  of  hysteria  are  perhaps  also  due  to  the  con- 
trol of  the  common  paths  from  the  brain  by  an  inhibitory  influence 
which  cannot  be  displaced  by  ordinary  volitional  impulses. 

The  Relation  of  the  Cerebrum  to  the  Distance  Receptors. — The  de- 
velopment of  the  brain  in  the  leading  segments  of  the  body  is  asso- 
ciated in  all  animals  with  the  acquirement  of  the  distance  receptors 
of  the  head,  i.  e.,  the  eye,  ear,  and  olfactory  organ.  These  sense  organs 
serve  to  acquaint  the  organism  with  parts  of  its  environment  with 
which  it  has  not  yet  come  into  immediate  contact.  They  are  suited 
to  bring  about  responses  which  are  anticipatory  of  the  consequences 
of  more  direct  contact  with  objects  in  the  environment,  that  is,  of  the 
seizure  and  consumption  of  food,  the  appropriation  of  a  mate,  or  the 
avoidance  of  objects  wrhich  might  prove  harmful  on  closer  contact.  In 
order  that  responses  toward  distant  objects  may  be  made  with  dis- 
crimination, a  mechanism  has  been  evolved  which  apprehends  the  dis- 
tant object  not  merely  as  a  stimulus  possessing  a  single  quality,  but 
as  a  " thing"  built  up  of  a  number  of  properties,  and  the  response  is 
determined  by  these  properties  as  a  group.  Since  the  properties  of 
such  environmental  objects  appeal  to  a  variety  of  receptors,  the  sensa- 
tions aroused  by  each  must  be  combined  in  the  nervous  system  and  built 
up  into  a  definite  concept  by  a  process  of  association. 

Moreover,  since  the  response  to  the  distant  object  is  of  an  anticipatory 
nature,  it  must  be  made  with  reference  to  the  past  experience  which  the  ani- 
mal has  had  with  objects  presenting  a  similar  group  of  properties.  Conse- 
quently the  results  of  contact  with  the  object  must  be  associated  as  part  of 
the  concept  with  the  various  properties  which  have  appealed  to  the  distance 
receptors,  in  order  that  when  such  an  object  enters  the  environment  at 
a  later  time  the  results  of  the  previous  encounter  may  be  recalled  and 
behavior  modified  accordingly.  In  other  words  distant  objects  appeal 
to  the  nervous  system  by  virtue  of  the  meaning  which  is  placed  upon  the 
particular  combination  of  receptors  which  they  excite,  and  the  sensations 
which  arise  as  a  result.  The  nature  of  the  response  which  is  thus  called 
forth  depends  on  the  memory  of  past  experience  with  similar  objects. 
For  this  reason  the  development  of  distance  receptors  is  associated  with 
the  development  of  the  cerebrum  in  which  association  and  memory  mani- 
fest themselves.  The  modification  of  behavior  through  the  correlation 
of  present  and  past  experience  is  the  process  of  learning,  which  is  one 
of  the  chief  characteristics  by  which  responses  influenced  by  the  cere- 


INTEGRATTVTE    ACTION    OP    THE    CEREBRUM 


953 


brum  are  differentiated  from  those  of  the  loAver  levels  of  the  nervous 
system. 

The  relation  which  the  distance  receptors  bears  to  the  cerebral  proc- 
esses is  well  illustrated  by  a  comparison  of  the  responses  of  animals  of 
different  kinds  toward  light.  Many  of  the  lower  organisms  possess  eyes 
incapable  of  forming  an  image  such  as  is  produced  in  the  eye  of  the 
vertebrate.  Their  eyes  are  so  arranged  as  to  be  stimulated  by  light 
coming  only  from  a  certain  direction.  Consequently  the  eye  may  form 
a  guide  which  determines  the  direction  of  progression,  which  will  be 
either  toward  or  away  from  the  light  according  to  the  kind  of  animal 
which  is  studied.  Such  an  animal  obviously  cannot  act  with  much 
discretion  in  regard  to  light  from  different  sources,  since  the  shape  of  the 
source  of  light  and  perhaps  the  color  of  the  light  make  no  appeal  to 
it.  The  insects  and  Crustacea  possess  eyes  which  are  capable  of  forming 
an  image  and  consequently  might  be  capable  of  distinguishing  between 
the  light  of  a  candle  and  that  from  an  open  window.  The  development 
of  the  nervous  system  of  these  animals  has  not  kept  pace,  however,  with 


Fig.  243. — Postures  assumed  by  the  robber  fly  when  the  eyes  are  unequally  illuminated:  illustrat- 
ing the  influence  of  light  on  the  tone  of  the  muscles.  A,  the  lower  half  of  each  eye  is  blackened; 
B,  the  upper  half  of  each  eye  is  blackened;  C,  the  right  eye  is  blackened.  (After  Garry.) 

the  optical  perfection  of  the  ocular  mechanism.  Each  part  of  the  retina 
is  connected  in  a  rather  inflexible  way  with  certain  parts  of  the  motor 
mechanism.  Unequal  stimulation  of  the  different  parts  of  the  retina 
causes  certain  parts  of  the  musculature  to  become  more  active  than  other 
parts — in  other  words  sets  up  a  characteristic  reflex  figure  (Fig.  243). 
In  the  robber  fly,  for  example,  light  falling  on  the  upper  half  of  the 
retina,  when  the  lower  half  is  covered  by  opaque  cement,  causes  the  trunk 
to  be  curved  upward,  the  forelegs  extended  and  the  hind  legs  flexed. 
On  taking  flight  the  insect  tends  to  swerve  upward  and  backward 
and  consequently  loops  the  loop.  Blinding  the  upper  half  of  the  retina 
has  the  reverse  effect.  If  one  eye  only  is  covered,  the  legs  of  that  side 
are  extended,  those  of  the  opposite  side  flexed,  and  in  walking  the  fly 
tends  to  circle  toward  the  side  on  which  the  eye  is  exposed  to  light.  By 
virtue  of  the  physiological  influence  of  the  eyes  on  the  muscles  the 
direction  of  locomotion  of  these  insects  is  guided  with  mechanical  pre- 


954  CENTRAL  NERVOUS  SYSTEM 

cision  toward  the  light.  The  flight  of  the  moth  into  a  candle  is  deter- 
mined in  a  similar  way.  The  nervous  system  of  the  insects  is  singularly 
incapable  of  modifying  its  responses  as  a  result  of  past  experience;  it  is 
weak  in  the  display  of  association  and  memory.  Consequently  the 
moth  does  not  learn  that  contact  with  a  candle  flame  is  attended  by  dis- 
aster and  repeats  its  flights  into  the  flame  until  it  has  achieved  its  self- 
destruction. 

It  is  because  of  the  development  of  the  associative  powers  of  the 
cerebrum  parallel  with  the  perfection  of  the  ocular  mechanism  that  the 
behavior  of  the  mammals  and  man  is  adjusted  to  past  experience  with 
greater  success  than  is  that  of  the  insects.  The  human  infant  devel- 
ops in  the  fifth  month  a  reaction  which  leads  it  to  reach  for  any  ob- 
ject brought  sufficiently  close  within  its  field  of  vision.  The  response 
is  elicited  by  a  lighted  candle  as  well  as  by  a  harmless  object  such  as 
a  piece  of  candy.  When  reaching  for  the  candle  is  first  developed,  the 
movement  is  not  checked  until  the  heat  of  the  candle  actually  reaches 
the  fingers  and  sets  up  a  protective  flexion  deflex.  By  repeated  trials 
the  baby  develops  within  two  months  a  modified  response  to  the  candle, 
the  reaching  reaction  being  completely  inhibited.  Reaching  for  candy 
still  persists  without  diminution.  The  infant  has  developed  an  asso- 
ciation between  the  particular  configuration  of  stimuli  which  the  candle 
produces  upon  the  retina  and  the  harmful  consequences  of  reaching  for 
this  object,  and  responds  to  the  stimulus  by  a  response  suitable  to  the 
painful  effects  which  have  previously  attended  its  experiences  with  the 
candle. 

Conditioned  Reflexes 

The  nature  of  the  responses  of  animals  with  the  cerebrum  intact  is  less 
predictable  than  that  of  the  spinal  animal  in  which  the  cord  is  removed 
from  cerebral  control,  because  these  responses  are  conditioned  by 
the  previous  experience  of  the  animal  and  the  associations  which  it  has 
formed  between  various  stimulating  objects  and  the  consequences  which 
result  from  its  hereditary  types  of  response.  The  altered  responses 
which  develop  by  virtue  of  the  modifying  influence  which  the  cerebrum 
exerts  over  reflex  action  are  consequently  called  conditioned  reflexes, 
in  contrast  to  the  unconditioned  reflexes  of  the  spinal  cord. 

It  must  be  considered  as  one  of  the  greatest  advances  of  modern 
physiology  that  Pavlov  and  others  should  have  succeeded  in  evolving 
methods  by  which  we  may  arrive  at  conclusions  regarding  the  nature  of 
certain  of  the  integrations  which  occur  when  such  conditioned  reflexes 
are  formed,  since  they  show  us  the  elementary  nature  of  the  processes 
by  which  the  association  of  the  results  of  sensory  stimuli  leads  to  modi- 
fied forms  of  behavior. 


1NTEGRATIVE    ACTION    OF    THE    CEREBRUM  955 

The  methods  employed  for  the  study  of  these  higher  integrations  of 
the  central  nervous  system  all  depend  on  the  reactions  of  the  animal 
that  are  associated  with  the  taking  of  food.  When  the  food  is  actu- 
ally placed  in  the  mouth,  it  excites  a  secretion  of  saliva,  whatever  the 
circumstances  may  be.  This  is  an  unconditioned  reflex.  Suppose,  how- 
ever, that  every  time  food  is  given  a  particular  sound  is  made;  after 
some  time  it  will  be  found  that  the  occurrence  of  the  sound  alone  is 
sufficient  to  cause  a  secretion  of  saliva.  In  other  words,  a  conditioned 
reflex  has  been  formed.  Similarly,  sight  or  smell  or  any  other  type  of 
sensation  may  be  made  the  excitant  for  the  conditioned  reflex.  The 
secretion  now  becomes  psychic  instead  of  merely  physiological.  To  quote 
Bayliss:  "Any  phenomenon  of  the  outer  world  for  which  the  animal  in 
question  possesses  appropriate  receptors  can  be  drawn  into  temporary 
association  with  salivary  secretion,  so  that  it  becomes  an  exciter  of  se- 
cretion if  only  it  has  been  frequently  presented  at  the  same  time  with 
the  unconditioned  reflex  stimulus,  food  in  the  mouth. " 

Work  along  lines  similar  to  that  devised  by  Pavlov  has  more  recently 
been  undertaken  by  students  of  animal  behavior,  who  have  utilized  the 
acquired  habits  of  an  animal  in  searching  for  its  food  in  order  to  study  the 
influence  of  conditioning  circumstances  on  its  procedure.  The  advantage 
of  this  method  depends  mainly  on  the  fact  that  it  can  be  applied  to  all 
groups  of  animals.  In  carrying  out  such  an  observation,  the  animal  is 
placed  in  one  compartment  of  a  cage,  from  which  it  is  then  released  to 
a  second  compartment,  the  end  of  which  is  divided  into  two  passage- 
ways, one  leading  to  food,  the  other  leading  to  some  compartment  in 
which  the  animal  is  punished  for  its  mistake  as  by  receiving  an  electric 
shock.  Objects  such  as  colored  lights  are  placed  in  the  different  pas- 
sageways, and  the  animal  by  repeated  trial  comes  ultimately  to  learn 
which  particular  colored  light  signifies  the  passage  along  which  he 
will  receive  food.  A  reflex  has  therefore  become  established  conditioned 
on  the  particular  colored  light. 

On  account  of  the  unavailability  of  his  publications,  it  is  impossible 
at  present  to  give  any  complete  account  of  Pavlov's  discoveries.  A  few 
facts,  however,  are  of  such  importance  that  it  is  necessary  for  us  to 
state  them  here  as  far  as  we  know  them.  (See  Bayliss,  Physiology.)  Two 
mechanisms  seem  to  be  concerned  in  the  conditioned  reflexes:  (1)  that 
of  temporary  association,  and  (2)  that  of  analysis.  Temporary  associa- 
tion is  well  illustrated  in  the  above  experiment  in  which  the  secretion  of 
saliva  is  induced  by  a  sound.  Temporary  association  of  the  sound  with 
the  secretion  of  the  saliva  may  readily  be  inhibited  by  all  kinds  of  ex- 
ternal phenomena;  thus,  if  the  dog's  attention  becomes  diverted  while 
the  conditioned  reflex  is  being  stimulated,  the  response  does  not  occur. 


956  CENTRAL  NERVOUS  SYSTEM 

In  a  dog  that  had  been  trained  to  secrete  saliva  at  the  sound  of  a  par- 
ticular metronome  beat,  inhibition  occurred  one  day  because,  just  as 
the  dog  was  being  presented  with  the  food,  the  laboratory  servant  made 
a  noise  outside  of  the  building  which  diverted  the  animal's  attention. 
The  conditioned  reflex  may  also  be  interfered  with  by  internal  inhibi- 
tion, which  is  illustrated  by  experiments  in  which,  after  a  dog  has  been 
trained  to  respond  to  a  given  conditional  reflex,  several  occasions  follow 
when  food  is  not  given  to  the  animal  after  the  particular  sensation  to  which 
it  has  been  trained  to  respond.  The  condition — for  example,  a  sound — loses 
its  effect.  This  is  internal  inhibition,  but  it  is  a  temporary  condition 
since  the  reflex  returns  of  itself  after  a  period  of  rest. 

These  experiments  illustrate  what  is  meant  by  the  formation  of  tem- 
porary associations  occurring  in  conditioned  reflexes,  but  in  order  that 
there  may  be  a  fine  discrimination  between  those  stimuli  which  shall 
and  those  which  shall  not  serve  to  call  forth  the  conditioned  reflex,  an- 
other mechanism  becomes  involved — that  of  analysis.  This  is  performed 
by  a  sense  organ  the  function  of  which  is  to  separate  and  distinguish 
the  complicated  phenomena  of  the  outer  world.  For  example,  it  has 
been  proved  that  small  differences  in  the  pitch  of  a  musical  note  may 
determine  whether  or  not  a  conditioned  reflex  will  be  excited  or  in- 
hibited, as  in  the  case  of  one  animal  that  was  trained  to  respond  by 
the  secretion  of  saliva  to  a  tuning  fork  vibrating  at  100  per  second.  It 
was  found  that  no  secretion  was  produced  by  a  tuning  fork  vibrating 
at  104  or  at  96.  Much  work  has  also  been  done  with  the  skin  receptors. 
Thus,  when  a  given  spot  of  skin  is  stimulated  every  time  that  food  is 
presented,  this  becomes  an  active  spot  for  the  conditioned  reflex.  At 
the  same  time  another  spot  may  be  stimulated  so  as  to  be  associated  by 
the  animal  with  the  nonpresentatioii  of  food;  it  is  a  conditioned  reflex 
for  no  food,  and  is  associated  with  the  absence  of  salivary  secretion. 

By  comparing  the  responses  from  active  and  inactive  spots  when  both 
are  stimulated  either  simultaneously  or  at  close  intervals,  much  can 
be  learned  concerning  the  delicacy  of  appreciation  for  external  stimuli 
and  the  influence  of  the  inhibitory  on  the  excitatory  process.  Bayliss 
cites  the  following  experiment.  Along  a  series  of  spots  on  the  skin 
of  the  leg  five  devices  are  arranged  for  producing  equal  mechanical 
stimulations  of  the  skin.  The  four  uppermost  of  these  .are  made  active 
spots  for  the  salivary  reflex,  and  the  lowest  one  inactive — that  is,  when- 
ever it  is  stimulated  no  food  is  presented.  Let  us  suppose  that  upon 
administering  mechanical  stimuli  of  equal  intensity  to  each  of  the  four 
active  spots,  a  certain  amount  of  saliva  is  produced  in  a  certain  time;  if 
now  the  inactive  spot  is  stimulated  and  then  thirty  seconds  later  one 
of  the  uppermost  spots,  there  will  be  no  secretion.  The  previous  stimu- 


INTEGRATIVE    ACTION    OF    THE    CEREBRUM  957 

lation  of  the  inactive  spot  must  have  caused  an  inhibition  to  be  set 
up  in  the  nerve  centers  concerned  in  the  reflex.  This  inhibition  only 
gradually  passes  away,  disappearing  first  in  the  spot  farthest  removed 
from  that  made  inactive,  but  it  may  take  several  minutes  before  all  the 
active  spots  have  reacquired  their  original  sensitivity. 

The  persistence  of  the  inhibition  produced  by  stimulating  the  inac- 
tive spot  in  the  above  experiment  indicates  an  important  factor  in  con- 
nection with  the  production  of  conditioned  reflexes.  For  example,  an 
animal  can  be  trained  to  know  that  in  a  certain  number  of  minutes  after 
the  sound  of  a  given  bell  food  will  be  presented  to  him;  the  condi- 
tioned reflex  will  become  established  so  that  he  salivates  at  exactly 
the  same  time  after  the  bell  is  sounded.  Something  must  be  going  on 
in  the  centers  during  this  time — something  inhibiting  the  reflex.  If 
during  this  interval  of  inhibition  some  other  sensory  stimulus  is  applied, 
it  will  be  likely  to  cut  short  the  inhibition;  in  other  words,  it  produces 
an  inhibition  of  inhibition,  so  that  the  secretion  of  saliva  occurs. 

Another  most  curious  combination  of  conditioned  stimuli  is  illustrated 
in  the  following  experiment.  Suppose,  for  example,  that  a  given  light 
and  sound  are  each  separately  made  a  stimulus  for  a  conditioned  reflex, 
but  that  when  they  occur  together  there  is  no  reflex.  Suppose  now  that 
while  one  of  these  active  stimuli  is  being  presented,  the  other  stimulus 
is  also  presented;  the  result  will  be  that  the  secretion  produced  by  the 
one  stimulus  will  stop.  Evidently,  although  each  is  in  itself  a  stimulus, 
acting  together  they  cause  inhibition. 

By  studying  the  conditioned  reflexes  after  a  certain  part  of  the  cere- 
bral cortex  has  been  removed,  it  has  been  found  that  the  power  of  estab- 
lishing certain  kinds  of  conditioned  reflexes  becomes  abolished,  while 
that  for  others  is  retained. 

The  writing  of  Sherrington,37  Loeb,38  Watson,39  and  Margulis41  should 
be  consulted  for  further  details  concerning  the  material  in  this  chapter. 


CHAPTER  CHI 

THE  HIGHER  FUNCTIONS  OF  THE  CEREBRUM  IN  MAN; 

APHASIA 

The  study  of  the  higher  functions  of  the  cerebrum  leads  us  to  the  border- 
land between  physiology  and  psychology,  but  into  this  vast  and  relatively 
unexplored  field  we  can  not  venture  here,  unless  just  far  enough  to  gain  a 
suitable  vantage  point  from  which  to  understand  the  pathology  of  the 
condition  known  as  aphasia*  As  we  have  seen  from  our  studies  on  cerebral 
localization,  the  cerebrum  must  be  regarded  as  a  great  sensorimotor  gan- 
glion, whose  functional  activities  are  indicated  by  various  movements. 
These  movements  may,  in  general,  be  classified  as  objective  indications 
either  of  feeling  and  emotion  or  of  intelligence.  Although  both  classes  are 
evident  in  all  animals,  it  is  particularly  in  the  case  of  man  that  the  evi- 
dences of  intelligent  activity  are  especially  prominent,  since  they  include 
gesticulation  and  the  muscular  activities  required  in  spoken  and  written 
language.  The  movements  that  express  emotional  conditions  are  evolved 
earlier  and  from  lower  planes  than  those  of  intellectual  activity.  Thus, 
very  young  infants  "make  faces"  when  there  is  reason  to  believe  they 
feel  pain,  and,  as  they  develop,  their  power  of  expressing  emotion  is 
evolved  long  before  they  present  evidence  of  intelligent  motor  activity, 
and  still  longer  before  they  can  articulate  words. 

The  phenomenon  of  human  psychic  activity  which  is  of  greatest  im- 
portance is  that  of  language,  and  to  understand  the  nature  of  the  cerebral 
integration  required  to  produce  it,  we  must  briefly  consider  the  cerebral 
processes  involved  in  the  intellectual  development  of  the  infant.  The 
first  step  in  this  development  is  the  storing  away  in  projection  centers  of 
memories  of  the  sensations  which  these  centers  have  received.  For  ex- 
ample, when  the  child  looks  at  a  bell,  there  is  stored  in  the  visual  center  a 
memory  of  the  shape  of  the  bell,  and  when  the  bell  moves  so  as  to  produce 
sound,  this  also  is  stored  as  a  sound  impression  in  the  auditory  center. 
Likewise,  when  he  touches  the  bell  impressions  of  its  hardness  and  smooth- 
ness and  temperature  are  stored  in  the  centers  for  cutaneous  sensations. 
At  first  each  of  these  memory  impressions  occupies  an  isolated  position; 
but  later,  association  tracts  open  up  between  them,  so  that  the  calling 
forth  of  one  memory  impression  is  associated  with  others,  and  the  child 


*Free  use  of  the  article  by  Bolton40  is  made  in  this  chapter. 

958 


HIGHER   FUNCTIONS   OF   THE    CEREBRUM   IN    MAN;    APHASIA  959 

comes  to  be  able  to  associate  the  appearance  or  image  of  the  bell  with  a 
certain  sound  and  with  certain  sensations  of  hardness,  rotundity,  etc.  This 
preliminary  use  of  observation  is  known  as  perception.  It  involves  the 
fusion  of  direct  sensations  as  well  as  their  correlation  with  memory  im- 
pressions, of  former  sensations.  The  number  and  variety  of  the  latter 
called  into  activity  by  a  particular  sensation  will  obviously  vary  at  dif- 
ferent times.  On  seeing  a  bell,  for  example,  a  child  may  associate  it  with 
sound  on  one  occasion,  and  on  the  next  with  the  feeling  of  the  bell.  On 
account  of  this  difference  in  the  detail  of  the  method  of  association,  it  is 
evident  that  perception  must  be  a  product  of  cerebral  integration  rather 
than  one  depending  on  memory  impressions  stored  in  the  isolated  centers. 
It  is  a  complicated  process  with  an  infinite  variety  of  possibilites  as  to  the 
exact  way  in  which  it  is  integrated  on  each  occasion. 

The  act  of  perception,  however,  becomes  considerably  simplified  in  the 
higher  animals  by  the  laying  down  of  short-cut  paths  of  association. 
These  are  formed  first  of  all  with  the  auditory  center,  in  which  the  memory 
impression  of  an  articulated  sound  representing  the  object — for  example, 
the  word  ''bell" — is  stored  away.  The  child  comes  to  learn  that  this  par- 
ticular word  is  to  be  associated  with  the  memory  impressions  it  has  stored 
awajr  of  the  sound,  the  sight,  and  the  feeling  of  the  bell.  Similar  short-cut 
paths  later  become  developed  in  connection  with  the  visual  centers,  where 
a  certain  symbol,  like  the  word  "bell,"  is  presented  to  the  child  as  signi- 
fying all  the  other  attributes  of  bell.  In  its  most  highly  developed  form, 
therefore,  perception  may  be  described  as  the  act  of  calling  up  one  or 
more  sensorimemorial  images  when  a  name  is  seen  or  heard. 

Having  acquired  the  ability  to  integrate  sensorimemorial  impressions 
in  the  above  described  manner,  the  child  next  learns  to  integrate  the  motor 
centers  concerned  in  the  control  of  the  articulatory  apparatus  so  as  to 
produce  a  sound.  This  sound  is  the  word  indicating  the  object  involved 
in  the  integrating  process.  It  is  the  integration  necessary  to  produce  the 
sound  which  symbolizes  the  particular  object. 

When  the  power  of  understanding  and  producing  language  has  been 
acquired,  the  crowning  process  of  intellectual  development — the  forma- 
tion of  a  concept,  or  general  notion — becomes  evolved.  Thus,  the  evolu- 
tion of  a  general  name  will  include  a  number  of  particular  objects  or  acts. 
"This  process  of  conception  involves  the  revivification  of  numerous  sen- 
sorimemorial images  which  present  common  points  of  similarity" — (Bol- 
ton).  It  is  relatively  a  simple  process  for  such  general  objects  as  animal, 
man,  building,  but  becomes  very  complex  for  such  abstract  concepts  as 
heaviness,  beauty,  etc.  It  is  obviously  a  process  to  which  no  one  cerebral 
center  can  be  assigned.  The  outward  manifestation  of  the  conception  is 
spoken  or  written  language. 


960  CENTRAL  NERVOUS  SYSTEM 

Language  consists,  therefore,  in  an  extremely  complex  symbolic  system, 
involving  various  centers  and  association  tracts  in  the  cerebrum,  and 
capable  of  an  almost  infinite  degree  of  development  by  the  laying  down 
of  new  symbolic  systems.  Language,  indeed,  becomes  the  instrument  of 
thought,  practically  all  of  the  higher  intellectual  processes  being  dependent 
on  its  evolution.  In  this  connection  it  is  interesting  to  note  that  a  great 
number  of  individuals,  especially  those  who  do  not  read,  depend  on  the 
sense  of  hearing  for  the  acquisition  of  the  impressions  required  for  their 
psychic  development,  while  others  depend  on  the  sense  of  sight  for  the 
same  purpose. 

At  least  four  different  types  of  center  are  involved  in  the  integration 
of  language;  namely,  auditory,  visual,  chirographic,  and  articulatory.  We 
may  call  these  "word  centers,"  and  we  must  assume  that  they  lie  near  to 
the  auditory,  visual  and  general  sensory  projection  areas  of  the  cortex. 
To  understand  and  to  be  able  to  produce  spoken  and  written  language,  it 
is  necessary  that  all  these  four  word  centers  participate  through  associa- 
tion tracts,  although  the  meaning  of  a  word  may  be  perceived  without  all 
of  them  being  involved. 

PSYCHOPATHOLOGICAL  APPLICATIONS 

In  the  study  of  mental  diseases  the  most  important  conclusion  which 
we  can  draw  from  the  above  facts  is  that  language  is  essentially  a  sym- 
bolic mechanism  for  the  integration  of  sensorimemorial  images.  It  is 
therefore  the  symbolic  system  of  the  integrated  processes  of  the  brain;  it 
is  the  servant  of  thought.  When,  as  is  often  the  case,  language  is  used 
without  the  proper  exercise  of  thought,  it  becomes  merely  an  automatic 
affair.  A  practical  deduction  from  these  facts  is  that  any  considerable 
derangement  of  the  language  mechanism  must  necessarily  involve  some 
interference  with  the  complicated  processes  of  association  that  go  to  make 
up  the  psychic  function. 

These  considerations  naturally  lead  us  to  the  subject  of  aphasia.  It  has 
been  usual  to  distinguish  three  varieties  of  this;  namely,  motor  aphasia, 
sensory  aphasia,  and  anarthria.  In  motor  aphasia  the  patient,  although 
he  understands  what  is  said  to  him,  is  unable  to  speak,  and  the  intellectual 
powers  are  little,  if  at  all,  impaired.  In  sensory  aphasia  speech  is  possible 
in  a  more  or  less  intelligible  manner,  but  there  is  a  distinct  impairment  of 
intelligence.  In  anarthria,  or  subcortical  aphasia,  the  only  disability  is  the 
loss  or  impairment  of  the  power  of  articulate  speech  because  of  some  lesion 
existing  in  the  center  coordinating  the  lower  neurons  concerned  in  the 
movements  of  the  laryngeal  and  tongue  muscles.  Pierre  Marie,  as  a 
result  of  very  extensive  experience  in  Paris,  has  shown  that  this  classifi- 
cation is  unjustified.  He  maintains  that  there  is  only  one  true  form  of 


HIGHER    FUNCTIONS   OF   THE    CEREBRUM   IN    MAN;    APHASIA  961 

aphasia,  and  that  such  a  thing  as  pure  motor  aphasia  as  above  defined 
does  not  exist,  the  condition  being  invariably  accompanied  by  intellectual 
impairment. 

Marie  points  out  that  the  various  claims  that  aphasia  may  exist  without 
intellectual  impairment  have  been  made  without  sufficient  investigation  of 
the  intellectual  status  of  the  patient.  He  shows  that  many  patients  suf- 
fering from  aphasia  if  asked  to  do  ordinary  things,  such  as  cough  or  spit 
or  raise  the  hand,  can  do  them  as  well  as  a  normal  individual,  but  that 
these  after  all  are  very  crude  acts  in  the  ordinary  performances  of  a  normal 
individual.  To  test  the  intellectual  powers  it  is  necessary  to  require  the 
patient  to  perform  acts  which  entail  a  considerable  amount  of  cerebral 
integration.  We  must  ask  him  to  perform  some  sequence  of  events  such 
as  walking  several  times  in  one  direction,  then  in  another,  touching  cer- 
tain objects,  etc.,  or  better  still  we  should  observe  the  patient  closely  in  his 
business  transactions  and  everyday  routine  of  life  to  see  whether  he  does 
things  exactly  as  he  did  them  before.  It  is  always  possible  by  such  tests 
to  show  that  in  aphasia  the  mental  powers  have  become  distinctly  de- 
preciated. 

The  portion  of  the  cerebral  cortex  affected  in  aphasia  is  always  in  the 
neighborhood  of  the  so-called  area  of  Wernicke,  which  is  closely  related  to 
the  visual  and  auditory  centers.  In  making  this  sweeping  conclusion, 
Marie  admits  that  cases  of  pure  word-blindness  but  not  of  word-deafness 
may  exist ;  that  is,  a  patient  still  retaining  his  intellectual  powers  may  lose 
his  ability  to  interpret  correctly  what  he  sees,  although  he  can  still  interpret 
accurately  what  he  hears. 

This  conclusion  conforms  exactly  with  those  of  the  psychophysiologists 
regarding  the  difference  in  the  language  mechanisms  of  educated  and  un- 
educated persons.  Language  is  learned  through  the  sense  of  hearing,  and 
it  is  only  by  later  education  that  more  is  learned  by  the  sense  of  sight; 
that  is  to  say,  a  person  learns  to  read  only  after  he  has  learned  to  under- 
stand spoken  language.  Word-blindness  may  therefore  occur  as  a  pure 
symptom,  and  is  less  likely  than  word-deafness  to  be  associated  with  ab- 
normal integrative  functions  of  the  cerebrum.  Word-deafness  however  de- 
pends upon  a  lesion  involving  the  auditory  center;  it  necessarily  means 
disturbance  in  the  association  functions  of  the  cerebrum,  and  is  always 
accompanied  by  a  certain  amount  of  mental  derangement. 

In  corroboration  of  these  facts  may  be  cited  the  well-known  fact  that 
a  deaf-mute  is  mentally  far  inferior  to  one  that  is  congenitally  blind. 
Loss  of  hearing  leads  to  more  serious  cerebral  disability  than  loss  of  sight. 
To  quote  Bolton  again,  "In  such  cases  deafness  is  therefore  a  more  serious 
deprivation  than  blindness,  as,  for  the  evolution  of  the  functional  activity 
of  the  cerebrum,  an  entirely  new  development  of  associational  spheres  to 


962  CENTRAL  NERVOUS  SYSTEM 

replace  those  normally  employed  for  auditory  and  spoken  language  has 
to  be  acquired.  In  the  case  of  congenital  or  early-acquired  blindness,  on 
the  other  hand,  the  complex  sphere  of  language,  with  all  its  psychic  com- 
ponents, can  be  employed  in  a  perfectly  normal  manner  and  almost  ex- 
actly as  it  is  brought  into  use  in  the  case  of  persons  who  neither  read  nor 
write." 

It  would  be  beyond  the  scope  of  this  work  to  go  into  the  clinical  and 
pathological  evidence  upon  which  Marie  bases  his  far-reaching  conclusions. 
Suffice  it  to  say  that  it  is  definitely  shown  that  the  old  contention  of  Broca, 
that  a  special  speech  center  exists,  is  entirely  unjustified  by  the  facts  of 
clinical  and  pathological  experience.  Broca,  it  will  be  remembered,  con- 
tended that  motor  aphasia  is  always  due  to  destructive  processes  occurring 
in  the  lower  portion  of  the  ascending  frontal  convolution  on  the  left  side, 
and  he  concluded  that  this  portion  of  the  cerebrum  represents  the  speech 
center.  Marie  has  shown,  however,  that  a  patient  may  show  distinct  evi- 
dence of  aphasia  without  any  lesion  involving  this  so-called  Broca  area, 
and,  on  the  other  hand,  that  cases  not  infrequently  occur  in  which  this  is 
completely  destroyed  without  any  evidence  of  aphasia.  Important  though 
this  discovery  of  the  inaccuracy  of  Broca 's  conclusion  is,  by  far  the  most 
important  conclusion  which  we  may  draw  from  Marie's  work  is  that,  since 
language  is  a  product  of  an  extended  integration  of  impressions  and 
memories  stored  in  different  parts  of  the  cerebrum,  it  is  not  so  likely  to  be 
interfered  with  by  destruction  of  any  one  of  the  centers  as  it  is  by  destruc- 
tion of  the  paths  which  connect  the  centers  with  one  another.  As  a  matter 
of  fact,  Marie  has  shown  that  in  cases  of  aphasia  the  lesion  is  nearly 
always  located  in  the  course  of  the  pathway  connecting  the  visual  and 
auditory  centers  with  the  other  centers  of  the  cerebrum ;  it  lies  around  the 
upper  end  of  the  fissure  of  Sylvius  in  the  region  which  in  previous  years 
had  been  considered  particularly  associated  with  the  condition  known  as 
sensory  aphasia.  Those  interested  in  this  subject  should  consult  Bolton's 
article. 


CHAPTER  CIV 

SUMMARY  OF  THE  ORGANIZATION  OF  THE  MAMMALIAN  NERV- 
OUS SYSTEM ;  SPINAL  SHOCK 

The  activity  and  organization  of  the  nervous  system  is  so  complex 
that  it  has  been  necessary  to  treat  each  aspect  of  it  separately  and  with 
little  reference  to  its  relation  to  the  organization  of  the  whole.  We  will 
now  consider  briefly  how  the  various  parts  of  the  nervous  system  are  com- 
pounded to  form  a  unified  machine  for  coordinating  the  activities  of  the 
body.  The  evolutionary  development  of  the  nervous  system  has  indi- 
cated that  two  primitive  types  of  nervous  organization  came  into 
existence  at  an  early  stage  and  persist  in  certain  parts  of  the  mammalian 
body.  The  most  primitive  of  these  was  the  nerve  net  which  was  evolved 
by  the  coelenterates  and  which  persists  in  the  mesenteric  plexus  of 
man.  The  other  is  the  segmental  synaptic  nervous  system  of  the  worms, 
which  finds  its  representative  in  the  spinal  reflex  system  of  the  verte- 
brates. We  have  seen  that  these  systems  are  not  independent,  but  that 
the  spinal  reflex  mechanism  exerts  a  controlling  influence  over  the 
peripheral  nerve  net  through  the  autonomic  nerves.  Vertebrate  evolution 
has  brought  to  perfection  two  additional  functional  systems  which 
modify  and  regulate  the  activity  of  the  spinal  reflexes,  and  through  them, 
to  a  certain  extent,  the  organs  controlled  by  the  peripheral  nerve  net. 

These  systems  are  (1)  the  mesencephalicospinal  system  for  the  con- 
trol of  postural  tone,  excited  by  the  proprioceptive  impulses  which 
arise  in  the  muscles,  joints,  and  from  the  labyrinth  and  (2)  the  cortico- 
spinal  system  for  the  execution  of  voluntary  movements  initiated  by  im- 
pulses received  in  large  part  by  the  distance  receptors  of  the  head  and 
conditioned  by  the  previous  associations  and  memories  which  the  stimula- 
tion of  the  distance  receptors  calls  up.  The  corticospinal  system  not 
only  controls  the  activity  of  the  spinal  reflex  mechanism  through  the 
connections  afforded  by  the  pyramidal  tracts,  but  to  it  the  system  for 
regulation  of  postural  tone  is  also  subservient.  The  arrangement  of  the 
different  levels  of  nervous  activity  in  their  relation  to  the  effectors  of  the 
body  is  somewhat  as  shown  in  the  diagram  on  page  964. 

In  the  intact  organism  we  see  the  entire  mechanism  at  work;  in  the 
experimental  animal  and  in  the  lesions  of  warfare  and  civil  life  we  see 
the  activity  of  the  residual  parts  of  the  mechanism  which  are  left  in- 
tact after  mutilation  has  freed  them  from  control  by  the  higher  centers. 

963 


964  CENTRAL  NERVOUS  SYSTEM 

When  a  lower  level  in  the  organization  of  the  nervous  system  is 
freed  from  control  by  a  superior  level  we  observe,  not  only  the  inde- 
pendent activities  which  this  level  carries  on  in  the  normal  animal, 
but  certain  additional  activities  commonly  held  in  check  by  the  higher 
centers.  Injury  to  the  nervous  system  consequently  results  in  certain 
positive  as  well  as  negative  symptoms,  and  these  are  attributed  to  the 
removal  of  an  inhibition  from  the  lower  levels  which  is  exerted  normally 
by  influences  from  higher  levels  now  cut  off  by  the  lesion.  Thus  we  have 
seen  in  the  decerebrate  animal  that  the  removal  of  the  control  of  the  high- 
est level  allows  the  postural  tone  of  the  extensor  muscles  to  become 
greatly  exaggerated.  The  spastic  paralysis  which  accompanies  many 

Cerebral  Cortex 


Cerebellum  and  Midbrain 


SpinaJ  Reflex 


Nerve  Net 


i 


Skeletal  Muscle          Smooth  Muscle  and 

Glands 

cerebral  and  spinal  lesions  is  probably  a  positive  symptom  due  to  a 
similar  cause  (Walshe34).  In  the  decerebrate  animal  many  reflexes  may 
be  elicited  with  a  certainty  and  to  a  degree  unobtained  in  the  unmutilated 
organism  because  of  the  removal  of  cerebral  inhibition.  The  symptom! 
of  cerebellar  injury  give  a  picture  of  the  activity  of  the  nervous  system 
deprived  of  the  normal  influence  of  the  mesencephalic  regulation  of  tone. 
Voluntary  movements  can  still  be  executed,  but  no  longer  with  the  cus- 
tomary smoothness  or  precision,  because  the  mechanism  which  governs 
the  coordination  of  muscular  movement  and  tone  is  no  longer  effective. 
In  the  isolated  visceral  organs,  and  particularly  in  the  bladder,  indepen- 
dent activity  of  the  peripheral  nerve  net  is  demonstrated.  We  have 
seen  that  these  organs  may  function  in  an  adequate  way,  but  their  ac- 


SUMMARY,    MAMMALIAN    NERVOUS    SYSTEM;    SPINAL    SHOCK  965 

tivities  are  no  longer  correlated  to  the  activities  of  the  body  as  a  whole. 
The  extent  to  which  the  spinal  cord  is  capable  of  carrying  out  co- 
ordinated neuromuscular  activity,  when  isolated  from  the  higher  centers 
of  the  brain  is  a  matter  of  great  interest.  We  have  seen  in  considering 
the  mechanisms  by  which  reflex  action  is  governed  that  the  spinal  cord 
contains  arrangements  capable  of  producing  highly  integrated  responses. 
We  will  consequently  examine  the  activities  of  the  isolated  spinal  cord 
in  laboratory  animals,  and  compare  them  with  similar  conditions  which 
are  observed  in  man,  in  order  to  obtain  an  idea  of  the  relative  importance 
of  the  spinal  cord  and  brain  which  show  some  diversity  in  their  devel- 
opment. 

Spinal  Shock  and  the  Recovery  of  Reflexes  in  Animals 

In  animals  the  spinal  cord  may  be  separated  from  the  brain  by  an 
incision  made  in  the  cervical  region.  Immediately  after  the  operation 
a  profound  condition  of  depression  sets  in,  involving  all  the  reflex  arcs 
in  the  separated  portion  of  the  cord.  This  condition  is  known  as  spinal 
shock.  It  supervenes  in  all  classes  of  animals  having  a  spinal  cord,  but  is 
much  more  profound  in  the  higher  than  in  the  lower  animals.  As  a  result 
of  this  depression,  the  part  of  the  body  below  the  section  exists  in  a  limp 
and  flaccid  condition,  and  the  application  of  even  very  strong  stimuli  to 
the  skin  will  evoke  no  form  of  reflex  movement.  In  the  case  of  the  lower 
vertebrates,  such  as  the  frog,  the  condition  begins  to  pass  off  in  from  twenty 
minutes  to  half  an  hour,  after  which  a  stimulus  applied  to  the  skin  of  the 
foot  is  followed  by  a  typical  flexion  movement  at  knee  and  hip,  the  so- 
called  flexion  reflex.  In  the  rabbit  very  little  reflex  response  is  elicitable 
for  several  hours  after  the  operation,  but  in  a  few  days  the  reflexes  return 
completely  below  the  level  of  the  section.  In  the  dog,  on  which  a  great 
deal  of  work  has  been  done,  the  involved  regions  of  the  body  are  pro- 
foundly paralyzed.  The  skin  is  in  a  more  or  less  unhealthy,  unnatural 
condition,  the  surface  cold,  the  hairs  ruffled;  and  if  care  is  not  taken,  the 
slightest  abrasion  of  the  surface  may  result  in  a  nasty  ulceration.  On 
account  of  the  paralysis  of  the  centers  of  micturition  and  defecation, 
there  is  also  incontinence  of  urine  and  of  feces. 

With  reasonable  attention,  however,  the  dog  makes  a  wonderful  re- 
covery. After  an  interval  of  two  weeks  the  hind  limbs,  although  com- 
pletely paralyzed  so  far  as  voluntary  movement  is  concerned,  begin  to 
show  considerable  signs  of  improvement.  The  first  reflexes  to  return 
are  those  concerned  with  the  deeper  structures,  such  as  the  vascular 
reflexes,  thus  bringing  the  skin  back  to  its  normal  temperature  and 
condition.  The  reflexes  of  micturition  and  defecation  also  soon  return, 
so  that  the  animal  no  longer  suffers  from  the  continuous  discharge  of 


966  CENTRAL    NERVOUS    SYSTEM 

urine  and  feces.  About  the  same  time  the  knee-jerk  becomes  elicitable. 
This  reflex  is  obtained  by  tapping  the  tendon  which  connects  the  patella 
with  the  tibia,  the  response  being  a  smart  contraction  of  the  extensor 
muscles  of  the  knee  joint.  The  flexion  reflex  also  begins  to  reappear. 
This  is  elicited  by  applying  a  pinprick  or  other  hurtful  stimulus  to 
the  skin  of  a  lower  extremity,  and  when  fully  developed  consists  in  a 
flexion  of  the  knee  and  hip  joints.  The  evident  object  of  this  move- 
ment is  that  the  stimulated  parts  may  be  removed  from  the  source  of 
stimulation,  and  it  is  plain  that  all  stimuli  that  produce  the  flexion 
reflex  are  such  as  would  cause  in  the  intact  animal  a  sensation  of  pain. 
Such  stimuli  are  thus  classified  as  nocuous,  and  the  reflex  is  styled  a 
nociceptive  reflex.  Accompanying  flexion  of  the  stimulated  limb  the  op- 
posite or  contralateiral  limb  usually  undergoes  a  definite  extension, 
called  the  crossed  extension  reflex.  That  the  nociceptive  reflexes  should 
be  among  the  first  to  return  after  spinal  transection  is  of  considerable 
interest  as  indicating  their  importance  in  the  protection  of  the  animal 
from  injury.  They  are  the  essential  reflexes  of  defense,  and  it  is  con- 
siderably later  in  the  recovery  of  the  animal  before  reflexes  dependent 
upon  stimulation  of  other  tactile  receptors  begin  to  show  themselves. 
The  most  important  of  this  latter  group  of  more  special  reflex  move- 
ments include  the  so-called  scratch  reflex  and  the  extensor  thrust.  The 
scratch  reflex,  as  its  name  implies,  is  the  scratching  movement  of  flexion  and 
extension  of  the  hind  limb  at  a  rate  of  about  four  contractions  per  second 
that  occurs  when  a  mechanical  stimulus  is  applied  to  the  flank  and  shoulder 
area  of  the  animal.  For  example,  if  we  gently  draw  a  pencil  or  the  fingers 
backward  and  forward  among  the  hairs  on  this  region  of  the  spinal  animal, 
the  corresponding  hind  limb  will  be  brought  up  so  that  the  claws  are 
approximately  at  the  place  stimulated,  and  the  limb  thus  directed  will 
undergo  a  series  of  flexions  and  extensions,  designed  evidently  for  the 
purpose  of  scratching  the  area  of  skin  that  has  been  stimulated.  If  the 
stimulus  is  a  weak  one,  only  the  initial  stages  of  the  movement  may 
occur,  such  as  the  preliminary  flexion  of  the  leg.  As  we  have  already 
stated,  the  receptive  stimulus  calling  forth  this  reflex  is  very  specific 
in  nature.  A  pinprick  or  rough  friction  of  the  reflex  area  will  not  produce 
it,  neither  will  the  application  of  heat,  nor  a  single  electric  shock.  The 
most  adequate  stimulus  is  one  simulating  as  nearly  as  possible  the  con- 
dition which  would  be  produced  by  the  movement  on  the  flank  of  the 
animal  of  some  insect.  This  more  or  less  complicated  scratch  reflex  can 
of  course  also  be  elicited  in  animals  whose  spinal  cord  has  not  been  cut, 
but  we  can  not  predict  in  such  cases  whether  the  reflex  will  occur.  The 
brain  may  inhibit  the  reflex  arc  and  prevent  the  movement.  In  a  spinal 


SUMMARY,    MAMMALIAN   NERVOUS   SYSTEM;   SPINAL  SHOCK  967 

animal,  however,  the  reflex  always  occurs  provided  an  adequate  stimulus 
is  applied. 

The  extensor  thrust  is  elicited  by  applying  pressure  to  the  pad  of  the 
paw  or  the  sole  of  the  foot.  It  consists  of  a  quick  extension  movement 
of  the  corresponding  limb  usually  with  a  flexion  of  the  opposite  limb. 

After  complete  recovery  from  shock,  the  paralyzed  parts  of  the  body 
are  capable  of  performing  even  more  complex  movements  than  those  al- 
ready mentioned.  For  example,  if  the  animal  is  held  up  with  the  hind 
legs  hanging  down,  these  will  often  exhibit  rhythmic  flexion  and  exten- 
sion movements,  with  the  two  limbs  acting  alternately,  as  they  would 
in  walking  or  running.  This  is  sometimes  called  the  mark-time  reflex. 
Another  complicated  movement  may  be  produced  by  placing  the  animal 
in  water,  when  it  may  make  the  movements  of  swimming,  but  its  swim- 
ming will  not  be  sufficient  to  keep  it  on  the  surface.  These  swimming 
movements  are  more  perfect  in  the  spinal  frog. 

After  complete  recovery  from  spinal  shock,  the  hind  limbs  are  more 
or  less  in  a  condition  of  extension  contracture;  the  vascular  and  other 
visceral  reflexes  are  in  perfect  condition,  and  a  marked  rise  in  blood 
pressure  occurs  when  one  of  the  sensory  nerves  of  the  hind  limb  is 
stimulated — an  experiment  which  can  be  performed  in  such  animals 
without  the  administration  of  any  anesthetic,  since  the  animal  feels 
no  pain.  In  female  spinal  animals  impregnation  may  occur  and  preg- 
nancy proceed  in  normal  fashion  accompanied  by  the  usual  secretion 
of  milk. 

Spinal  Shock  and  the  Recovery  of  Reflexes  in  Man 

The  potentialities  of  the  spinal  cord  of  man  have  not  been  fully 
realized  until  recent  years  when  investigations  by  Head  and  Riddoch42  on 
men  who  had  been  shot  through  the  spine  have  shown  just  how  complete 
a  recovery  can  be  made  from  such  an  injury  if  the  patient  is  given  proper 
care.  In  cases  of  complete  transection  of  the  cord  there  usually  re- 
sults in  man,  as  in  the  other  mammals,  a  complete  loss  of  reflex  activity 
and  of  tone  in  those  parts  of  the  body  innervated  from  segments  of  the 
cord  which  lie  below  the  lesion.  Occasionally  the  cremasteric  and 
bulbocavernous  reflexes  may  still  be  elicited.  Below  the  lesion  there  is 
complete  anesthesia,  the  skin  is  dry  and  readily  becomes  gangrenous, 
and  the  urine  and  feces  are  retained.  After  a  period  varying  from  one  to 
three  weeks  the  first  reflexes  reappear.  These  are  the  flexion  reflexes  in 
response  to  harmful  stimuli.  At  first  they  can  be  elicited  only  from  the 
part  of  the  receptive  field  which  normally  is  most  sensitive,  i.  e.,  the  sole 
of  the  foot,  and  involve  those  muscle  groups  which  are  normally  brought 
into  play  by  the  weakest  stimuli.  Movements  of  the  toes  are  conse- 
quently the  only  part  of  the  reflex  figure  to  display  itself  in  the  earliest  stage 


968  CENTRAL    NERVOUS    SYSTEM 

of  recovery.  Later  the  receptive  field  becomes  more  and  more  extensive 
and  the  response  spreads  to  additional  groups  of  muscles  until  the  entire 
leg  is  thrown  into  flexion.  As  it  does  so  the  reciprocal  inhibition  of 
the  muscles  antagonistic  to  the  flexors  takes  place  in  a  normal  manner, 
just  as  it  does  in  the  spinal  cat  or  dog.  Finally,  however,  a  stage  of 
recovery  is  reached  in  which  a  phenomenon  occurs  which  is  quite  unlike 
anything  seen  in  these  animals.  It  is  called  the  mass-reflex  and  consists 
in  an  extensive  spasm  of  the  flexor  muscles  of  the  abdomen  and  lower 
extremities  which  is  brought  about  by  harmful  stimuli  applied  almost 
anywhere  to  the  parts  of  the  body  affected  by  the  injury.  Accompany- 
ing the  response  there  is  a  pronounced  outburst  of  sweating  in  the  af- 
fected regions  and  if  the  bladder  is  as  much  as  half  full,  a  reflex  discharge 
of  the  urine.  The  mass-reflex  shows  that  the  spinal  reflexes  have  lost 
their  local  signature  and  have  consequently  become  diffuse  in  their  dis- 
tribution, resembling  in  this  regard  the  generalized  responses  of  those 
animals  such  as  the  sea  anemone  (page  830),  which  possess  a  nervous 
system  consisting  of  an  asynaptic  nerve  net. 

In  one  to  five  weeks  after  the  flexor  responses  first  appear  the  tone 
of  the  muscles  of  the  limbs  begins  to  recover  and  may  be  restored  to 
nearly,  but  never  to  equal,  the  state  found  in  the  normal  individual.  The 
posture  of  the  limbs  is  one  of  slight  flexion.  At  the  same  time  the  ten- 
don jerks  become  elicitable.  These  are  the  only  types  of  extensor  re- 
sponse which  have  been  observed  in  cases  of  complete  transection  of  the 
human  spinal  cord.  During  this  stage  of  recovery  the  contents  of  the 
rectum  and  bladder  are  voided  automatically  (Head  and  Eiddoch20' 42). 

The  chief  difference  in  the  condition  of  the  spinal  man  and  of  the 
spinal  cat  or  dog  consists  in  (1)  the  character  of  the  flexor  response, 
which  in  man  has  lost  its  local  signature,  is  diffuse,  and  is  elicited  from 
an  abnormally  extensive  receptive  field,  (2)  the  flexor  position  of  the 
limbs  at  rest;  and  (3)  the  absence  of  extensor  responses,  i.  e.,  of  those 
responses  significant  in  maintaining  the  upright  position  and  in  progres- 
sion. It  would  appear  from  this  that  in  man  the  higher  centers  in  the 
brain  have  taken  over  control  of  the  integration  of  spinal  reflexes  to  the 
extent  of  determining  the  local  signature  and  limiting  the  spread  of 
these  responses  and  of  governing  the  activities  of  the  extensor  muscles 
in  maintaining  postural  tone  and  the  extensor  movements  of  progres- 
sion ;  whereas  in  the  lower  mammals  these  phenomena  may  be  executed 
by  the  spinal  cord  alone.  Further  evidence  for  this  view  is  afforded  by 
cases  in  which  the  human  spinal  cord  is  incompletely  divided.  In  these 
individuals,  although  paralysis  and  anesthesia  is  complete,  the  reflex 
activities  may  not  differ  markedly  from  those  of  the  lower  animals.  The 
mass-reflex  is  absent,  flexor  responses  retain  their  local  signature,  and  are 
accompanied  by  crossed  extension  in  the  opposite  limb.  The  postural 


SUMMARY,    MAMMALIAN    NERVOUS    SYSTEM  ;    SPINAL    SHOCK  969 

tone  of  the  extensor  muscles  holds  the  resting  limbs  in  slight  extension. 
Responses  comparable  to  the  extensor  thrust  and  the  mark  time  reflex 
of  the  spinal  animal  occur. 

The  Cause  of  Spinal  Shock 

It  would  seem  natural  to  suppose  that  the  cause  of  the  depression  in 
reflex  activity  which  follows  transection  of  the  spinal  cord,  and  which 
is  known  as  spinal  shock,  is  the  irritation  set  up  directly  in  the  tissues 
injured  by  the  lesion.  This  irritation  might  be  thought  to  have  an  in- 
hibitory influence  on  spinal  reflexes.  That  this  supposition  is  incorrect 
is  shown  by  the  fact  that  after  the  shock  induced  by  a  cervical  tran- 
section of  the  cord  has  worn  off,  a  second  transection  at  a  lower  level 
does  not  cause  its  reappearance.  The  abnormal  character  of  reflexes 
recovering  from  spinal  shock  does  not  resemble  that  of  reflexes  which 
are  being  inhibited,  but  rather  those  which  have  experienced  fatigue. 

Spinal  shock  might  be  thought  to  be  due  to  the  disturbance  in  the  cir- 
culation which  follows  the  spinal  transection,  but  this  cannot  be  the  case 
because  all  parts  of  the  body  would  suffer  alike  from  the  fall  in  blood 
pressure,  whereas  only  those  parts  of  the  nervous  system  below  the  lesion 
exhibit  shock.  This  aboral  incidence  of  shock  is  a  very  striking  character. 
So  slight  is  the  effect  of  a  spinal  transection  upon  the  higher  centers  that 
men  who  have  been  shot  through  the  spine  may  not  even  lose  conscious- 
ness. They  are  aware  that  sensations  from  the  lower  limbs  have  sud- 
denly been  cut  off,  and  their  first  impression  is  that  they  have  been  blown 
in  two.  Sherrington  has  described  a  monkey  the  cord  of  which  was 
cut  below  the  cervical  region,  and  which  immediately  after  the  opera- 
tion amused  itself  by  catching  flies  with  the  anterior  extremities,  whereas 
the  posterior  extremities  were  in  a  condition  of  the  profoundest  shock. 

The  most  probable  explanation  of  shock,  which  is  in  accord  with  the 
preceding  facts,  is  that  it  is  due  to  cutting  off  from  the  spinal  reflex 
arcs  of  some  influence  normally  exerted  by  fibers  descending  from  the 
brain.  Just  what  this  influence  is,  or  how  it  facilitates  reflex  activity 
is  impossible  to  state,  but  it  would  appear  that  once  this  influence  is  cut 
off,  some  time  is  required  before  the  cord  can  acquire  the  power  of 
carrying  out  its  reflex  functions  without  its  assistance.  We  have  seen 
that  a  parallelism  exists  between  the  depth  and  persistence  of  spinal 
shock  and  the  development  of  the  nervous  system,  particularly  of  the 
brain,  in  vertebrate  evolution.  This  fact  consequently  supports  the 
view  that  spinal  shock  is  due  to  isolating  the  cord  from  the  influence 
of  the  higher  centers.  Moreover  those  neuromuscular  mechanisms  are 
affected  which  are  normally  under  control  of  the  brain  centers.  Dis- 
turbances in  the  visceral  activities  controlled  by  the  automatic  nerv- 
ous system  are  insignificant  except  in  the  case  of  the  discharges  of 


970  CENTRAL  NERVOUS  SYSTEM 

urine   and   feces,    functions   which    are   normally    controlled    by    spinal 
reflexes  and  volitional  activity. 

The  centers,  whose  influence  is  cut  off  when  spinal  shock  appears, 
lie  in  the  brain-stem,  probably  in  the  nuclei  of  the  pontine  or  mid- 
brain  region.  Consequently  removal  of  the  cerebral  hemispheres  does 
not  produce  anything  like  the  severe  spinal  depression  which  occurs 
when  the  transection  passes  behind  the  level  of  the  pons  (Sherrington37). 

KEFERENCES  TO 

MONOGRAPHS  AND  ORIGINAL  PAPERS  ON  THE  NERVOUS 

SYSTEM 

Evolution  of  the  Nervous  System 

Barker,  G.  H. :  The  Elementary  Nervous  System,  Philadelphia,  1919,  J.  B.  Lippincott 
Co. 

Fundamental  Properties  of  Nervous  Tissue 

2Adrian,  E.  D. :     Brain,  1918,  xli,  23. 

sLucas,  K. :  The  Conduction  of  the  Nervous  Impulse,  revised  by  E.  D.  Adrian,  Lon- 
don, 1917,  Longmans,  Green  &  Co. 

^Tinel,  J.  N. :  Nerve'  Wounds,  English  Trans.,  London,  1918,  Bailliere,  Tindall  and 
Cox. 

sTashiro,  S.:     Am.  Jour.  Pliysiol.,  1913,  xxxii,  107. 

effill,  A.  V.:     Jour.  Physiol.,  1912,  xliii,  433. 

7Mathison,  G.  C. :     Jour.  Physiol.,  1910-11,  xli,  416. 

sCannon  and  Burkett:     Am.  Jour.  Physiol.,  1913. 

Sensation  and  Sensory  Localization 

"Head,  H.:     Brain,  1919,  xli,  57. 
icHolmes,  G.,  and  Lister:     Brain,  1916,  xxxix,  34. 
uRiddoch,  G. :     Brain,  1917,  xl,  15. 

"Gushing,  H. :     Proc.  Am.  Physiol.  Soc.,  Am.  Jour.  Physiol.,  1909. 
isHead,  H.:     Brain,  1893,  et  seq. 
i4Lennander:     Keen's  Surgery,  v,  156. 
isHead,  H.,  and  Thompson:     Brain,  1906,  xxix,  537. 
leHolmes,  G. :     Brit.  Med.  Jour.,  1915,  ii,  Nov.  27,  Dec.  4,  Dec.  11. 

Autonomic  Nervous  System 

17Gaskell,  W.  H. :      The  Involuntary  Nervous  System,  London,  1916,  Longmans,  Green 

&  Co. 
isPottenger,   F.  M. :      Symptoms  of  Visceral  Disease,   St.   Louis,   2nd  ed.,   1922,   C.   V. 

Mosby    Co. 

isFearnside,  E.  G.:     Brain,  1917,  xl,  149. 
soHead,  H.,  and  Eiddoch,  G.:     Brain,  1917,  xl,  188. 
21Cannon,  W.  B. :     Bodily  Changes  in  Pain,  Hunger,  Fear  and  Rage,  New  York,  1915, 

D.  Appleton  &  Co. 

Muscle 

22Forbes,  A.,  and  Rappleye,  W.  C.:     Am.  Jour.  Physiol.,  1917,  xlii,  228. 

2spratt,  F.  H.,  and  Eisenberger,  J.  P.:     Am.  Jour.  Physiol.,  1919,  xlix,  1. 

24Bayliss,  W.  M. :     Principles  of  General  Physiology,  London,   1915,  Longmans,  Green 

&  Co. 

ssFletcher,  W.  M.,  and  Hopkins,  F.  G. :     Jour.  Physiol.,  1907,  xxxv  247. 
26Gunn,  J.  A.,  and  Underbill,  J.  F. :     Quart.  Jour.  Exper.  Physiol.,  viii,  275. 


SUMMARY,    MAMMALIAN    NERVOUS   SYSTEM;    SPINAL   SHOCK  971 

Tone  and  Postural  Coordination 

27Sherringten,  G.  S. :     Quart.  Jour.  Exper.  Physiol.,  1909,  ii,  109;  Brain,  1915,  xxxviii, 

191. 

2«Lee,  T.  S.:     Jour.  Physiol.,  1894,  xv,  311;  1894-5,  xvii,  192. 
ssLyon,  E.  P. :  .  Am.  Jour.  Physiol.,  1900,  iv,  77. 
soBlack,  D.:     Jour.  Lab.  and  Clin.  Med.,  1916,  i,  467. 
sigherrington,  C.  S.:     Jour.  Physiol.,  1898,  xxii,  319. 
32Weed,  L.  H.:     Jour.  Physiol.,  1914,  xlviii,  205. 
ssThiele,  H. :     Jour.  Physiol.,  1905,  xxxii,  358. 
34Walshe,  F.  M.  E.:     Brain,  1919,  xlii,  1. 
35Holmes,  G.:     Brain,  1917,  xl,  461. 
seLuciani,  L. :     Human  Physiology,  iii,  (English  trans.),  London,  1914. 

Integrative  Action  of  Nervous  System 

37Sherrington,  C.  S. :     The  Integrative  Action  of  the  Nervous  System,  New  York,  1906. 
ssLoeb,  J.:     Forced  Movements,  Tropisms  and  Animal  Conduct,  Philadelphia,  1918. 

The  Cerebrum 

soWatson,  J.  B. :     Psychology  from  the  Standpoint  of  a  Behaviorist,  Philadelphia,  1919. 

Psychological  Review,  1916,  xxiii,  89. 
*°Bolton,  J.  S. :     Eecent  Researches  on  Cortical  Localization  and  on  the  Function  of  the 

Cerebrum  in  Further  Advances  in  Physiology,  ed.  by  Leonard  Hill,  London,  E. 

Arnold,  1909. 
4iMorgulis,  S.:     Jour.  Animal  Behavior,  1914,  iv,  142;   ibid.,  1914,  iv,  362. 

Keflex  Functions  of  the  Spinal  Cord  in  Man 
"Riddoch,  G.:     Brain,  1917,  xl,  264. 


INDEX 


Abdominal  respiration,  324 
Abnormal  pulses,  291 
Absorption,  in  general,  13 
from    stomach,    490  ' 
of  fats,  722 
Acapnia,  306 

Accessory  food  factors,  618 
Acetoacetic  acid,  715,  738 
Acetone,  715,  738 
Acid: 

buffer  action,  36 
excretion  of,  by  kidneys,  47 
chemistry  of  fatty,  718 
Acid-base  balance,  38,  363,  372 
Acidity,  actual  degree  of,  23 
Acidosis : 

ammonia-urea  ratio  during,   650 
compensated,    39 
in  diabetes,  715 
in  nephritis,  715 
in   starvation,   602,  603 
relation  to  alveolar  CO,,  371 
relationship  to  breathing,  371 
theory  of,  38 
uncompensated,  39 
Acids,  of  urine,  558 
Acromegaly,  816 

Action  currents   in  skeletal  muscle,   906 
Actual  degree  of  acidity  and  alkalinity, 

23 

Adaptation,   sensory,    862 
Addison's  disease,  772 
Adenine,  667,  669 
Adenosine,  671 
Adrenal  glands,  768 

and  diabetes,  708,  790 
assaying  content  of,  779 
cortex  of,  776 
disease  of,  in  man,  772 
medulla  of,  770 
sexual  precocity  and,   776 
Adrenaline    (see  Epiuephrine) 
Adsorption,  66 
compounds,  71 
conditions  influenced  by,  68 
effect  of  chemical  forces  on,  69 
effect  of  electric  changes  on,  68 
everyday  reactions  depending  on,  67 
of  gases,  67 

Afferent    nerves,    segmental    distribution 
of,  866 


Afferent  paths: 

in  spinal  cord,  868 
in  brain-stem,  871 
of  spinal  reflexes,  872 
of  visceral  reflexes,  873 
of  cerebellar  reflexes,  874 
After  discharge,  915 

effect  on  creatinine  excretion,  657 
Alanine,  634,  635,  636,  639,  698 
Albolene  absorption,  723 
Albuminuria,  552 

Alkali  retention,  determination  of,  48 
Alkaline  buffer,  36 
Alkaline  reserve,  38 
Alkalosis,  373,,  380,  559. 
Alkaptonuria,  536 
Allantoin,  668,  672,  678 
Allied    reflexes,    simultaneous    combina- 
tion of,  945,  946 
successive  combination  of,  946 
Allocheiria,  859 
All-or-none  law: 

of  conduction,  837,  839 

of    contraction    of    skeletal    muscle, 

908 

of  contraction  of  heart  muscle,  177 
Alloxan,  668 
Alveolar  air: 

clinical  investigation  of,  364 
estimation   of  gases  in,  361 
Fridericia  method,  357 
Haldane  method,  357 
Pearce  method,  362 
tension  of  CO2,  46,  361,  373 

during  breathing  in  confined  space, 

366 

tension  of  oxygen,  362 
Ambard's    equation,    562 
Amboceptor,   97 
Amino  acids,  634 
in  blood,  641 
chemistry  of,   634 
determination  of,  635 
fate  of,  645 
groups,  636,  638 
in   growth,   609 
in  tissues,  642 
in  urine,  564,  654 
structure  of,  638,  639 
Aminoacetic  acid  (see  Glycocoll) 
Aminopropionic  acid    (see  Alanine) 


973 


974 


INDEX 


Ammonia : 

ammonia-urea  ratio: 

influence  of  acidosis  on,  563,  650 

in  disease,  661 

influence  of  liver  on,  654. 

as  reserve  alkali,  563 

excretion  of,  652 

excretion  of  acid  in  combination  with, 
47 

of  urine,  562 

Ammonium  carbamate,  649 
Ammonium  carbonate,  649 
Amylases,  81,  91,  525 
Amylolysis,   525 

in  stomach,  489 
Amylopsin,  525,  689 
Anacrotic  wave,  pulse,  203 
Anaphylactic  reaction,  632,  638,  755 
Anaphylaxis,  90 
Anarthria,  960 
Anastomosis,  intestinal,  504 
Anemia,  94 

bloodflow  in,   298 
Aneurism,  bloodflow  in,  299 

pulse  in,  144,  200 
Angina  pectoris,  fibrillation  in,  196 
Animal  calorimeter,  572 
Anions,  16,  60 
Anoxemia : 

acid  excretion  in,  381 

acidosis  and,  380 

alkalosis  and,  381 

alveolar  CO,  tension  in,  374 

ammonia  excretion  in,  381 

as    a    stimulus    to    respiratory    center, 
380 

changes  in  body  in,  378 

general  effects  of,  374 

in  mountain  sickness,  415 

lactic  acid  in  relation  to,  379 

pneumatic  cabinet  and,   377 
Antagonistic  muscles,  915 
Antagonistic  reflexes,  945 
Anticoagulants,  100 
Antidromic  impulses,   239 
Antiferments  in  blood,  90 
Antiperistalsis  in  cecum,  503 
Antithrombin,  105,  113 
Antitoxins,  70 
Aiititrypsin,   91 

Aortic  regurgitation,  pulse  in,  133 
Apex  beat,  tracing  of,  289 
Aphasia,  motor,  960 

sensory,  960 

subcortical,  960 
Apnea,  349,  382 

nervous  element  in,  384 
Apparatus  for  measuring  respiratory  ex- 
change, 589 
Appetite,  506 

Appetite  juice,  nature  of,  470,  474 
Arc,  reflex,  832 
Arginase,  81,  650 


Arginine,  640,  650,  660 
Aromatic  sulphates,  665 
Aromatic  oxyacids  in  urine,  564 
Arrhythmia  of  sinus,  278,  292 
Arterial  pressure,  124 
Arteries,  bloodflow  in,  200 
Arteriosclerosis,     diastolic     pressure     in, 

144 

Aspartic  acid,  640,  699 
Asphyxia,  366 
Assimilation  limit,  685 
Association  neurons,  834 
Astasia,  cerebellar,  927 
Asthenia,  cerebellar,  927 
Asthma,  dead  space  in,  328 
Asynergia,  cerebellar,  927 
Atonia,  cerebellar,  926 
Atophan,  684 
Atr opine,  effect  on  glands,  457 

effect  on  heart,  231 
Auditory  area,  879 
Auricle,   pressure   in,   146 

propagation  of  beat  in,  191 
Auricular  curve,  contour  of,  153 
Auricular  fibrillation,  196,  281,  295 
Auricular  flutter,  196,  281,  293 
Auriculoventricular   orifice,   149 
bundle,  183 
node,  183 

Auscultatory    method     (of    blood    pres- 
sure), 130 
Autocatalysis,  77 
Autocoids,  767 
Autonomic  nerves,  cerebral,  458 

sympathetic,  458 
Autonomic   nervous   system,    893 

axon  reflexes  in,  898 

bulbosacral   outflow,   894 

connector  fibers  of,  894 

functions  of,  897 

general  plan  of  construction,  893 

parasympathetic,  882,  895 

sacral  outflow,  494 

thoracicolumbar   outflow,   895 
Axon,  831 

reflexes,  829,  898 
Azelaic  acid,   740 


Bacillus  coli  communis,  534 
Bacteria,  in  intestine,  533,  690 

in  stomach,  516 
Bacterial  digestion,  533 
Balance,  energy,  571 

carbon,  582 

material,   579 

sheet  of  body,  579 
Banting  cure,  605 
Basal  heat  production,   574 
Basal  ration,   610 
Basophile  cells,  97 
' '  Bends ' '  in  caisson   workers,  425 


INDEX 


975 


Benedict's    method    for    respiratory    ex- 
change, 580 
Benzoic  acid,  664,  738 
Benzoyl  chloride,  663 
Beriberi,  619 

Beta-hydroxy  butyric  acid,  738 
Bile,  526 

and  fat   digestion,   721 
chemistry  of,  528 
constituents  of,   526 
from  gall  bladder,  526 
functions  of,  527 
pigments  of,  529 
salts,  528 
Bilirubin,  529 
Biliverdin,  529 
B-imidazolylethylamine,    effect    on   blood 

vessels,  253,  413 
as  a  factor  in  shock,  307 
Birds,  removal  of  liver  from,  652 
Bladder,  emptying  of,  900 
Blood: 

absorption  into,  13    — - 
amino  acids  in,  641 
amount  in  body,  85 
antiferments   of,   90 
circulation  of,  124 
dissociation  curve  of,  396 
epinephrine  content  of,  780 
fat    of, 

estimation,  726 
variations  in"  727 
ferments  of,  90 
gases  of,  transportation,  392 
general  properties   of,   85 
mass  movement  of,  296 
means  by  which  gases  are  carried,  403 
oxidation  in,  412 
proteases  of,  90 
proteins  of,  88,  89 
regeneration  after  hemorrhage,  89 
quantity  of,  in  body,  85 
refractive  index  of,  89 
specific  gravity  of,  87 
sugar  level  of,  690 

regulation,  703 
transfusion  of,  94,  131,  194 
viscosity  of,   141 
volume  of,  138 
in  shock,  306 
water  content  of,   87 
Blood  cell,  red,  fate  of,  95 
origin   of,   93 
regeneration    of,    94 
stroma  of,  92 
white,  97 
Blood  clotting,  99 
in  diseases,  111 

in   physiological    conditions,    111 
influence  of  calcium  on,  104 
influence   of  tissues  on,   105 
intravascular,    108 


Blood  clotting— Cont  'd 

methods     of    retarding,     in     drawn 

blood,  100 

negative  phase  of,  109 
theories  of,  107 
time  of,  101,  109 
visible  changes  during,  99 
Blood   corpuscles   in   mountain   sickness, 

419 
Bloodflow : 

clinical    conditions    affecting    anemia, 

298 

cardiovascular    diseases,    299 
fever,  298 

diseases  of  nervous  system,  300 
mass  movement  of,  208 
measurement  of,  209,  296 
movement  in  veins,  214 
normal  flow,  297 
variations  in,   297 
velocity  of,  206 
visceral,  212 

Blood  gas  manometer,  395 
Blood  platelets,  98 
Blood  pressure,  124 
diastolic,   129,   133 
effect  of  hemorrhage  on,  136 
effect  of  pleural  pressure  on,  323 
factors  maintaining,  135 
H-ion  of  blood  on,  248 
mean  arterial,  125 
measurement  of,   129 
in  shock,   303,   304 
systolic,  129 
tracing,  126 
Blood  vessels: 

elasticity  of,  143 
tone  of,  241 

Body  fluids,  reactions  of,  35 
Body  surface  and  energy  production,  575 
Body  weight  and  energy  production,  575 
Botulism,  537 
Bowman,  capsule  of,  541 
Bradycardia,    193 
Brain : 

circulation  in,  254 
vasomotor  nerves,   262 
volume   of,   256 

Breathing,  in  compressed  air,  420 
in  rarefied  air,  374,  415 
periodic,  385,  386 
Brownian  movement,  colloids,  58 
Bruits,  158 

Buffer  action  of  blood,  388 
Buffer  substances,  36 
Building  stones  of  protein,  609 
Bulbocavernosus  reflex,   967 
Bulbosacral  outflow,  894 
Butyric  acid,  737 


976 


INDEX 


Cadaverine,  002 
Caffeine,   668,   681 
Caisson  disease,  420 
cause  of,  421 

decompression   of   workers,   424 
prevention,  422 
symptoms,  420 
working  conditions  in,  425 
Calcium  ion,  influence  on  clotting,  104 

influence  on  heart,  167 
Calcium  rigor,  167 
Calomel  electrode,  30 
Calorie,   571 

Calorie  requirement,  625 
Calorie  test  of  labyrinth,  920 
Calorimeter,  571 
animal,   572 
Benedict,  573 
bomb,  573 
hand,   296 
respiration,  572 
Eussel-Sage,  573 
Calorimetry,  direct,  572,  580 

indirect,  580 
Caloro-receptors,  855 
Canalization,  844 
Canals,   semicircular,   918 

removal  of,  918 
Cannabin,  611 

Capillary  analysis  of  colloids,  57 
Capillary  circulation,  251 

during  muscular  contraction,  252 
Krogh  on,  251 
Carbamino  reaction,   635 
Carbohydrates,  absorption  of,  689 
assimilation  limits,  685 
digestion  of,  689 
and  growth,  617 
metabolism  of,  685 
production  from  protein,  699 
saturation  limit,   685 
Carbon  balance,  582 
Carbon  dioxide,  combining  power,  42 

effect    on    respiratory    center,    366, 

368 

estimation  in  blood,   403 
output,  585 

volume  percentage  in  blood,  404 
Carbon  dioxide  tension,  354 

in  alveolar  air,  after  exercise,  435 
estimation  of,   357,   361 
in  mountain  sickness,  416 
in  periodic  breathing,  388,  389 
in  arterial  blood,  354 
in  venous  blood,  359 
Carbonic  acid   (see  Carbon  dioxide) 
Carboxyl  group,   634 
Cardiac  decompensation,  219 

dead  space  in,  328 
Cardiac  depressor  nerve,  243 


Cardiac   muscle,   physiologic   characteris- 
tics of,  176 

Cardiac  pouch  (stomach),  487 
Cardiac   sphincter,   482 
Cardiorenal  disease,  bloodflow  in,  299 

energy   output  in,  578 
Cardiopneumatic  movements,  154 
Cardiograms,  276,  289 
Cardiovascular  disease,  bloodflow  in,  299 
Casein,  521,  611 
Caseinogen,  521 
Castration,  821 
Catabolism,  571 
Catalase,  91 
Catalysts,  73 
Cations,  16 
Catalytic  power,   23 
Caval  pocket,  784 

Coelenterates,  nervous  system  of,   828 
Cellulose,  digestion  of,  533 
Centers : 

diabetic,  704 
motor,  885 
sense, 

auditory,  879 
visual,  880 
sensory,  878 
word  centers,  960 
Cephalin,  720 
Cereals  and  growth,  615 
Cerebellar  ataxia,  927 
Cerebellum : 

ablation  of,  926 
clinical  observations,  926 
functions  of,  926 
lobes  of,  929 

localization  of  function  of,  929 
Cerebral  circulation,  254 
Cerebral  compression,  258 
Cerebral  cortex,  stimulation  of,  885 
Cerebral  localization,  886,  878 
Cerebral  vessels,  ligation  of,   254 
Cerebrin,  720 

Cerebrospinal  fluid,  121,  255 
Cerebrum,  functions  of,  951,  958,  963 
relation  to  distance  receptors,  952 
relation  to  spinal  reflexes,  951 
CH  method  of  expressing,  27    / 
Chemo-receptors,  855 
Cheyne-Stokes  breathing,   385,  390 
Chlorides,  urine,  565 
Chalone,  767 
Chlorophyl,  530 
Cholesterol,  528,  688,  720 

estimation  of,  726 
Choline,  720 

Chorda  tympani,  236,  239,  412,  458 
Chromaffin  cells,  771 
Chromatolysis,   847 
Chromatine,   670 
Chromosomes,  670 
Chyme,  490,  516 
Circle  of  Willis,  254 


INDEX 


977 


Circulation  of  blood: 

control   of,   221 

influence  of  gravity  on,  248 

mass  movement  of  blood,  208 

through  the  heart,  267 

through  the  liver,  265 

through  the  lungs,  264 

time  of,  206,  214 
Circulation  time,  206,  214 
Clinical   application,   circulation,   270 

respiration,   364,   393 
Clotting  of  blood    (see  Blood  clotting) 
Coagulative   ferments,,   82 
Cod-liver  oil,  nutritive  value,  735 
Coefficient   of   oxidation,   408 
Coefficient  of  solubility  of  gases,  354 
Coefficient  of  utilization,  410 
Cold,  sensation  of,  860 
Cold  spots,   860 
Collaterals,   831 
Colloids: 

Brownian   movement,   58 

capillary   analysis,   57 

characteristic  properties  of,   51 

diffusibility  of,  52 

dispersion  means,  55 

dispersoid,  55 

electric  properties  of,  56 
osmotic  pressure,  58 

electrophoresis,   57 

external  phase,  55 

gelatinization,  .62 

heterogeneous,  52 

homogeneous,  52 

imbibition,  63 

internal  phase,  55 

isoelectric  point,   65 

lyophobe,  61 

mutual  precipitation  of  colloids,  57 

osmotic  pressure  of,  142 

size  of  colloid  particles,  54 

suspensions,   54 

suspensoids   and   emulsoids,   action    of 
electrolytes  on,  64 

Tyndall  phenomenon,   52 
Compensated  acidoses,  39 
Compensatory  movements  of  eyes,  918 
Complemental  air,  317 
Compressed  air  sickness,  420 

cause   of   symptoms,  421 
prevention  of,  422,  424 
treatment  of,  424 
Concentration  cell,  30 
Concentration   point,    auricles,    185 
Concept,  952,  959 
Conditioned  reflexes,  466,  954 
Conduction : 

all  or  none  law,  837,  839 

between  neurons,  841 

energy  of,  838 

in  nerve  trunk,  827 

in  reflex  arc,  841 


Conduction — Cont  'd 

polarity  in,  841 

refractory  period  in,   839 
Conductivity,  determination  of,  17 

equivalent,  19 

molecular,  19 

specific,  17 
Conductivity  cell,  18 
Conglutin,  612 

Construction  of   autonomic  nervous  sys- 
tem,  893 

Contraction  of  skeletal  muscle: 
isometric,  904 
isotonic,  904 
tonic,  904 
tetanic,  905,  906 

chemistry  of,  910 
Contracture,    extension,    967 
Cooking,  630 

Coronary  circulation,   267 
Coronary  vessels,  vasomotor  nerves,  268 
Corpus  luteum,  822 

functions  of,   822 
Corpuscles  of  blood,  red,  92 

white,  97 

Cortico-spinal  system,  963 
Coughing,   317,   351 
Cranial  cavity,  pressure  in,  258 
Creatine,  647,  656 

chemistry  of,  656 

estimation  of,  657 

in  disease,  661 

metabolism  of,  658 

origin  of,  660 
Creatinine,  647 

chemistry  of,   656 

coefficient,   658 

estimation,  657 

in  urine,  .563 

metabolism,  658 

of  blood  in  disease,  683 

origin  of,  660 
Cremasteric  reflex,   967 
Cretinism,  795 
Critical  concentration,   8 
Crossed  extension  reflex,  966 
Cuorin,  720 
Curare,    effect    on    myoneural    junction, 

845 
Current  of  action,  of  heart,  188 

of  skeletal  muscle,  906 
Cyanosis,  378,  444 
Cysteine,  639 
Cystine,  611,  629,  639 
Cystosine,  667 
Cytases,  497 


Dalmatian    dog,    purine    metabolism    of, 

673,   679 

Dalton's  law,  353 
Dead  space,  319,  327 
Deafness,  880 


978 


INDEX 


Deamidization,  deaminization,  535 

Deaminizing  enzyme,  671 

Decerebrate  rigidity,  925 

Decolorization  of  liquids  by  charcoal,  67 

Decompensation  of  heart,  220 

Decompression  of  caisson  workers,  424 

Defecation,  504 

Defects  of  branches  of  A-V  bundle,  284 

Defibrinated  blood,  102 

Degeneration  of  nerve  fibers,  846 

Degeneration,  successive,  849 

Deglutition,  479 

Delayed   conduction,   282,   291 

Delirium  cordis,  196 

Denervated  iris,  784 

Dendrites,  831 

Depression  of  freezing  point,  10 

of  urine,  557 

Depressor  nerve,  243,  244,  245 
Depressor  substances,  253,  415 
Dessert,  physiological  value  of,  472 
Detoxication    compounds,    662 
Detoxication  process,   535 
Dextrins,   525,   689 
Dextrose    (see  Glucose) 
Diabetes : 

acidosis  in,   715 

and  the  ductless  glands,  710 

assimilation  limits  in,  685 

blood  examination  in,  691    * 

blood  fat  in,  726 

center,  diabetic,  704 

early  diagnoses  of,  685,  692 

energy  output  in,  578 

experimental,  704 

fat  metabolism  in,  715 

insipidus,  815 

ketosis,  715 

pancreatic,   712 

nervous,  in  man,  706 

permanent,  707 

phlorhizin,  697 

postprandial   hyperglycemia,   691 

renal,  693 

starvation  treatment  in,  716 

treatment  of,  623,  686 
Diabetic  acidosis,  715 
Diabetic  center,  704 
Diabetic  gangrene,  300 
Dialuric  acid,  678 
Dialysate,  53 
Dialysis,   12 

method,  colloids,  52 
Diaphragm,  action  of,  337,  338 

physiology  of,  341 
Diastasis,  219 

Diastolic  filling  of  heart,  153,  217 
Diastolic  pressure,  129,  133 

measurement   of,   in  man,   129 
Dicrotic   notch,    203 

wave,   203 
Diet  at  different  ages,  627 

of   different   communities,  626 


Dietetics,  625 

Differential   manometer,   394 
Diffusion,  12 

Digestibility  of  foods,  630 
Digestion,    by   pancreatic    juice,    523 
in  intestine,  523 
in  stomach,  515 
mechanism   of,  478 
Digestive  glands: 
control   of, 
hormone,  460 
nervous,  458 

general  physiology  of,  453 
microscopic    changes    during    activity, 

423 

Disaccharides,  689 
Dispersion  medium,  colloids,  55 
Dispersoid,   colloids,   55 
Dissociation,  16,   17 
Dissociation   constant,    19,    401 
Dissociation  curve : 
of  blood,  396 
of   hemoglobin,   397 

influence  of  salts  on,  398 
influence    of   H-ion   concentration 

on,  339 

influence   of   temperature   on,   399 
Dissociation  of  sensation,  868 
Dissociation  hypothesis,  applications  of, 

21 

Dissociation,  rate  of,  399 
Distance  receptors,  relation  to  cerebrum 

952 
Diuresis,  552 

and  pituitrin,   811 
Diuretics,  552 
Diver's  palsy,  420 
Douglas  method,  489 
Dropped  beat,  282,  291 
Du  Bois  formula,  576 
Ductless  glands,  766 
in  diabetes,  710 
Dudgeon's  sphygmograph,  201 
Dyspnea,  330,  366 
Dystrophia    adiposo-gonitalis,   818 


B 


Earth-worm,  nervous  system  of,  830 

Eck  fistula,  651 

Eclampsia,   654 

Edema,  63,  120 

Edestin   and  growth,   611 

Effectors,  829 

independent,  828 
Efferent  pathways: 

in  brain  and  cord,   888 

to  viscera,  893 
Effort  syndrome,  441,  442 
Einthoven's  triangle,  271,  272 
El.istin,   digestion  of,   520 
Electric  conductivity,  16 
Electric   currents,    development    of, 


INDEX 


979 


Electric  properties  of  colloids,  56 
Electrocardiograms,    159,    270 

normal,   273 

standardization   of,    271 

ventricular  complex,  274 

waves   of,   272 
P-wave,  189,  273 
T-wave,  225,  273,  278 
Electrocardiograph,  271 
Electrocution,   cause  of   death   in,   195 
Electrolytes,    16 

action  of,  on  colloids,  64 
Electrolytic  solution  pressure,  29 
Electrophoresis  of  colloids,  57 
Electrostatic   attraction,    29 
Emboli,   108 
Emetics,  484 

Emotional  glycosuria,  706 
Emphysema,   328,  330,  341 
Empyema,  341 
Emulsions,    719 
Emulsoids,  colloids,  61 
Endocrine  organs,   766 
Endoenzyme,  71 
Endogenous   metabolism,    649,   656 

of  purines,  676 
Energy  balance,  571 
Energy  output,  and  age,  597 
and  body  weight,  575 
and  disease,  578 
and  muscular  work,  586 
and  sex,  577 
and  surface  area,  575 
and  temperature,  586 
in  starvation,  602 
Enterokinase,  477,  523 
Enzymes,   72 

action  of  temperature  on,  75 

amylases,  82 

and  catalysis,  73 

antienzymes,  82 

arginase,  82 

coagulative  ferments,  83 

conditions  of  activity,  83 

endoenzymes,  72 

glyoxylase,  83 

invertases,  82 

Upases,  82 

nature  of,  73 

oxidases,  83 

peculiarities  of,  81 

peroxidases,  83 

properties  of,  94 

proteases,  81  « 

reversibility  of  action  of,  25,  78 

specific  action  of,  74 

types  of,  80 

urease,  83 

velocity  constant,   75 
Epilepsy,  Jacksonian,  883,  887 
Epinephrine,    241,   502,   536,   773,   902 

and  diabetes,   708 

emergency  hypothesis  of,  786 


Epinephrine — Cont  'd 

estimation  of,  779,  785 

methods   of  determining,   779,   785 

physiological    action    of,    774 

r  ever  give  action  of,  777 

secretion   of,   in   fright,   786 

variation  in  action  of,  779 
Equilibrium,  nitrogen,  605 
Equivalent,  conductivity,  19 
Erepsin,  520,  524,  525 
Ergastoplasm,   455 
Ergot,  536 

Ergotoxine,  236,  538,  776,  897 
Erythrocytes,    92 

fate  of,  95 

regeneration   of,   94 
Escapement,    223 
Esophagus,   during  swallowing,   480 

inhibition  of,  482 

peristaltic  wave  in,  482 
Esters,  718 
Ester  value,   719 
Ethereal  sulphates,  535,  665 
Ethylamine,  536,  662 
Excelsin,  612 
Excitation,  827 
Exogenous  metabolism,  649 
Exophthalmic  goiter,  799 

energy  output  in,  578 
Excretion    of    acid    combined    with    am- 
monia, 47 

Excretion  of  urine,  541  • 
Extension  contracture,  967 
Extensor  thrust,   967 
Exteroceptors,  917 
Extrasystole,  278,  292 
Eyes,  movements  of,  887 


Facilitation,   843 

Factor   safety,  in   diet,   629 

Fatigue  level,  911 

Fatigue  of  muscle,  910,  911 

Fatigue  of  reflexes,  845 

Fats: 

absorption  of,  722 
chemical  theory,   723 
mechanistic    theory,    723 
and  growth,  617 
blood,  726,  727 

destination  of,  729 
determination,   726 
during   absorption,   728 
during  fasting,  728 
variations  in,  727 
chemistry  of,  721 
depot  fat,  729,  730 

destination  of,  731 
desaturation  of,  734,  740 
digestion  of,  722 
fat  dust,  726 
liver  fat,  729,   731 


980 


INDEX 


Fats— Cont'd 

metabolism  of,  718,  726,   736 

tissue  fat,  729,  735 

transportation  to  liver,  732 
Fatty  acids,  718 

acid  number,  719 

breakdown  of,  737 

ester  value,  719 

formation  from  carbohydrates,  730, 

736 

in  liver  in  disease,  733 
iodine  value,  719 
melting   point,    719 
Keichert-Meissl  value,  719 
saponification  value,   719 
Feces,  533,  555 
Ferments  (see  Enzymes) 
Ferments  in  blood,  90 
Fever,  bloodflow  in,  298 

body  changes  in,  750 

causes  of,  748 

cold-bath  treatment,  299 

purine  excretion  during,   680 
Fibers,  anterior  root,  238 

connector,  894 

internuncial,  894 

postganglionic,  894 

preganglionic,  894 
Fibrillation,  auricular,  196,  281,  295 

ventricular,  195 
Fibrin,  100 

fibrin  needles,  100 

source  of,  102 

Fibrin  ferment  (see  Thrombin),  103 
Fibrinogen,  89,  102,  104,  112 
Filtration,  13 
Final  common  path,  945 
Fistula,  biliary,  526 

gastric,  468 

salivary,  466 
Flexion-reflex,  966 

Flutter,  auricular,  269,  196,  281,  293 
Food : 

.accessory  factors  of,  618,  630 

cooking,   importance   of,   630 

effect  of,  on  circulation,  247 

effect  on  creatinine  excretion,  657 

laxative  qualities,  631 

palatability,  630 

Food  factors,  accessory,  618,  630 
Food  factors  of  growth,  608 
Foodstuffs,  rate  of  leaving  stomach,  492 
Forced  breathing,  341 
Formaldehyde  titration,  amino  acids,  521 
Formation  of  solid  surface  films,  67 
Free   nerve   termination,   854 
Freezing  point,  constant,  10 
Freezing  point,  depression  of,  10 
Fridericia's  method  for  alveolar  air,  3.17, 

358 

Fructose,  698 
Fundus  of  stomach,  485 


G 

Gallstones,  528 

Galvanometer,  string,  187,  270 

Ganglia,  831 

Gas  in  stomach,  496 

Gas  laws,  3,  353 

Gases,  adsorption  of,  67 

coefficient  of  solubility,  354 

estimation  of,  361 

partial  pressure  of,  353 

solution  of,  353 

tension  of,   353 

transportation  in  blood,  392 
Gaskell's  clamp,  175 
Gastric  contents,  regurgitation  of,   483 
Gastric  digestion,  515 

rate  of,  521 
Gastric  fistula,  468 
Gastric  juice,  quantity  secreted,  474 

strength  of,  475 
Gastric  secretion,   467 

hormone  control  of,  472 
local  stimulation  of,  472 
nervous   control   of,   469 
Gastric  tube,   487 
Gastric  ulcer,   490 
Gastrin,  474,  490 
Gastroenterostomy,  494 
Gastrointestinal    contents,     reaction     of, 

539 

Gelatinization,   62 
Glands,  changes  during  activity,  453,  456 

electric  changes,   457 

normal  conditions  of  activity,  465 

oxygen  consumption  of,  408,  411,  456 

respiration  of,  408,  411 
Globulin,  611 
Gliadin,  612 
Glomerulus,  541 
Gluconeogenesis,   694,   708,   712 

direct  method,  695 

indirect  method,   696 

in  normal  animals,  699 
Glucose :  ' 

fate   of   absorbed,   694 

glucose   to   nitrogen   ratio,    696 

injections,   intravenous,   687 
subcutaneous,  688 

parenteral  assimilation,   688 

tolerance  for,  688 

utilization  of,  in  tissues,  708 
Glutamic   apid    (see   Glutaminic   acid) 
Glutaminic  acid,  640,  699 
Glutein,  611 
Glutelin,  611 
Glycol  aldehyde,  697 
Glycerol,  697 
Glycoholic  acid,  528,  664 
Glycine, '  494,   639 
Glyeininj  611 
Glycocoll,  637,  639,  664,  699,  738 


INDEX 


981 


Glyeogen,  694 

fate  of,  701 

sources  of,  694 
Glycogenase,  694 
Glycogenolysis,  701 

hormone,  707 

nervous,  704: 

postmortem,  702 
Glycolaldehyde,   697 
Glycolysis,  702 

Glyconeogenesis   (see  Gluconeogenesis) 
Glycosuria,   alimentary,   690 

emotional,  702 

postprandial,   691 

relation  to  sugar  of  blood,  692  y 

renal,  693 
Glycuronates,  665 
Glycuronic  acid,  665,  666 
Glyoxal,  664 
Glyoxylase,  82,  698 
Glyoxylic  acid,  664 
G-N-ratio,  696 
Goiter,  exophthalmic,  799 
Gonads,  821 

of  female,  822 

of  male,  821 
Gout,  681,  683 

etiology  of,  683 

guanine,  673 

uric  acid  excretion  in,  681 
Gram  molecule,  3,  5 
Gram  molecular   solution,   22 
Gravity,  on  circulation,  248 

compensation  for,  249 
Growth,  608 

accessory  factors,  618 

basal  ration,  610 

carbohydrates  and,  583 

curves  of,  610,  611 

curves  of  inhibition,  614 

fats  and,  617 

inorganic  salts  and,  618 

lysine  and,  612 

proteins   and,  609 

trypanophanc   and,   612 

vitamines,   618 
Guanidine,  640,  656,  804 
Guanine,  667 

gout,   673 
Guanosine,  671 
Giinsberg  reagent,  521 
Gustatory  area,  879 

H 

Haldane-Barcroft  apparatus,  45 
Haldane  gas  apparatus,  593 
Haldane's  method  for  alveolar  air,  357 
Hallucinations,  883 
Heart : 

action  of,  145 

auricular  curve,  153 

diastole  of,   146 

isometric  period  in,   150 


Heart— Cont  'd 
law  of,  216 
minute  volume  of,  218 
muscle,   properties,   176 
nutrition  of,  161 

opening  and  closing  of  valves,  154 
output  of,  216 

in  relation  to  venous  inflow,  216,  217 
oxygen  requirements  of,  408,  411 
oxygen  supply  of,  166 
perfusion  of  outside  body,  161 
postsphygmic  period,   150 
presphygmic  period,  150 
pressure  in,  146 
pumping  action  of,  135,  145 
resuscitation   in  situ,   165 
rhythmic  power  in,  170,  174 
sounds  of,  156 
systole  of,  146 
tone  of,  218,  219 
utilization  of  glucose  in,  713 
vagus  control  of,  cold  blooded,  222 
vagus  control  of,  mammalian,  225 
vagus  terminations  in,  230 
ventricular  curve,  151 
work  of,  213 
Heart  beat: 

arrhythmia  of,  278,  292 
disorders  of,  219,  278,  291 
myogenic  hypothesis  of,  170,  171 
neurogenic  hypothesis  of,  170,  172 
origin  of,  in  cold-blooded  animals,  170 
origin  of,  in  mammalian,  182,  189 
pace  maker  of,  174 
propagation  of,  191 
reserve  power,  220 
sympathetic  control  of,  232 
ultimum  moriens,  185 
vagus  control  of,  222,  225 
Heart  block,  174,  282,  291 

effect  of  vagus  on,  224 
Heart  disease,  vital  capacity  of  lungs  in, 

330 

Heart-lung  preparation,  163 
Heat  production  and  age  and  sex,  577 
and  body  weight,  575 
surface,  576 
disease,  578 
sensation   of,    861 
Heat  spots,  860 
Heat  value  of  foods,  571 
Hematin,  530 
Hematocrit,  7 
Hematoporphyrin,  530 
Hemiplegia,  889 
Hemodromograph,  207 
Hemoglobin,  92 

dissociation  constant,  401 
dissociation,   curve   of,   396,398,399 
estimation  of,  93 
rate  of  dissociation,  399 
relationship  to  bile  pigments,  530 
specific  oxygen  capacity  of,  392 
transportation  of  02  by,  392 


982 


INDEX 


Hemolysis,  7,  9(3 

Hemolytic  jaundice,  94 

Hemophilia,   113 

Hcmopoietic  activities   of  bone   marrow, 

94 
Hemorrhage,  95,  138 

immediate   effects    of,    138 

recovery  from,  89,  139 
Hemorrhagic  diseases,  113 
Henle,  loop  of,  541 
Hepatic  artery,  flow  in,  265 
Heterocyclic  compounds,  640 
Hexone  bases,  638 
Hexoses,  685 

Hibernating  animal,  metabolism  of,  581 
Hibernation,  breathing  during,  389 
Higher  functions  of  cerebrum,  951,  958, 

963 

H  ion  or  hydrogen  ion,  168 
H-ion  concentration,  22 
after  hemorrhage,   143 
catalytic  power  of,  23 
determination  of,  31 
of  intestinal  contents,  539 
law  of  mass  action  and,  26 
method  of  expressing,  27 
method    of   measurement : 
electric  method,  29 
indicator  method,   32 
standard  solutions  for,  34 
H-ion  concentration  in  blood: 

effect   on  dissociation   curve,   398,   401 

effect  on  respiratory  center,  352 
Hippuric  acid,  564,  663,  738 
Hirudin,  101 
Histamine,  536 

as  a  factor  in  shock,  307 

effect  upon  capillaries,  253,  413 
Histidine,  639,  641,  656 
Homogentisic  acid,  536,  565 
Hordein,  612 
Hormones,   3,  766 

in  control  of  circulation,  221 

respiratory,   352,,   366 
Howell  theory   (blood  clotting),  107 
Hunger,  506 
Hunger  contractions : 

alcoholic  beverages  and,  512 

control  of,   511 

during  starvation,  510 

in  esophagus,  509 

inhibition  of,   511 

in  stomach,  506 

nerve  centers  and,  513 

remote  effects  of,  509 

rhythmic,   506 

splanchnic  nerve  and,  511 

vagus  nerve  and,  511 
Hiirthle  manometer,  128,   147 
Hydrocephalus,  255,   263 


Hydrochloric  acid,  amount  of,  516 

and  emptying  of  stomach,  491,  494 
functions  of,  516 
source  of,  517 

Hydrogen  ion  (see  H  ion) 

Hyperacidity,  495 

Hyperglycemia,    in    pancreatic    diabetes. 

712 

postprandial,  691 
splanchnic,  704 

Hypernephroma,  769 

Hyperpituitarism,   816 

Hyperpnea,  366,  371,  377 

Hyperthyroidism,   798 

Hypertonic  solution,  6 

Hypopituitarism,  817 

Hypothyroidism,  797 

Hypotonic   solution,   6 

Hypoxanthine,  667,  671 


Ignition  juice,  473 

Ileocolic  sphincter,   501,  503 

Imbibition,   63 

Imidazole  and  growth,  639,  656 

Imidazole  ring,  656 

Imidazolylethylamine,  253,  413,  461,  536 

Immediate  induction,   947 

Impulses,  nature  of,  837 

Indican,  565,  665 

Indicator  method,  list  of  indicators,  33 

Indole,  535,  639,  665 

Indoxyl  sulphate  of  potassium,  665 

Induction,  immediate,  947 

successive,  949 
Inhibition,   843 

reciprocal,  914,  937 
Inhibitory   effects   of   autonomic   nerves, 

896 
Innervation,    double    of   visceral    organs, 

896 

Inorganic  constituents  of  urine,  565 
Inorganic  salts  and  growth,  618 
Inosine,   670,   671 
Inosinic  acid,  668 
Inspiration,    negative    pressure     during, 

322 

Insulin,  714 

Integration   of   allied    reflexes,   945,    946 
Intercostal  muscles,  336 
Interganglionic   connectives,   832 
Internal  respiration,  391 
Interstitial  cells  of  ovary,  822 
Intestinal  bacteria,   533,   690 
Intestinal  ballast,  631 
Intestinal  juice,   control  of,  477 
Intestinal  muscle : 

metabolic  gradient  of,  500 

rhythmicity    of,    499 

segmenting  movements  of,  497 
Intestinal   obstruction,   505,    538 
Intestinal   secretions,   476 


INDEX 


983 


Intestine : 

absorption  from,  13 

anastomosis    of,    504 

bacterial  digestion  in,  533 

digestion  in,  523 
law  of,  501 

movements  of: 
large,  503 

clinical  conditions  affecting,  504 
small,  497 

nature  of,  501 
nervous  control  of,  501 
Intracardiac  pressure  curves,  146,  151 
Intracranial   pressure,    258 
Intragastric  pressure,  488 
Intrapleural  pressure,  321 
Intrapulmonic  pressure,  316 
Intra  vitam  anticoagulants,  101 
Intravascular  clotting,  108 
Inulin,  696 

Invertase,  82,   526,  689 
Iodine  value  of  fats,  719 
lodothyrine,  798 
lonization,  16 

Irradiation  on  to  respiratory  center,  430 
Iris,   denervated,   784 
Isoelectric  point,   64 
Isoleucine,   639 
Isomaltose,  79 
Isometric  period,  150 
Isotonic   solution,   6 

J 

Jacksonian  epilepsy,  883,  887 
Jugular  pulse  tracing,  285 
Juice,  gastric,  467,  516 

intestinal,  476 

pancreatic,  476,  523 

K 

Keith    and   Flack,    conducting    tissue    in 

heart,  185 
Keith,  Kowntree,  and  Geraghty  method, 

85 

Kent,  bundle  of,  183 
Ketosis,  715 
Kidney,    oxygen    requirements    of,    408, 

412 

removal  of,  655 
structure  of,  541 
Knee-jerk,  966 

L 

Labyrinth,  918 

clinical  tests  of,  920 

Lactalbumin,    611 

Lactam,  682 

Lactase,  525,  689 

Lactic  acid,  413,  639,  689,  697,  708 
effect  on  respiratory  center,  379 
in  relation  to  anoxemia,  379 
produced  by  exercise,  431,  435 

Lactim,  682 

Language,  958 


Laws  of  gases,  353 

of  mass  action,  23 

applied  measurement  of  H-ion  concen- 
tration, 26 
Lead  poisoning,  684 
Lecithin,  720 

estimation  of,  726 

in  bile,  532 

in  blood,  726,  728 
Leech  extract,  101 
Legumelin,   612 
Legumin,  612 
Leucine,  640,  698 
Leucemia,   681 
Leucocytes,  97 

sensitizing  of,  70 

transitorial,   98 
Levulose,  698 

Levy  and  Eowntree  method,  41 
Leydig  cells,  821 
Limulus,  heartbeat  of,  173 
Lipase,  25,  91,  522,  525,  719 
Lipemla,    728 
Lipoids  of  blood,  728 
List  of  indicators,  33 
Litten's   diaphragm   phenomenon,   338 
Liver : 

circulation  through,   265 

disease  of,  654 

glycogen  in,  695 

metabolism  of  fats  in,  731 

perfusion  of,  652 

removal  of,  651 

urea  formation  in,  651 
Local  irritants,  248,  253 
Localization : 

one  dimensional,  861 

two  dimensional,  861 

three  dimensional,  861 
Locke   solution,   168 
Loven  reflex,   248 
Lungs,   circulation  through,   264 

mode  of  expansion  of,  342 
Lymph : 

absorption  into,  13 

electric  conductivity,  16 

filtration  in,  118 

formation  and  circulation,  115 

formation  of,  15 
Lymph  spaces,  115 
Lymphagogues,  119 
Lymphatics,  115 
Lymphocytes,  97 
Lyophobe  colloids,  61 
Lysine,  629,  640 
Lysine  and  growth,   612,  614,  616 


M 

Maintenance,   diets  for,   61G 
Maltase,  525,  689 
Maltose,   525,    689 


984 


INDEX 


Manometer : 

blood-gas   differential,   39;") 

Hurthle,   128,  147 

mercury,    125 

optical,   147 

spring,   128 

valved    mercury,    152 
Mark-time   reflex,   967 
Mass  action,  23 

Mass  action  and  H-ion  concentration,  26 
Mass  movements  of  blood,  208 

measurement  of,  296 
Mass-reflex,   968 
Mastication,  478 
Mechanics   of  respiration,   316 
Mechanism  of  urine  excretion,  544 
Megacaryocytes,   104 
Melting  point,  fats,  719 
Mercury  manometer,  125 
Mesencephalico-spinal   system,    963 
Metabolism : 

calculations,  596 

endogenous,  649 

exogenous,  649 

general,   570 

in  starvation,  600 

normal,  604 

of  carbohydrates,  685 

of  central  nervous  system,  851 

of  fats,  718 

of  nerve  fibres,  856 

of  proteins,  632 

of  purines,  676 

special,  570 
Methyl  glyoxal,  698 
Methyl  group,  634 
Methyl  purines,  668 
Methylation,  660 
Methylglyoxal,  698 
Mett's  method,  521 
Microcytes,  95 
Microtonometer,  356 
Mid-capacity  of  lungs,  328 
Milk,  clotting  of,  521 
Miniature  stomach,  468 
Minimal  air,   317 
Mononuclear   leucocytes,   97 
Monoplegia,  887 
Monosaccharides,  689 
Morphogenetic,   767 
Morawitz  theory,  blood  clotting,  108 
Motor  areas: 

representation  of  function  in,   886 
stimulation  of,  885 
Mountain  sickness,  378,  415 

acid  and  ammonia  excretion  in,  420 
acid-base  equilibrium  in,  416 
adaptation  to,  418 
alveolar  CO2  in,  416 
blood  corpuscles  in,  419 

•    symptoms  of,  417 
Movements,  of  intestine,  497 

of  stomach,  485 


Municipal   food    statistics,    628 
Muscarine,  action  on   heart,  232 
Muscle,  cardiac,  properties  of,  176 

refractory    period,    178 

respiration   in,   408,   409 

staircase  phenomenon   (treppe),  177 
skeletal,  177 

respiration  in,  394 
Muscular  exercise,   248,   574 

circulatory   changes   during,   427 

effect  on  metabolism,  586 

effect  on  respiration,  427 

H-ion  during,   431,  432 

purines  during,  480 

redistribution   of  blood  during,  433 

respiratory  changes   during,  427 

temperature  of  blood  during,  433 
Mutual  precipitation  of  colloids,  57 
Myenteric  reflex,  830 
Myogenic  hypothesis  of  heartbeat,  171 
Myoneural  junction,  845 
effect  of  curare  on,  845 
effect  of  epinephrine   on,   845 
Myxedema,  796 

energy  output  in,  578 


N 


Narcotics  and  blood  fat,   727 
Necrosis  of  liver,  654 
Negative  heart  pulse,  154 
Negative  pressure  in  ventricle,  152 
Nephelometer,  726 
Nephrectomy,  655 
Nephritis,  683,  684 

acidosis  in,  715 

urea  retention  in,  562 
Nerves : 

degeneration  of,   846 

regeneration   of,    846 

specific  properties  of,  859 

vasodilator,  239 

Nerve  cell  body,  function  of,  846 
Nerve  fiber: 

conduction  in,   837 
degeneration   of,   846 
direction    of   conduction   in,    837 
fatigue  of,  841 

isolation  of  conduction  in,  837 
metabolism  of,  850 
regeneration  of,  846 
Nerve  net,  830 
Nervi  erigentes,  239,  895 
Nervous  control : 

of  gastric  secretion,  469 

of   ileocolic   sphincter,   503 

of  intestinal  glands,  477 

of  intestinal  movements,  501 

of  pancreas,  462 

of  respiration,  344 

of  salivary  glands,  458 

of  stomach  movements,  492 
Nervous  conduction,  polarity  in,  830,  841 


INDEX 


985 


Nervous  impulse: 

conduction   of,   836 

rhythm  of,   841 
Nervous  diabetes,  704 

in  man,  706 
Nervous   system : 

autonomic,  893 

bulbar  outflow,  894 
enteral,   895 
internuncial  fibres,  894 
oculo-molor,  895 
sacral  outflow,  894 
thoracico-lumbar  outflow,  895 

evolution  of,  827 

influence  on  excretion  of  urine,  563 

integration  of,  945,  951 

metabolism  of,  851 

nutrition  of,  846,  849 
Network,  nerve,  830 
Neurogenic  hypothesis,  of  heart,  172 
Neurons,  830 

association,  834 

effector,  894 

internuncial,  894 
Neuroid  transmission,  828 
Neurolemma,  848 
Neutrality,  regulation  of,  36 
Nicotine : 

action  on  vagus,  231 
Nitrogen : 

action  on  synapse,  238,  844,  895 

excretion  of,  premortal  rise,  600 

in  starvation,  600 

undetermined,  urine,  647,  662 
Nitrogen  balance,  605 
Nitrogenous  constituents  of  urine,  560 
Nitrogenous  equilibrium,  605 
Nitrogenous    metabolites,    in    starvation, 

602 
Nociceptives : 

reflex,  966 
Noeud  vital,  344 
Nonelectrolytes,  16 
Nonthreshold   substances,    546 
Normal   acid,    22 
Normoblasts,  94 
Noxious  stimuli,  862 
Nuclease,  671 
Nucleic  acid,  669,  720 
Nuclein  ferments,  91 
Nucleins,  669 
Nucleoside,  670 
Nucleotide,   670 
Nystagmus,  920 
Nutrition,   608 

of  nervous  tissue,  846,  849 


Obesity,  Banting  cure  for,  605 
Oleic  acid,  718 
Olein,  719 
Olfactory  area,  879 


Oncometer,  235 
Opsonins,   70 

Optic  thalamus,  sensory  center  of,  876 
Organs,    loss    of    weight    during    starva- 
tion, 602 

perfusion  of,  652 
Ornithine,  650,  664 
Ornithuric  acid,  664 
Orthopnea,  329,  335 

Oscillatory  method  of  blood  pressure,  132 
Osmometer,  5 
Osmosis,  4 
Osmotic  pressure,  4,  10 

and  formation  of  lymph,  13 
and  hemolysis,  7 
and  plasmolysis,  8 
measurement  by  depression  of  freez- 
ing point,  11 

in  physiologic  mechanisms,  13 
in  production  of  urine  by  kidneys, 

14 

of  transfusates,  142 
Ovary,  822 

Ovalbumin,  as  food,  611 
Ovovitellin,  as  food,  611 
Oxidases,  82 
Oxidation  of  blood,  400 
Oxybutyric  acid,  650,  715,  740 
Oxygen : 

coefficient  of  oxidation,  408 
coefficient  of  utilization,  410 
determination  of,   596 
estimation  in  blood,  403 
requirements  of  tissues,  408 
tension  in  alveolar  air,  361 
tension  in  arterial  blood,  354,  356 
therapeutic  value  of,  445 
transportation  by  blood,   392 
volume  percentage  in  blood,  403 
Oxygen  insufficiency,   (see  anoxemia) 
Oxygen  supply  of  heart,  163,  166 
Oxyproteic  acid,   662 


Pacchionian  body,   256 

Pain: 

referred,  858 
sensation  of,   862 

transmission  in  cord,  868 
sense,  862 

Palatability,  630 

Palmitic  acid,  718,  736 

Pancreas : 

hormone  control  of,  460 
histologic  changes  of,  464 
oxygen  requirements,  396 
nervous  control  of,  462 
sugar  metabolism  and,  710 

Pancreatic  diabetes,  712 

Pancreatic  digestion,  523 


986 


INDEX 


Pancreatic   juice,   476 

and  fat  digestion,  721 

secretion  of,  460 
Pancreatin,  524 
Parasympatlietic  system,   895 
Parathyroids,  800 

disease   of,   800 

injury    of,    800 

removal  of,  800 
Paralysis,  flaccid,  924 
Paroxysmal  tachycardia,  281,  293 
Partial  dissociation,  283 
Partial   pressure   of  gases,   353 
Past  pointing,  920 
Pelvic  nerve,  895 
P'elargonic  acid,  740 
Pentose,   670,  696 
Pepsin,   action   of,   519 

products  of,  520 
Pepsinogen,    519 
Peptides,  636 
Peptone,  106,  520 
Perfusion,  of  kidney,  664 

of  liver,  652 

Perfusion  fluid,  of  heart,  166 
Perfusion  of  heart,   161 
Periodic  breathing,  causes  of,  385,  386 

types  of,  385 
Peripheral  resistance,  135,  234 

as  cause  of  shock,  304 
Peristalsis : 

in  esophagus,  481 

in  large  intestine,  503 

in  small  intestine,  497 

in  stomach,  486,  489 
Peristaltic  rush,  500,  505 
Peristaltic  wave,  499 
Pernicious  anemia,  energy  output  in,  578 
P'eroxidases,  82 
PH,   27 

Phagocytes,  98 
Phenaceturic  acid,  738 
Phenol,  534 
Phenolacetic  acid,  536 
Phenolphthalein,    516,    558 
Phenylacetic  acid,  664,  738 
Phenylalanine,    639 
PTienyl  group,  639 
Phlorhizin,  695,  696 
Phono-receptors,  855 
Phosphates,  excretion  of,  47 
Phosphate  solutions  for  H-ion,  34 
Phosphates  of  urine,  566 
Phospholipins,   720 

in  bile,  532 
Photo-receptors,  855 
Phrenic  center,  345 

isolation  of,  345 
PTiysiochemical  basis,   1 
Physiological  processes  depending  on  ad- 
sorption, 70 

Pigments,  absorption   of,   117 
Pilocarpine,   action   on   heart,   232 


Pilomotor  fibers,  897 
Pineal  gland,  820 
Pituitary  gland,  806 

anterior  lobe  of,  808 
disease  of,  816 
functions   of,   807 
pars  intermedia  of,  815 
posterior  lobe,  809 
Pitot's  tubes,  201 
Pituitrin,   effect   on  vessels,   811 

effect     on     carbohydrate     metabolism, 
814 

effect  on  kidney,  812 

effect  on  milk  secretion,  813 
Plasma,   100 
Plasmolysis,  8 
Plastic  tonus,  905 
Platelets,  of  blood,  98,  107 
Plethora,  87 

Plethysmograph,   209,   235,   320 
Pleurisy,  341 

Plexus  of  Auerbach  and  Meissner,  500 
Pneumothorax,  322 
P'oikilocytes,  95 
Polarity,  in  conduction,  841 

in  reflex  arc,  841 
Polygraph,  286 
Polynuclear  cells,  97 
Polypeptides,  520,  636 
Poly  phosphoric  acid,  670 
Polysaccharides,  522 
Polysphygmograms,    285 
Portal  vein,  bloodflow  in,  265 
Postdicrotic  wave,  pulse,  203 
Postprandial    hyperglycemia,    691 
Postsphygmic  period,   150 
Postural   co-ordination,    914 

central  control  of,  924 
Posture  of  body,  917 
Potassium,   microchemical   test   for,   4.~>n 
Potassium  ions,  on  heart,  167 
Potential  acidity  of  urine,  559 
Precipitins,    632 
Predicrotic  wave,  pulse,  203 
Premature  beats,  278,  292 
Premortal  rise,  600 
Presphygmic   period,    150 
Pressor  impulses,  243,  244,  245 
Pressure : 

intragrastric,  488 

intrapleural,  321 

effect  of,  in  blood  pressure,  323 

intrapulmonic,  316 

negative,   322 

osmotic,  10 
Pressure  pulse,   129 
Principle  of  Willard  Gibbs,  66 
Proline,  640 
P'roprioceptors,    914 

clinical  tests  for,  920 
Prosecretin,  461 
Proteases,  90 
Protein  sparers,  636 


INDEX 


987 


Proteinases,  81 
Proteins : 

as  colloids,  64 
bacterial  digestion  of,  535 

chemistry  of,  633 

metabolism  of,  631,  647 
end  products,  647 

minimum   requirement,   606,   629 

of  blood,  88 

relative  value   of,  for  growth,  646 

salting  out  of,  61 
Proteose,  520 

Prothrombin,  104,  107 ,  112 
Psychopathology,  960 
Ptomaines,  536,  662 
P'tyalin,  525,  689 
Pulmonary   circulation,   264 
Pulmonary  ventilation,  367 
Pulses,   198 

abnormal,  291 

alternans,  181 

bigeminus,  181 

contour  of  wave,  200 

length  of  wave,  199 

palpable,   202 

pressure,  129 

pulse  curves,  202 

pulse  waves,  198,  199,  200,  202 

rate  of  transmission,  199 

velocity,  200 

venous,  central,  205,  285 

venous,   peripheral,   205 
Purkinje  fibers,  184 
Purine  bodies   (see  Purines) 
Purines: 

chemistry  of,  563,  647,  667,  674 

endogenous,  676,   677 

exogenous,  674 

metabolism  of,  667 

in  starvation,  603 

synthesis  of,  677 

in  urine,  563 

Putrefaction,  intestinal,  535,  565 
Putrescine,  662 
Pyloric  canal,  485 
Pyloric  sphincter,  control  of,  490 
Pyloric  vestibule,   485 
Pyrimidine   bases,   669,   670 
P'yruvic  acid,  635 

E 

Eami  communicantes,  238 

Raynaud's   disease,   bloodflow   in,    300 

Reaction  of  urine,  558 

Reactions   depending   on   adsorption,    67 

Reactions  of  body  fluids,  35 

Receptor-effector   system,    829 

Receptors,  829,  854,  933 

chemo,  855 

distance,  952 

extero,  917 

evolution  of,  854 

of  skin,   859 


Receptors — -Cont  'd 
phono,  855 
photo,  855 
proprio,  914 
tango,  855 
temperature,  861 
touch,  860 

Reciprocal  inhibition,  915,  937 
action  of  strychnine  on,  941 
action  of  tetanus  toxin  on,  941 
Reciprocal  innervation  of  blood  vessels, 

247 

Red  blood  corpuscles,  origin  of,  93 
Reduction  of  blood,  400 
Referred  pain,  858 
Reflex,  832 

conditioned,  466,  954 
unconditioned,  466 
Reflex  arc,  832 

integration  within,  933 
polarity  of,  841 
Reflex  conduction: 
canalization,  844 
facilitation,  843 
induction,  843 
inhibition,   843 
summation,  843 
Reflexes : 

abdominal,   892 
Achilles  tendon,  892 
allied,  945 

simultaneous  combination  of,  946 
successive  combination  of,  946 
antagonistic,  945 
axon,  829,  898 
bulbocavernosus,  967 
conditioned,    854 
cremasteric,   967 
crossed  extension,  966 
extensor  thrust,  967 
flexion,  966 
genital,  892 
mark-time,   967 
mass-reflex,  968 
myenteric,   830 
nociceptive,  966 
palmar,  892 
plantar,  892 
proprioceptive,    914 
pupillary,  892 
scapular,  892 
scratch,  966 
triceps,  892 
unconditioned,  466 
Reflex  fatigue,  948 
Reflex  figure,  941 

spread  of,  943 
Refractive  index,  blood,  89 
Refractory  period,   839,  934 
Refractrometric   methods,   89 
Regeneration  of  erythrocytes,  94 

of  nerve  fibres,  846 
Regulation   of   neutrality,   36 


988 


INDEX 


Regurgitation  of  gastric  contents,  483 
Reichart-Meissl  value   of  fats,   719 
Eenal  diabetes,   693 
Renal  function,  theories  of,  545 
Renal  threshold  for  sugar,  692 
Rennin,  521 

Reserve  alkalinity,  measurements  of,  in- 
direct methods,  41,  46 
measurement   of,   titration   methods, 

41 

Residual  air,  317,  328 
Respiration : 
abdominal,   324 
beyond  the  lungs,  391 
during  muscular  exercise,  427 
external,  391 
in  compressed  air,  420 
in  rarefied  air,  415 
internal,  391 
mechanics  of,  316 
movements  of  diaphragm  in,  337 
movements  of  ribs  in,  332 
Respiration  calorimeter,  572 
Respiratory  center,  344 

afferent  impulses  to,  348,  350 
automaticity  of,  346 
hormone  control  of,  352,  366 
reflex  control  of,  348 
sensitivity  to  alveolar  CO,,  371 
stimulation  by  CO2,  366,  3~67 
subsidiary,  345 

Respiratory    changes    in    muscular    exer- 
cise, 427 
Respiratory  exchange: 

according  to  body  weight,  585 

and  body  temperature,   586 

and  muscular  exercise,  586 

and     temperature     of     environment, 

586 

clinical  method  for  determining,  589 
in   diabetes,   709 
in  tissues,  408,  412 
Respiratory  hormone,  nature  of,  366 
Respiratory  movements,  322,  325 
Respiratory  passages,  pressure  of  air  in, 

316 

Respiratory  quotient,   582 
in  diabetes,   709 
influence  of  diet  on,  582 
influence  of  metabolism  on,  584 
influence    of    muscular    activity    on, 

435 

Respiratory  tracings,   320 
Respiratory  valves,  Pearce  's,  589 
Reticulated  erythroblasts,  94 
Reversible   action  of  enzymes,   25 
Ribs,  movements  of,  332 
musculature  of,  336 
undulatory  movements  of,  334 
Right  lateral  connection,  heart,  185 
Romberg's  sign,  921 
Rotation  test   of  labyrinth,   920 
Rhythmic  segmentation,  497 


Sacral  outflow,  894 

Salicylates,  681 

Saline    injection,    effect    on    blood    pres 

sure,  139 

Saliva,  control  of  secretion,  nervous,  458 
psychic,  466 

normal  secretion,  466 
Salt,  dietetic  value,  618 
Salted  blood,  101 
Salting  of  proteins,  61 
Saponification,  719 
Sarcosine,   656 
Saturation  limits,  685,  687 
Scratch  reflex,  966 
Scurvy,  622 

Sea  anemone,  nervous  system  of,  828 
Second  wind,  438 
Secretory  fibers,  varieties  of,  459 
Secretion,  460 

chemical  nature  of,  461 

mechanism  of  action  of,  455 
Secretion    (see   under   various   glands) 

general  considerations,  453 
Segmentation  movements,  497 
Semicircular  canals,  918 
destruction  of,  918 
eye  movements  and,  918 
Semilunar  valves,    150,   155 
Semipermeable  membrane,  4 
Sensation : 

afferent  paths  of,   866 

distribution  of,   863 

local  sign  of,  856 

quality  of,  855 
Sense,  temperature,  861 

touch,  860 
•     pain,  862 
Sensibility : 

cutaneous,  859 

deep,  859 

Sensory  adaptation,  862 
Sensory    area    of    cutaneous    and    deep 

sensibility,  878 
Sensory  centers,  876 
of  brain,  876 
of  cerebral  cortex,  876 
of  optic  thalamus,   878 
Serine,  639 
Serum  albumin,  88 
Serum  globulin,  88 
Sex,  effect  on  creatinine  excretion,  658 

effect  on  energy  output,  577 
Sham  feeding,  469 
Shell  shock,  302 
Shock,  301 

action  of  heart  in,  305 

anesthetic,  302 

blood  pressure  in,  303 

experimental  investigations,,  304 

gravity,  301 


INDEX 


989 


Shock — Cont  'd 

hemorrhagic,   302 

histamine  as  a  factor  in,  307 

nervous,   302 

prognosis  of,  311 

oligemia  in,  306 

recovery  from,  312 

secondary  symptoms  of,  310 

shell,  302 

spinal,  302,  924,  965 

surgical,  303 

toxemia  as  a  cause  of,  309 

trauma  as  a  cause  of,  309 

treatment  of,  311 

vasomotor  control  in,  304,  305 
Sinoauricular   node,   185,   278,   293 
Sinus  arrhythmia,  292 
Sinus  bradycardia,  292 
Skatole,  535,  665 

in  urine,  565 

Skeletal  muscle,  respiration  in,  408,  409 
Skin,  receptors  of,  859 
Smooth  muscle: 

contraction  of,  912 
fatigue  of,  912 
metabolism  of,  912 
rhythmicity  of,  913 
Soap,   718 
Sodium  ions,  166 
Solution  of  gases,  353 
Solutions : 

gas  laws  and,  3 

gram  molecular,  5,  22 

hypertonic,  hypotonic,  and  isotonic,  6 

nature  of,  3 
Sb'rensen   method    for    estimating   amino 

groups,  635 
Sounds,  cardiac,  156 

recording  of,   158 
Specific  conductivity,  17 
Specific  dynamic  action,   574 
Specific  gravity  of  urine,  557 
Sphingomyelin,    720 
Sphygmic  period-,   290 
Sphygmograph,  Dudgeon's,  201 
Spinal  cord: 

section  of,  849 

in  laboratory  animals,  965 
in  man,  967 

hemisection  of,  870 

sensory  pathways  in,  868 

successive  degeneration  in,  849 
Spinal  reflexes,  965 
Spinal  shock,  924,   965 
cause  of,  969 
in  animals,  965 
in  man,  967 
Spirometer,  556 

Splanchnic  circulation  in  shock,  305,  306 
Splanchnic  nerve,  238,  704 
Sponges,  nervous  system  of,  828 
Spot  finding,  861 
Stalagmometer,  66 


Standard  of  neutrality,  26 

Standard   solutions,  preparation  of,   34 

Stannius'  ligature,  176 

Starvation,  600 

acidosis  during,  602,  603 

cause  of  death,  604 

effect  of  creatinine  excretion,  658 

energy  output  during,  602 

excretion  of  nitrogen,   600 

loss  of  weight,  602 

nitrogenous   metabolism,   602 

purines  during,   603 

secretion  of  gastric  juice  during,  511 

sensations  during,  510 

sulphur  during,  603 

treatment  of  diabetes,  716 
Statistical  method,   in   diet  control,   626 
Stearic  acid,  718 
Stilling,  "Summer  cells"  of,  769 
Stomach : 

arrangement  of  food  in,  489 

digestion  in,  515 

emptying  of,  491 

effect  of  pathological  conditions  on, 

494 
rate  of,  492 

gas  in,  496 

miniature,  468 

movements  of,  485 
effect  on  food,  488 

tonus  rhythm  of,  506 
Stroma  of  red  cell,  92 
Stromuhr,    207 

Strychnine,   action  on   reciprocal  inhibi- 
tion, 941 

action  of,  on  synapse,  844 
Subarachnoid  space,  116,  255 
Subcostal  angle,  338 
Subcostal  borders,  338 
Subdural  space,  116 
Submicrons,  55 
Successive   degeneration,   949 
Sugar,  storage  of,  694 
Sugar  level  in  blood,  690 
Sugar  metabolism    (see  Carbohydrates), 

685 

relation  of  pancreas  to,   710 
Sulphates,  ethereal,  535,  665 
Sulphates,  of  urine,  566 
Sulphur,  excretion   of,   648 

in  starvation,  603 
Summation,   934 

in  conduction,   843 

in  reflexes,  842 
Superior    laryngeal    nerve,    influence    on 

respiration,  351 
Supplemental  air,  317 
Surface   area,   and   energy   output,   575 
Surface    tension,    measurement    of,    65 
Surgical  shock,  303 
Survival  period,  615 
Suspensions,  52 
Suspensoids,  colloids,  61 


990 


INDEX 


Swallowing,   479 

center,  481 

of  liquid  food,  482 

nervous  control  of,  481 

sounds   produced  by,   483 

x-ray  during,  483 
Sympathetic  control  of  heart,  232 

afferent,  228 
Sympathetic  nerve,  458 
Sympathetic  system,  895 
Synapse,  830,  841 
Synaptic  fatigue  in  shock,  311 
Synaptic  resistance,   842 
Syntonin,   520 
Systolic  index,  134 
Systolic  pressure,  129 

measurement  of,  in  man,  129 


Tabes  dorsalis,  300 
Tachycardia,  paroxysmal,  293 
Tango-receptors,   855 
Taurine,  528 
Taurocholic  acid,  528 
Temperature : 

effect  on  dissociation  curve,  399 

effect  on  metabolism,  586 

sensation  of,  861 

transmission  in  cord,  868 
Tendon  jerks,  921 
Tension  of  CO2  in  venous  blood,  359 

of  gases  in  alveolar  air,  46,  356,  373 
Testicles,  821 
Tetanus,  905,  906 

in  stomach,  507 

Tetanus  toxin,  action  on  reciprocal  inhi- 
bition, 941 
Tetany,  802 

calcium  deficiency  in,  804 

cause  of,  804 

electrical  excitability  in,  803 

experimental,  800 

guanidine  metabolism  in,  804 

symptoms  of,  802 
Theinc,  668 
Theobromine,  668 
Thirst,  514 

Thoracic  operculum,  333 
Thoracicolumbar  outflow,  895 
Threshold : 

of  receptors,  855 

of  touch,  861 
Thrombin,  103 
Thrombogen,  107 
Thrombokinases,  107 
Thromboplastin,    107,   112 
Thrombosis,  108 
Thrombus  formation,   113 


Thymic  acid,  682 
Thymine,  669 
Thymus,  824 
Thyroid  gland,  791 

disease   of,   795 

removal  of,  794 
Thyroidectomy,  794 
Thyroxin,  798 
Thymus,  824 
Tidal  air,  317 
Tissot  method,   580,   591 
Tissue   fluid,    116 
Tissue   juice,   117 
Tissues: 

amino  acids  in,   641 

influence  of,  on  clotting,  105 

oxygen  requirements  of,  408,  412 

utilization  of  glucose  by,  708 
Titrable.  acidity  and  alkalinity,  22 
Tonometer,  356,  393 
Tone,  905 

inhibition  of,  925 

influence  of  brain  on,  924 

of  heart,  220 

reflex  adjustment  of,  914 
Tonus,  905 

plastic,  905 

Tonus  rhythm,  of  stomach,  506 
Torcular   herophili,   259 
Touch : 

localization,  861 

sense,  860 
Toxins,  70 

Transfusion  of  blood,  142,  179 
Trephining,    263 
Treppe,  178,  910,  911 
Trichlorlactamide,    668 
Trimethylamine,   629,   662 
True   colloidal   solutions,   52 
Trypsin,  461,  463,  638 

action  of,  523 
Trypsinogen,  461,  463 
Tryptic  digestion,  products  of,  524 
Tryptophane,  629,  633,  640,  665 

and  growth,  614,  615 
Tubules,  uriniferous,  function  of,  549 
Tumors  and  diet,  616 
Turbidity  of  colloids,  52 
Tyndall  phenomenon,   colloids,   52 
Tyrodes   solution,   168 
Tyrosine,  640,  665,  698,  773 


Uncoinpensated  acidosis,  39 
Unconditioned  reflex,  466 
Undetermined  nitrogen,  629,  647,  6(52 
Undulatory  movement  of  ribs,  334 


INDEX 


991 


Urea,  561,  643,  650 
in  blood,  645 

during  disease,  683 
excretion  of,  561,  649 
retention  of,  in  nephritis,  562 
Urease,   82,   645 
Uric  acid,  563,  564,  667,  681 
amount  of,  556 
chemical  nature  of,  667,  671 
endogenous  excretion,  680 
in  disease,  683 
metabolism  of,  667,  676 
of  blood,  681 
salts  of,  564 

synthesis  of,  677 
under  drugs,  681 
Uric  acid  diathesis,  667  . 
Uricase,  673 
Uricemia,  683 
Uricolytic  index,  674 
Urine : 

acids  of,  563,  564 
amino  acid,  564 
amount  of,  556 
aromatic   oxyacids   of,   564 
chlorides  of,  565 
composition,  560 
crcatinine  of,  563 

depression  of  freezing  point  of,  557 
excretion    of,    544 
H-ioii  concentration  of,  558 
in  disease,  567 
hippuric  acid,  564 
homogentisic  acid,   565 
inorganic   constituents   of,   565 
nitrogenous  constituents   ofj   560 
normal  organic  salts  of,  560 
phosphates,  566 

physical  processes  involved  in  produc- 
tion of,  14 

purine  bodies  of,  563 
rate  of  excretion,  675 
reaction  of,  558 
skatole,  565 

solid  constituents  of,  560 
specific  gravity  of,  556 
sulphates  of,  566 
total    potential   acidity   of,    550 
urea  of,  561 
Uriniferous  tubule,  541 
Urobilin,  529 
Urobilinogen,  530 
Utilization   limit,    688 

V 

Vagus : 

control  of  heart,  222 
impulses,  afferent,  227 
Vagus  center,  effect  of  nicotine  on,  231 
location  of,  227 
tonicity  of  226 


Vagus    nerve,    influence    on    respiration, 

348 

Valine,  640,  641 

Valves,  cardiac,  mechanism  of,  154 
auriculoventricular,   154 
semilunar,  155 
Valvular  disease,  220 
Van  Slyke  method  for  acidosis,  42,  43 
Van  Slyke  method  for  amino  groups,  636 
Vascular  reflex,  297 
Varicose  veins,  215 
Vasoconstriction,   236 
Vasoconstrictor    fibers,    237 
methods  of  detecting,  236 
of  extremities,   238 
of  head,  238 
of  viscera,  238 
origin  of,  237 
Vasodilator  fibers,  239 

methods  for  detecting,  236 
origin  of,  239 
Vasomotor  center: 

afferent  impulses,  243,  244 
chief  center,  240 
effect  of  H-ion  of  blood  on,  242 
hormone  control  of,  242 
subsidiary   centers,   240 
Vasomotor  fibers,   236 

origin  of,  237 
Vasotonic  impulses,  241 
Veins,   disappearance   of   pulse   in,    205 
Velocity  constant,  enzymes,  75 
Velocity,  mean  lineal,   206 

pulse,  200 

Venous  blood,  tension  of  CO2  in,  359 
Venous  inflow,   216 
Venous  outflow,   235 
Venous  pulse   tracing,   285 
Venous   sinuses,   intracranial,   255 
Ventilation : 

chemical  conditions  of  air  and,  754 
physical  conditions  of  air  and,  757 
physiological  principles  of,  754 
susceptibility  to  infection  and,  759 
Ventilation  of  lungs,  367 
Ventricle,  curves  of  pressure  in,  146,  148, 

151 
Ventricles : 

conductivity  tissue  of,  182 
fibrillation,    195 
spread  of  beat  in,  192,  194 
Ventricular  hypertrophies,  284 
Vignin,  612 

Viscera,  blood  supply  of,  254 
Visceral  bloodflow,  212 
Viscosity  of  blood,  141 
Visual  area,  880 
Visuo-motor  areas,  886 
Vital  activity,  14 


992 


INDEX 


Vital  capacity,  317,  329 

in  disease,  329 

Vital  theory  of  urine  excretion,  545 
Vitamines,    618 
Vividiffusion,  641 
Vomiting,  483 

W 

Water  content  of  blood,  87 
Water  hammer,  in  blood  pressure  meas- 
urement, 134 
Wheatstone  bridge,  18 
White  crescentic  line,  231 
Wiggers  manometer,  147 
Willard  Gibbs,  principle  of,  66 


Word  blindness,  861 
Word  centers,  860 
Word  deafness,  861 


Xanthine,  667,  671 

Xanthine  oxidase,  671 

Xanthosine,  671 

X-rays,  in  study  of  stomach,  469 

movements  of  stomach  seen  by  aid  of 
485,  489 


Zein,  inadequacy  for  growth,  612 
Zymogen  granules,  454,  455,  464 


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